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Mathis CL, Meeks HD, Watt KM, Maese LD, Constance JE. Acetaminophen and Acetaminophen-Opioid Combination Prescribing Trends Among Hospitalized Children, Adolescents, and Young Adults with Cancer. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.05.08.25327260. [PMID: 40385449 PMCID: PMC12083635 DOI: 10.1101/2025.05.08.25327260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
Purpose Acetaminophen ( APAP ) is a ubiquitous antipyretic and analgesic used in children in the United States ( US ), including those with cancer. The effects of US Food & Drug Administration ( FDA ) guidance on APAP prescribing have been described for healthy adults and children; however, APAP use patterns in children with cancer are unknown. Considering their increased risk of liver injury, APAP's potential for causing hepatoxicity, and FDA guidance changes, this study examined the recent evolution of APAP use in children with cancer. Methods This retrospective, multi-center analysis extracted APAP prescribing data from the Pediatric Health Information System® ( PHIS ). Eligible children were aged 0-26 years, had a cancer diagnosis per International Classification of Diseases ( ICD ) codes, and were prescribed a chemotherapeutic. APAP and APAP-opioid combination prescribing were assessed at hospital, regional, and national levels. Changes in APAP and APAP-opioid combination use rates were assessed using the non-parametric Mann-Kendall test. Findings PHIS records for the complete years of 2004-2021 yielded 388,364 inpatient encounters for 50,779 unique patients. Of these, 87.3% of patients received APAP. Although APAP-opioid combination use was infrequent overall, children receiving APAP were more likely to receive an APAP-opioid combination medication (N=25,880, 13.4%, p < 0.001) compared to those who did not receive APAP. Among specialty children's hospitals, national APAP use was stable over the study period. Regionally, APAP use increased among hospitals in the Northeast. APAP-opioid combination use decreased nationally with regional variation. In contrast to the steady decline in other regions, Southern APAP-opioid combination use was consistently elevated before declining in 2014. Implications This article describes acetaminophen and acetaminophen-opioid prescribing trends among children with cancer in the United States. These trends are key to help clinicians assess changes in pain management strategies over time, contextualize analgesic exposure and efficacy, and provide a foundation for future studies in drug safety. Extensive acetaminophen use can affect liver health, and further work is needed to evaluate acetaminophen exposure in children with cancer. Data Statement Deidentified data were obtained and evaluated under an IRB-approved protocol. Due to privacy requirements, the data are not available to be shared.
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Daaboul O, Arman G, Alom M, Swied A. Diagnostic Dilemma: Metastatic Breast Adenocarcinoma Presenting With a Cholestatic Liver Injury Without Radiological Findings of Liver Metastases. Cureus 2025; 17:e81368. [PMID: 40291193 PMCID: PMC12034330 DOI: 10.7759/cureus.81368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/28/2025] [Indexed: 04/30/2025] Open
Abstract
Cholestasis refers to a reduction in bile flow caused by either impaired secretion or obstruction. Cancers may manifest with cholestasis due to metastasis (either obstruction or infiltration), paraneoplastic syndromes, or as a side effect of treatment (chemotherapy, immunotherapy, or radiation). Various imaging techniques, including ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) scans, are typically used to assess the obstruction, its location, and the underlying cause. We are presenting a complex and challenging case of metastatic breast cancer in the liver that presented as cholestatic liver injury without corresponding radiological findings. We aim to highlight the importance of considering liver metastasis as a differential diagnosis, even in the absence of supporting radiological evidence.
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Affiliation(s)
- Obada Daaboul
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
| | - Genan Arman
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
| | - Mulham Alom
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
| | - Aman Swied
- Internal Medicine, Southern Illinois University School of Medicine, Springfield, USA
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Amrati FEZ, Lim A, Slighoua M, Chebaibi M, Mssillou I, Drioiche A, Di Cristo F, Al-Sheikh YA, Aboul-Soud MAM, Edderkaoui M, Bousta D. Unraveling the hepatoprotective and anti-pancreatic cancer potential of Caralluma europaea: a comprehensive in vivo, in vitro and in silico evidence. Drug Chem Toxicol 2025; 48:120-135. [PMID: 39415714 DOI: 10.1080/01480545.2024.2402430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 08/21/2024] [Accepted: 09/04/2024] [Indexed: 10/19/2024]
Abstract
Caralluma europaea Guss. (C. europaea) is a medicinal plant used for cancer treatment. However, these treatments may be associated with complications that need to be investigated. This work aims to evaluate not only the chemical composition but also the hepatoprotective and anticancer properties of C. europaea extracts. The chemical constitution of the hydroethanolic extract was explored using gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC). The hydroethanolic extract, flavonoids, and polyphenols-rich extract at 100, 15, and 50 mg/kg, respectively, were administered to acetaminophen-treated rats for seven days. We used Western blotting and Real-Time quantitative Polymerase Chain Reaction (RT-qPCR) to determine the protein and the mRNA levels of cancer stemness markers in pancreatic cancer cell lines MIA PaCa-2 and BxPC-3 exposed to increasing doses of C. europaea extracts. In silico analysis was used to evaluate the effects of phenolic compounds revealed in C. europaea on caspase-3 and HSP90, and on liver damage on CYP2E1. The primary phenolics detected by GC-MS and HPLC were ferulic acid and benzofurazan. The positive control group showed an increase in AST, ALT, ALP, triglycerides, and VLDL levels. C. europaea extracts demonstrated hepatoprotective effects by ameliorating acetaminophen-induced alterations of biochemical and hispathological parameters. Immunoblotting and RT-qPCR profiling of cancer stemness markers indicated a reduction in the expression levels of Oct-4 and Nanog proteins, as well as a reduction in the mRNA levels of CD133 by 50-60% and Sox2 by 80-90% in pancreatic cancer cells. Molecular docking showed that naringenin presented the highest docking Gscore on CYP2E1 (-8.199) and HSP90 (-7.742). In conclusion, C. europaea extracts could be considered as a safe and promising therapeutic strategy to sensitize pancreatic cancer cells to chemotherapy.
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Affiliation(s)
- Fatima Ez-Zahra Amrati
- Laboratory of Cell Biology and Molecular Genetics (LBCGM), Department of Biology, Faculty of Sciences, Ibn Zohr University, Agadir, Souss Massa, Morocco
| | - Adrian Lim
- Departments of Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Meryem Slighoua
- Laboratory of Biotechnology, Environment, Agri-Food, and Health (LBEAS), Faculty of Sciences, University Sidi-Mohamed-Ben-Abdellah (USMBA), Fez, Morocco
- Ministry of Health and Social Protection, Higher Institute of Nursing Professions and Health Techniques, Marrakech, Morocco
| | - Mohamed Chebaibi
- Ministry of Health and Social Protection, Higher Institute of Nursing Professions and Health Techniques, Fez, Morocco
- Biomedical and Translational Research Laboratory, Faculty of Medicine and Pharmacy of the Fez, University of Sidi Mohamed Ben Abdellah, Fez, Morocco
| | - Ibrahim Mssillou
- Laboratory of Natural Substances, Pharmacology, Environment, Modeling, Health & Quality of Life (SNAMOPEQ), Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Aziz Drioiche
- Laboratory of Innovative Materials and Biotechnology of Natural Resources, Faculty of Sciences, Moulay Ismail University, Meknes, Morocco
| | - Francesca Di Cristo
- Research Institute on Terrestrial Ecosystems (IRET), National Research Council, Porano, Italy
| | - Yazeed A Al-Sheikh
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Mourad A M Aboul-Soud
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Mouad Edderkaoui
- Departments of Medicine and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | - Dalila Bousta
- National Agency of Medicinal and Aromatic Plants, Taounate, Morocco
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Tippareddy C, Martinez OM, Benza AR, Bera K, Ramaiya N, Tirumani SH. From guidelines to radiology practice: navigating the 2023 ASCO guidelines for advanced gastroesophageal cancer and beyond. Abdom Radiol (NY) 2025; 50:78-93. [PMID: 39123051 PMCID: PMC11711647 DOI: 10.1007/s00261-024-04499-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 07/09/2024] [Accepted: 07/13/2024] [Indexed: 08/12/2024]
Abstract
The American Society of Clinical Oncology (ASCO) updated the guidelines for the treatment of advanced gastroesophageal (GE) cancer in 2023, signifying a major shift towards targeted therapeutics and precision medicine. This article serves as an imaging-based review of recent developments in the care of patients with GE cancer. We cover the epidemiology, the developing treatment paradigms, and the imaging assessment of GE malignancy. In addition, this review aims to familiarize radiologists with the unique adverse effects pertaining to therapeutics, surgeries, radiation therapies, and associated imaging corollaries. A case-based approach will be used to both explore the efficacy of modern treatments and demonstrate their adverse effects, such as chemotherapy-associated pneumonitis, radiation esophagitis, and anastomotic failure. With this comprehensive exploration of gastroesophageal cancer, radiologists will be equipped with the essential tools to inform the treatment decisions made by medical oncologists, radiation oncologists, and surgical oncologists in the new era of precision medicine.
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Affiliation(s)
- Charit Tippareddy
- Department of Radiology, University Hospitals Cleveland Medical Center, Case Western Reserve University, 1110 Euclid Ave, Cleveland, OH, 44106, USA.
- Case Western Reserve University School of Medicine, Cleveland, OH, USA.
| | | | - Andrew R Benza
- Department of Radiology, University Hospitals Cleveland Medical Center, Case Western Reserve University, 1110 Euclid Ave, Cleveland, OH, 44106, USA
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Kaustav Bera
- Department of Radiology, University Hospitals Cleveland Medical Center, Case Western Reserve University, 1110 Euclid Ave, Cleveland, OH, 44106, USA
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Nikhil Ramaiya
- Department of Radiology, University Hospitals Cleveland Medical Center, Case Western Reserve University, 1110 Euclid Ave, Cleveland, OH, 44106, USA
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Sree Harsha Tirumani
- Department of Radiology, University Hospitals Cleveland Medical Center, Case Western Reserve University, 1110 Euclid Ave, Cleveland, OH, 44106, USA
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
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Adeneye AA, Babatope FE, Adesiji-Adelekan AE, Olorundare OE, Okoye II. Tadalafil pretreatment attenuates doxorubicin-induced hepatorenal toxicity by modulating oxidative stress and inflammation in Wistar rats. Toxicol Rep 2024; 13:101737. [PMID: 39391709 PMCID: PMC11465077 DOI: 10.1016/j.toxrep.2024.101737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/23/2024] [Accepted: 09/13/2024] [Indexed: 10/12/2024] Open
Abstract
Doxorubicin (DOX) is a widely used anticancer agent, but its clinical application is limited by significant off-target hepatorenal toxicity. Tadalafil (TAD), a selective phosphodiesterase-5 inhibitor used mainly for erectile dysfunction and pulmonary arterial hypertension, has shown potential in reducing oxidative stress. This study investigated TAD's chemoprotective effects and underlying mechanisms in DOX-induced hepatorenal toxicity in rats over 12 days. Eight groups of six rats each were orally pretreated with sterile water, silymarin (SIL), or TAD one hour before receiving intraperitoneal injections of 2.5 mg/kg DOX. On the 13th day, the rats were humanely sacrificed under inhaled halothane anesthesia, and serum was collected for hepatic and renal function tests, while liver and kidney tissues were analyzed for antioxidant enzyme activity, pro-inflammatory cytokines assay, and histopathological evaluation. DOX successfully induced hepatorenal toxicity, evidenced by significant increases (p<0.001, p<0.0001) in serum K+, urea, and creatinine levels, along with decreases in HCO3 -, TCa2+, and Cl-. Tissue analysis showed reduced SOD, CAT, GST, and GPx activities, with elevated MDA and GSH levels. TAD pretreatment significantly ameliorated these biochemical alterations (p<0.05, p<0.001, p<0.0001), suggesting its potential as an effective chemoprophylactic adjuvant in the development of DOX-induced hepatorenal toxicity.
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Affiliation(s)
- Adejuwon Adewale Adeneye
- Department of Pharmacology, Therapeutics & Toxicology, Faculty of Basic Clinical Sciences, Lagos State University College of Medicine, 1-5 Oba Akinjobi Way, G.R.A., Ikeja, Lagos State, Nigeria
- Directorate of Research Management and Innovation, 3rd Floor, Babatunde Raji Fashola Senate Building, Lagos State University, Ojo, Lagos State, Nigeria
| | - Fidaraoluwa Esther Babatope
- Department of Pharmacology, Therapeutics & Toxicology, Faculty of Basic Clinical Sciences, Lagos State University College of Medicine, 1-5 Oba Akinjobi Way, G.R.A., Ikeja, Lagos State, Nigeria
| | - Ademilayo Eunice Adesiji-Adelekan
- Department of Pharmacology, Therapeutics & Toxicology, Faculty of Basic Clinical Sciences, Lagos State University College of Medicine, 1-5 Oba Akinjobi Way, G.R.A., Ikeja, Lagos State, Nigeria
| | - Olufunke Esan Olorundare
- Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Kwara State, Nigeria
| | - Ikechukwu Innocent Okoye
- Department of Oral Pathology and Medicine, Faculty of Dentistry, Lagos State University College of Medicine, 1-5 Oba Akinjobi Way, G.R.A., Ikeja, Lagos State, Nigeria
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Aguiar RPSD, Souza JMT, de Menezes AAPM, do Nascimento MLLB, de Castro E Sousa JM, Cavalcante AADCM, Ferreira PMP, Araújo AJ, Marinho-Filho JDB. Ascorbic acid regulates in vitro and in vivo toxicogenetic effects of hydroxyurea on eukaryotic cells. Drug Chem Toxicol 2024:1-10. [PMID: 39538962 DOI: 10.1080/01480545.2024.2425990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 10/04/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024]
Abstract
Hydroxyurea (HU) exerts unique and diverse biological effects as an anti-leukemic agent, irradiation sensitizer, and HbS inducer in patients with sickle cell anemia. Herein, we assessed the potential toxicogenic and/or oxidant effects of hydroxyurea associated with ascorbic acid by in vivo examinations in Allium cepa and human cancer cells and systemically on mice tissues. Growing A. cepa roots and HCT-116 colorectal tumor cells were examined after HU and HU plus ascorbic acid exposure. DNA damage and antioxidant enzymatic activity were quantified in peripheral blood mononuclear cells (PBMC), bone marrow leukocytes and livers of mice after 7 day-HU treatment (7.5, 15 and 30 mg/kg/day) and Vitamin C 2 μM. Hydroxyurea presented toxic effects on meristematic Allium cepa cells, causing chromosomal abnormalities and reduction of mitotic index, killed HCT-116 colorectal carcinoma cells and induced DNA injuries upon mice cells (hepatocytes, bone marrow leukocytes and PBMC). Simultaneously, hydroxyurea decreased levels of CAT and GSH activities and expand lipid peroxidation. All these biochemical and physiological changes were ameliorated when associated with ascorbic acid, indicating it restored antioxidant enzymes, decreased MDA levels, removed peroxides and, consequently, presented cytoprotection against HU-provoked cellular damage in normal cells. On the other hand, antioxidants compounds may interfere on effectiveness of HU during anticancer chemotherapies.
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Affiliation(s)
- Raí Pablo Sousa de Aguiar
- Cell Culture Laboratory of the Delta (LCCDelta), Parnaiba Delta Federal University, Parnaíba, Brazil
| | - Jéssica Maria Teles Souza
- Cell Culture Laboratory of the Delta (LCCDelta), Parnaiba Delta Federal University, Parnaíba, Brazil
| | - Ag-Anne Pereira Melo de Menezes
- Laboratory of Toxicological Genetics (Lapgenic), Department of Biochemistry and Pharmacology, Postgraduate Program in Pharmaceutical Sciences, Federal University of Piauí, Teresina, Brazil
| | - Maria Luísa Lima Barreto do Nascimento
- Laboratory of Toxicological Genetics (Lapgenic), Department of Biochemistry and Pharmacology, Postgraduate Program in Pharmaceutical Sciences, Federal University of Piauí, Teresina, Brazil
| | - João Marcelo de Castro E Sousa
- Laboratory of Toxicological Genetics (Lapgenic), Department of Biochemistry and Pharmacology, Postgraduate Program in Pharmaceutical Sciences, Federal University of Piauí, Teresina, Brazil
| | - Ana Amélia de Carvalho Melo Cavalcante
- Laboratory of Toxicological Genetics (Lapgenic), Department of Biochemistry and Pharmacology, Postgraduate Program in Pharmaceutical Sciences, Federal University of Piauí, Teresina, Brazil
| | - Paulo Michel Pinheiro Ferreira
- Laboratory of Experimental Cancerology (LabCancer), Department of Biophysics and Physiology, Federal University of Piauí, Teresina, Brazil
| | - Ana Jérsia Araújo
- Cell Culture Laboratory of the Delta (LCCDelta), Parnaiba Delta Federal University, Parnaíba, Brazil
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Plummer R, Greystoke A, Naylor G, Sarker D, Anam ANMK, Prenen H, Teuwen LA, Van Cutsem E, Dekervel J, Haugk B, Ness T, Bhoi S, Jensen M, Morris T, Baumann P, Sjögren N, Tunblad K, Wallberg H, Öberg F, Evans TRJ. A Phase 1a/1b Study of Fostroxacitabine Bralpamide (Fostrox) Monotherapy in Hepatocellular Carcinoma and Solid Tumor Liver Metastases. J Hepatocell Carcinoma 2024; 11:2033-2047. [PMID: 39469286 PMCID: PMC11514655 DOI: 10.2147/jhc.s481410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 10/11/2024] [Indexed: 10/30/2024] Open
Abstract
Purpose To evaluate safety, preliminary efficacy, pharmacokinetics, and pharmacodynamics, of fostroxacitabine bralpamide (fostrox, MIV-818), a novel oral troxacitabine nucleotide prodrug designed to direct exposure to the liver, while minimizing systemic toxicity. Patients and Methods Fostrox monotherapy was administered in an open-label, single-arm, first-in-human, phase 1a/1b study, in patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, or solid tumor liver metastases. The first part (1a) consisted of intra/inter-patient escalating doses (3 mg to 70 mg) QD for up to 5 days, and the second part (1b), doses of 40 mg QD for 5 days, in 21-day cycles. Safety and tolerability were evaluated by the Safety Review Committee, and efficacy was assessed every 6 weeks with CT or MRI using RECIST 1.1 and mRECIST. Results Nineteen patients were treated with fostrox. Most common adverse events (AEs) were hematological and increased AST. Grade 3 treatment related AEs (TRAE) were seen in 53% of the patients, with transient neutropenia and thrombocytopenia as the most common. No grade 5 AE was observed. Recommended Phase 2 dose of fostrox was 40 mg QD for 5 days in 21-day cycles. Preliminary efficacy showed a clinical benefit rate in the liver of 53% and stable disease (SD) as best response in 10 patients. Liver targeting with fostrox was confirmed with higher exposure of troxacitabine and its metabolites in liver compared to plasma. Systemic exposure of fostrox was generally low with troxacitabine as main analyte. Biopsies demonstrated tumor-selective, drug-induced DNA damage. Conclusion The phase 1a/1b monotherapy study of fostrox, in patients with liver tumors, showed a tumor selective effect in the liver and that 40 mg QD for 5 days in 21-day cycles is safe and tolerable. Safety and preliminary efficacy in patients with advanced HCC supports clinical development of fostrox in combination with other modes of action in HCC.
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Affiliation(s)
- Ruth Plummer
- Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Alastair Greystoke
- Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Gregory Naylor
- Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK
| | - Debashis Sarker
- School of Cancer and Pharmaceutical Sciences, King’s College London, London, UK
- Department of Medical Oncology, Guy’s Hospital, London, UK
| | | | - Hans Prenen
- Department of Oncology, Antwerp University Hospital, Edegem, Belgium
| | - Laure-Anne Teuwen
- Department of Oncology, Antwerp University Hospital, Edegem, Belgium
| | - Eric Van Cutsem
- Department of Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - Jeroen Dekervel
- Department of Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - Beate Haugk
- Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Thomas Ness
- Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
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Pires IS, Covarrubias G, Gomerdinger VF, Backlund C, Shanker A, Gordon E, Wu S, Pickering AJ, Melo MB, Suh H, Irvine DJ, Hammond PT. "Target-and-release" nanoparticles for effective immunotherapy of metastatic ovarian cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.05.602135. [PMID: 39005274 PMCID: PMC11245112 DOI: 10.1101/2024.07.05.602135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Immunotherapies such as checkpoint inhibitors (CPI) are effective in treating several advanced cancers, but these treatments have had limited success in metastatic ovarian cancer (OC). Here, we engineered liposomal nanoparticles (NPs) carrying a layer-by-layer (LbL) polymer coating that promotes their binding to the surface of OC cells. Covalent anchoring of the potent immunostimulatory cytokine interleukin-12 (IL-12) to phospholipid headgroups of the liposome core enabled the LbL particles to concentrate IL-12 in disseminated OC tumors following intraperitoneal administration. Shedding of the LbL coating and serum protein-mediated extraction of IL-12-conjugated lipids from the liposomal core over time enabled IL-12 to disseminate in the tumor bed following rapid NP localization in tumor nodules. Optimized IL-12 LbL-NPs promoted robust T cell accumulation in ascites and tumors in mouse models, extending survival compared to free IL-12 and remarkedly sensitizing tumors to CPI, leading to curative treatments and immune memory.
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Affiliation(s)
- Ivan S Pires
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
- Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA
| | - Gil Covarrubias
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
| | - Victoria F Gomerdinger
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
- Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA
| | - Coralie Backlund
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
| | - Apoorv Shanker
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
| | - Ezra Gordon
- Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA
| | - Shengwei Wu
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
| | - Andrew J Pickering
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
- Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA
| | - Mariane B Melo
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
| | - Heikyung Suh
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
| | - Darrell J Irvine
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
- Department of Biological Engineering, MIT, Cambridge, MA 02139, USA
- Department of Materials Science and Engineering, MIT, Cambridge, MA 02139, USA
- Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA 02139, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
| | - Paula T Hammond
- Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA
- Department of Chemical Engineering, MIT, Cambridge, MA 02139, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02139 USA
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Choi Y, Kim BK, Won JH, Yoo JW, Choi W, Jung S, Kim JY, Choi IY, Chung NG, Lee JW, Choi JY, Kang HJ, Lee H. A Study to Evaluate the Effectiveness and Safety of Prephase Steroid Treatment before Remission Induction Chemotherapy in Patients with Pediatric Acute Lymphoblastic Leukemia Using Common Data Model-Based Real-World Data: A Retrospective Observational Study. Clin Epidemiol 2024; 16:293-304. [PMID: 38681782 PMCID: PMC11049150 DOI: 10.2147/clep.s454263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/09/2024] [Indexed: 05/01/2024] Open
Abstract
Background Rapid reduction of leukemic cells in the bone marrow during remission induction chemotherapy (RIC) can lead to significant complications such as tumor lysis syndrome (TLS). We investigated whether prephase steroid treatment before RIC could decrease TLS incidence and improve overall survival in pediatric patients with acute lymphoblastic leukemia (ALL). Methods Data were extracted from the Common Data Model databases in two tertiary-care hospitals in Seoul, South Korea. Patients were classified into the treated or untreated group if they had received RIC with prephase steroid treatment ≥7 days before RIC in 2012-2021 or not, respectively. Stabilized Inverse Probability of Treatment Weighting (sIPTW) was applied to ensure compatibility between the treated and untreated groups. The incidence of TLS within 14 days of starting RIC, overall survival (OS), and the incidence of adverse events of special interest were the primary endpoints. Multiple sensitivity analyses were performed. Results Baseline characteristics were effectively balanced between the treated (n=308.4) and untreated (n=246.6) groups after sIPTW. Prephase steroid treatment was associated with a significant 88% reduction in the risk of TLS (OR 0.12, 95% CI: 0.03-0.41). OS was numerically greater in the treated group than in the untreated group although the difference was not statistically significant (HR 0.64, 95% CI 0.25-1.64). The treated group experienced significantly elevated risks for hyperbilirubinemia and hyperglycemia. The reduction in TLS risk by prephase steroid treatment was maintained in all of the sensitivity analyses. Conclusion Prephase steroid treatment for ≥7 days before RIC in pediatric patients with ALL reduces the risk of TLS, while careful monitoring for toxicities is necessary. If adequately analyzed, real-world data can provide crucial effectiveness and safety information for proper management of pediatric patients with ALL, for whom prospective randomized studies may be difficult to perform for ethical and practical reasons.
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Affiliation(s)
- Yoona Choi
- Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
- Center for Convergence Approaches in Drug Development, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
| | - Bo Kyung Kim
- Department of Pediatrics, Seoul National University Hospital, Seoul, Republic of Korea
- Seoul National University Cancer Research Institute, Seoul, Republic of Korea
| | - Jung-Hyun Won
- Center for Convergence Approaches in Drug Development, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
| | - Jae Won Yoo
- Department of Pediatrics, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Wona Choi
- Department of Medical Informatics, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Surin Jung
- Department of Medical Informatics, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Jae Yoon Kim
- Department of Medical Informatics, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
- Department of Biomedicine & Health Sciences, the Catholic University of Korea, Seoul, Republic of Korea
| | - In Young Choi
- Department of Medical Informatics, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Nack-Gyun Chung
- Department of Pediatrics, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Jae Wook Lee
- Department of Pediatrics, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Yoon Choi
- Department of Pediatrics, Seoul National University Hospital, Seoul, Republic of Korea
- Seoul National University Cancer Research Institute, Seoul, Republic of Korea
| | - Hyoung Jin Kang
- Department of Pediatrics, Seoul National University Hospital, Seoul, Republic of Korea
- Seoul National University Cancer Research Institute, Seoul, Republic of Korea
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Howard Lee
- Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
- Center for Convergence Approaches in Drug Development, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
- Advanced Institutes of Convergence Technology, Suwon, Republic of Korea
- Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul, Republic of Korea
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Chuah YY, Lee YY, Chou CK, Chang LJ. Catharanthus roseus intoxication mimicking acute cholangitis. BMC Complement Med Ther 2024; 24:139. [PMID: 38575897 PMCID: PMC10993546 DOI: 10.1186/s12906-024-04441-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 03/18/2024] [Indexed: 04/06/2024] Open
Abstract
BACKGROUND Catharanthus roseus, a Madagascar native flowering plant, is known for its glossy leaves and vibrant flowers, and its medicinal significance due to its alkaloid compounds. As a source of vinblastine and vincristine used in chemotherapy, Catharanthus roseus is also employed in traditional medicine with its flower and stalks in dried form. Its toxicity can lead to various adverse effects. We report a case of Catharanthus roseus juice toxicity presenting as acute cholangitis, emphasizing the importance of healthcare providers obtaining detailed herbal supplement histories. CASE PRESENTATION A 65-year-old woman presented with abdominal pain, fever, anorexia, and lower limb numbness. Initial diagnosis of acute cholangitis was considered, but imaging excluded common bile duct stones. Further investigation revealed a history of ingesting Catharanthus roseus juice for neck pain. Laboratory findings showed leukocytosis, elevated liver enzymes, and hyperbilirubinemia. The patient developed gastric ulcers, possibly due to alkaloids in Catharanthus roseus. No bacterial growth was noted in blood cultures. The patient recovered after discontinuing the herbal extract. CONCLUSIONS Catharanthus roseus toxicity can manifest as fever, hepatotoxicity with cholestatic jaundice, and gastric ulcers, mimicking acute cholangitis. Awareness of herbal supplement use and potential toxicities is crucial for healthcare providers to ensure prompt diagnosis and appropriate management. This case emphasizes the need for public awareness regarding the possible toxicity of therapeutic herbs and the importance of comprehensive patient histories in healthcare settings.
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Affiliation(s)
- Yoen Young Chuah
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ping Tung Christian Hospital, Pingtung, Taiwan
- Department of Nursing, Meiho University, Pingtung, Taiwan
| | - Yeong Yeh Lee
- Department of Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kota Bahru, Malaysia
| | - Chu-Kuang Chou
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
- Obesity center, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Li-Jen Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.
- Min-Hwei Junior College of Health Care Management, Tainan, Taiwan.
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11
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Adico MD, Bayala B, Zoure AA, Lagarde A, Bazie JT, Traore L, Buñay J, Yonli AT, Djigma F, Bambara HA, Baron S, Simporé J, Lobaccaro JMA. In vitro activities and mechanisms of action of anti-cancer molecules from African medicinal plants: a systematic review. Am J Cancer Res 2024; 14:1376-1401. [PMID: 38590420 PMCID: PMC10998760 DOI: 10.62347/auhb5811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 07/27/2023] [Indexed: 04/10/2024] Open
Abstract
Cancer is one of the leading causes of death worldwide. In recent years, African countries have been faced with a rapid increase in morbidity and mortality due to this pathology. Management is often complicated by the high treatment costs, side effects and the increasing occurrence of resistance to treatments. The identification of new active ingredients extracted from endemic medicinal plants is definitively an interesting approach for the implementation of new therapeutic strategies: their extraction is often lower cost; their identification is based on an ethnobotanical history and a tradipratic approach; their use by low-income populations is simpler; this can help in the development of new synthetic molecules that are more active, more effective and with fewer side effects. The objective of this review is to document the molecules derived from African medicinal plants whose in vitro anti-cancer activities and the mechanisms of molecular actions have been identified. From the scientific databases Science Direct, PubMed and Google Scholar, we searched for publications on compounds isolated from African medicinal plants and having activity on cancer cells in culture. The data were analyzed in particular with regard to the cytotoxicity of the compounds and their mode of action. A total of 90 compounds of these African medicinal plants were selected. They come from nine chemical groups: alkaloids, flavonoids, polyphenols, quinones, saponins, steroids, terpenoids, xanthones and organic sulfides. These compounds have been associated with several cellular effects: i) Cytotoxicity, including caspase activation, alteration of mitochondrial membrane potential, and/or induction of reactive oxygen species (ROS); ii) Anti-angiogenesis; iii) Anti-metastatic properties. This review points out that the cited African plants are rich in active ingredients with anticancer properties. It also stresses that screening of these anti-tumor active ingredients should be continued at the continental scale. Altogether, this work provides a rational basis for the selection of phytochemical compounds for use in clinical trials.
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Affiliation(s)
- Marc Dw Adico
- Laboratoire de Biologie Moléculaire et Génétique (LABIOGENE), Université Joseph KI-ZERBO Ouagadougou, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA) Ouagadougou, Burkina Faso
| | - Bagora Bayala
- Laboratoire de Biologie Moléculaire et Génétique (LABIOGENE), Université Joseph KI-ZERBO Ouagadougou, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA) Ouagadougou, Burkina Faso
- Ecole Normale Supérieure Koudougou, Burkina Faso
| | - Abdou A Zoure
- Laboratoire de Biologie Moléculaire et Génétique (LABIOGENE), Université Joseph KI-ZERBO Ouagadougou, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA) Ouagadougou, Burkina Faso
- Laboratoire de recherches Biomédicales (LaReBio), Département de santé publique et biomédicale, Institut de Recherche en Sciences de la Santé (IRSS/CNRST) Ouagadougou, Burkina Faso
| | - Aurélie Lagarde
- Institute Génétique, Reproduction, Développement, UMR CNRS 6293, INSERM U1103, Université Clermont Auvergne 28, Place Henri Dunant, BP38, F63001, Clermont-Ferrand, France
| | - Jean Tv Bazie
- Laboratoire de Biologie Moléculaire et Génétique (LABIOGENE), Université Joseph KI-ZERBO Ouagadougou, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA) Ouagadougou, Burkina Faso
- Département des Substances Naturelles (DSN), Institut de Recherche en Sciences et Technologies Appliquées (IRSAT) Ouagadougou, Burkina Faso
| | - Lassina Traore
- Laboratoire de Biologie Moléculaire et Génétique (LABIOGENE), Université Joseph KI-ZERBO Ouagadougou, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA) Ouagadougou, Burkina Faso
| | - Julio Buñay
- Institute Génétique, Reproduction, Développement, UMR CNRS 6293, INSERM U1103, Université Clermont Auvergne 28, Place Henri Dunant, BP38, F63001, Clermont-Ferrand, France
| | - Albert T Yonli
- Laboratoire de Biologie Moléculaire et Génétique (LABIOGENE), Université Joseph KI-ZERBO Ouagadougou, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA) Ouagadougou, Burkina Faso
| | - Florencia Djigma
- Laboratoire de Biologie Moléculaire et Génétique (LABIOGENE), Université Joseph KI-ZERBO Ouagadougou, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA) Ouagadougou, Burkina Faso
| | - Hierrhum A Bambara
- Service d'oncologie, Centre hospitalier universitaire BOGODOGO, Université Joseph KI-ZERBO Ouagadougou, Burkina Faso
| | - Silvère Baron
- Institute Génétique, Reproduction, Développement, UMR CNRS 6293, INSERM U1103, Université Clermont Auvergne 28, Place Henri Dunant, BP38, F63001, Clermont-Ferrand, France
| | - Jacques Simporé
- Laboratoire de Biologie Moléculaire et Génétique (LABIOGENE), Université Joseph KI-ZERBO Ouagadougou, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA) Ouagadougou, Burkina Faso
- Faculté de médecine, Université Saint Thomas d'Aquin (USTA) Ouagadougou, Burkina Faso
| | - Jean-Marc A Lobaccaro
- Institute Génétique, Reproduction, Développement, UMR CNRS 6293, INSERM U1103, Université Clermont Auvergne 28, Place Henri Dunant, BP38, F63001, Clermont-Ferrand, France
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12
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Almalki RS. The Protective Effect of Roflumilast Against Acute Hepatotoxicity Caused by Methotrexate in Wistar Rats: In vivo Evaluation. Drug Des Devel Ther 2024; 18:453-462. [PMID: 38374827 PMCID: PMC10875972 DOI: 10.2147/dddt.s438703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 02/09/2024] [Indexed: 02/21/2024] Open
Abstract
Introduction Methotrexate (MTX) is one of the most widely used drugs in cancer chemotherapy and treating rheumatoid arthritis. The hepatotoxicity of MTX is one of its major side effects. Roflumilast (ROF) has been recognized to have antioxidant and anti-inflammatory activity in in-vivo and in-vitro models. The present study aimed to explore the potential protective effects of roflumilast against MTX-induced liver toxicity in male Wistar rats. Methods High dose of 5 mg/kg for 4 consecutive days subcutaneous (S.C) injection of methotrexate for induction of acute liver injury. A total of 24 Wistar rats, rats were used in four different groups. The NS injections were given S.C to the control group once a day for 4 consecutive days. SC injections of MTX (5 mg/kg) were given to the MTX group daily for four days. At 5 mg/kg once daily for four days, the roflumilast group was given daily oral roflumilast. An injection of MTX and oral roflumilast were given to the MTX + roflumilast group once daily for four consecutive days. Results Administration of high dose MTX (5 mg/kg) today 4 produced a significant decrease in hepatic glutathione (GSH) levels and a significant increase in ALT and AST liver enzymes, hepatic malondialdehyde (MDA), tumor suppressor protein (p53), interleukin 6, interleukin 1 levels compared to the control group. Treatment with roflumilast for 4 days significantly attenuated unfavorable changes in these parameters. According to histopathological findings, Roflumilast significantly reduced MTX-induced inflammation and degeneration in the liver. In conclusion, the findings indicate that roflumilast may have a potential therapeutic benefit in treating rats with MTX-induced liver toxicity by mitigating its effects. Purpose The aim of this study is to investigate the potential protective effects of roflumilast against MTX-induced liver toxicity in Wistar rats.
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Affiliation(s)
- Riyadh S Almalki
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Umm AL-Qura University, Makkah, Saudi Arabia
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13
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Atteia HH. MicroRNAs in Anticancer Drugs Hepatotoxicity: From Pathogenic Mechanism and Early Diagnosis to Therapeutic Targeting by Natural Products. Curr Pharm Biotechnol 2024; 25:1791-1806. [PMID: 38178678 DOI: 10.2174/0113892010282155231222071903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/11/2023] [Accepted: 11/24/2023] [Indexed: 01/06/2024]
Abstract
Patients receiving cancer therapies experience severe adverse effects, including hepatotoxicity, even at therapeutic doses. Consequently, monitoring patients on cancer therapy for hepatic functioning is necessary to avoid permanent liver damage. Several pathways of anticancer drug-induced hepatotoxicity involve microRNAs (miRNAs) via targeting mRNAs. These short and non-coding RNAs undergo rapid modulation in non-targeted organs due to cancer therapy insults. Recently, there has been an interest for miRNAs as useful and promising biomarkers for monitoring toxicity since they have conserved sequences across species and are cellular-specific, stable, released during injury, and simple to analyze. Herein, we tried to review the literature handling miRNAs as mediators and biomarkers of anticancer drug-induced hepatotoxicity. Natural products and phytochemicals are suggested as safe and effective candidates in treating cancer. There is also an attempt to combine anticancer drugs with natural compounds to enhance their efficiencies and reduce systemic toxicities. We also discussed natural products protecting against chemotherapy hepatotoxicity via modulating miRNAs, given that miRNAs have pathogenic and diagnostic roles in chemotherapy-induced hepatotoxicity and that many natural products can potentially regulate their expression. Future studies should integrate these findings into clinical trials by formulating suitable therapeutic dosages of natural products to target miRNAs involved in anticancer drug hepatotoxicity.
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Affiliation(s)
- Hebatallah Husseini Atteia
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Sharkia, 44519, Egypt
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14
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Katolkar UN, Surana SJ. Exploring the Potential Role of Phytopharmaceuticals in Alleviating Toxicities of Chemotherapeutic Agents. Curr Protein Pept Sci 2024; 25:753-779. [PMID: 38919003 DOI: 10.2174/0113892037307940240606075208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/17/2024] [Accepted: 04/24/2024] [Indexed: 06/27/2024]
Abstract
BACKGROUND Chemotherapy is the mainstay of cancer treatment, bringing patients optimism about recurrence and survival. However, the clinical effectiveness of chemotherapeutic drugs is frequently jeopardized by their intrinsic toxicity, resulting in side effects affecting the quality of life of cancer patients. This analysis explores the ethnopharmacological impact of phytopharmaceuticals, highlighting their traditional use in many cultures. The present study, which takes its cues from indigenous knowledge, aims to close the knowledge gap between traditional medicine and modern medicine in reducing the toxicities of chemotherapy treatments. AIM The present in-depth study aims to highlight the current research and upcoming developments in phytopharmaceuticals for reducing the toxicity of chemotherapeutic drugs. Further, we address the mechanisms through which phytopharmaceuticals may reduce chemotherapy-induced side effects that include nausea, vomiting, myelosuppression, nephropathy, neuropathy, and cardiotoxicity using data from a variety of preclinical and clinical investigations. MATERIALS AND METHODS The literature search was carried out by employing search engines such as PubMed and Google Scholar with keywords such as cancer, chemotherapy, CNS toxicity, hematopoietic toxicity, renal toxicity, GI toxicity, CNS toxicity, and phytopharmaceuticals. RESULTS Bioactive chemicals found in plants, such as fruits, vegetables, herbs, and spices, are being studied for their capacity to improve the safety and acceptability of chemotherapy regimens. The current review also dives into the investigation of phytopharmaceuticals as adjuvant medicines in cancer treatment, which is a viable path for addressing the pressing need to lessen chemotherapy-induced toxicities. CONCLUSION The present review revealed that the potential of phytopharmaceuticals in alleviating chemotherapeutic drug toxicities would pave the way for better cancer treatment and patient outcomes, harmonizing with the larger trend towards personalized and holistic approaches to chemotherapy.
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Affiliation(s)
- Ujwal N Katolkar
- Department of Pharmacology, R.C. Patel Institute of Pharmaceutical Education and Research, Karwand Naka, Shirpur Dist. Dhule Maharashtra 425405, India
| | - Sanjay J Surana
- Department of Pharmacology, R.C. Patel Institute of Pharmaceutical Education and Research, Karwand Naka, Shirpur Dist. Dhule Maharashtra 425405, India
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15
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Sehgal M, Jain V, Agarwala S, Dhua A, Goel P, Yadav DK, Bakhshi S, Kalaivani M. Looking Beyond Toxicities: Other Health-related Morbidities Noted in Childhood Solid Tumor Survivors. J Indian Assoc Pediatr Surg 2023; 28:472-478. [PMID: 38173641 PMCID: PMC10760608 DOI: 10.4103/jiaps.jiaps_104_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 05/25/2023] [Accepted: 07/23/2023] [Indexed: 01/05/2024] Open
Abstract
Aim In addition to the well-known toxicities of treatment, survivors of pediatric solid tumors can also develop other health-related conditions. They may either be an indirect consequence of therapy or could be unrelated to their prior history of malignancy. We aim to evaluate the nontoxicity related health conditions in survivors of pediatric solid tumors. Materials and Methods The study included a cohort of hepatoblastoma (HB), Wilm's tumor (WT), and malignant germ cell tumors (MGCT) survivors registered at pediatric surgical-oncology clinic from 1994 to 2016. Follow-up was done according to standard protocols and children were evaluated at each visit for any health-related conditions. Results Of the survivors, 318 survivors, comprising of 48, 81, and 189 survivors of HB, MGCT, and WT, respectively, were included in the analysis. We found 20.8% of patients with HB, 11.1% of patients with MGCT, and 16.4% of patients with WT to report nontoxicity-related health issues. A high prevalence of surgical conditions (3.4%), secondary malignancies (1.2%), gynecological conditions in girls (16.9%), tuberculosis (1.2%), gallstone disease (0.9%), pelvi-ureteral junction obstruction (0.9%), and neurological issues (0.9%) was noted. Two presumed survivors had died, one due to a late recurrence and the other due to a secondary malignancy. Conclusions A high prevalence of medically or surgically manageable conditions makes it imperative to keep these children under follow-up to address any health-related conditions they may subsequently develop.
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Affiliation(s)
- Mehak Sehgal
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Vishesh Jain
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Sandeep Agarwala
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Anjan Dhua
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Prabudh Goel
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Devendra Kumar Yadav
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Sameer Bakhshi
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Mani Kalaivani
- Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
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Yang C, Xiao W, Wang R, Hu Y, Yi K, Sun X, Wang G, Xu X. Tumor organoid model of colorectal cancer (Review). Oncol Lett 2023; 26:328. [PMID: 37415635 PMCID: PMC10320425 DOI: 10.3892/ol.2023.13914] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 06/01/2023] [Indexed: 07/08/2023] Open
Abstract
The establishment of self-organizing 'mini-gut' organoid models has brought about a significant breakthrough in biomedical research. Patient-derived tumor organoids have emerged as valuable tools for preclinical studies, offering the retention of genetic and phenotypic characteristics of the original tumor. These organoids have applications in various research areas, including in vitro modelling, drug discovery and personalized medicine. The present review provided an overview of intestinal organoids, focusing on their unique characteristics and current understanding. The progress made in colorectal cancer (CRC) organoid models was then delved into, discussing their role in drug development and personalized medicine. For instance, it has been indicated that patient-derived tumor organoids are able to predict response to irinotecan-based neoadjuvant chemoradiotherapy. Furthermore, the limitations and challenges associated with current CRC organoid models were addressed, along with proposed strategies for enhancing their utility in future basic and translational research.
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Affiliation(s)
- Chi Yang
- Department of Gastroenterology, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
| | - Wangwen Xiao
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
| | - Rui Wang
- School of Pharmacy, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Yan Hu
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
| | - Ke Yi
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
| | - Xuan Sun
- Department of Gastroenterology, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
| | - Guanghui Wang
- School of Pharmacy, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215123, P.R. China
| | - Xiaohui Xu
- Department of Gastroenterology, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
- Central Laboratory, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Soochow Medical College of Soochow University, Suzhou, Jiangsu 215400, P.R. China
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Chitrangi S, Vaity P, Jamdar A, Bhatt S. Patient-derived organoids for precision oncology: a platform to facilitate clinical decision making. BMC Cancer 2023; 23:689. [PMID: 37479967 PMCID: PMC10362580 DOI: 10.1186/s12885-023-11078-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 06/16/2023] [Indexed: 07/23/2023] Open
Abstract
BACKGROUND Despite recent advances in research, there are still critical lacunae in our basic understanding of the cause, pathogenesis, and natural history of many cancers, especially heterogeneity in patient response to drugs and mediators in the transition from malignant to invasive phenotypes. The explication of the pathogenesis of cancer has been constrained by limited access to patient samples, tumor heterogeneity and lack of reliable biological models. Amelioration in cancer treatment depends on further understanding of the etiologic, genetic, biological, and clinical heterogeneity of tumor microenvironment. Patient-derived organoids recapitulate the basic features of primary tumors, including histological complexity and genetic heterogeneity, which is instrumental in predicting patient response to drugs. METHODS Human iPSCs from healthy donors, breast and ovarian cancer patients were successfully differentiated towards isogenic hepatic, cardiac, neural and endothelial lineages. Multicellular organoids were established using Primary cells isolated from tumor tissues, histologically normal tissues adjacent to the tumors (NATs) and adipose tissues (source of Mesenchymal Stem Cells) from ovarian and breast cancer patients. Further these organoids were propagated and used for drug resistance/sensitivity studies. RESULTS Ovarian and breast cancer patients' organoids showed heterogeneity in drug resistance and sensitivity. iPSCs-derived cardiomyocytes, hepatocytes and neurons showed donor-to-donor variability of chemotherapeutic drug sensitivity in ovarian cancer patients, breast cancer patients and healthy donors. CONCLUSION We report development of a novel integrated platform to facilitate clinical decision-making using the patient's primary cells, iPSCs and derivatives, to clinically relevant models for oncology research.
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Affiliation(s)
- Swati Chitrangi
- Department of Integrated Drug Discovery and Development, Yashraj Biotechnology Limited, C-232 and C-113, TTC Industrial Area, MIDC, Pawane, Maharashtra, 400705, India
| | - Pooja Vaity
- Department of Integrated Drug Discovery and Development, Yashraj Biotechnology Limited, C-232 and C-113, TTC Industrial Area, MIDC, Pawane, Maharashtra, 400705, India
| | - Aishwarya Jamdar
- Department of Integrated Drug Discovery and Development, Yashraj Biotechnology Limited, C-232 and C-113, TTC Industrial Area, MIDC, Pawane, Maharashtra, 400705, India
| | - Shweta Bhatt
- Department of Integrated Drug Discovery and Development, Yashraj Biotechnology Limited, C-232 and C-113, TTC Industrial Area, MIDC, Pawane, Maharashtra, 400705, India.
- Yashraj Biotechnology GmbH, Uhlandstraße 20-25, 10623, Berlin, Germany.
- Yashraj Biotechnology Limited, 8, The Green STE A, Dover, Delaware State, 19901, USA.
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Pope MC, Olson MC, Flicek KT, Patel NJ, Bolan CW, Menias CO, Wang Z, Venkatesh SK. Chemotherapy-associated liver morphological changes in hepatic metastases (CALMCHeM). Diagn Interv Radiol 2023; 29:571-578. [PMID: 37310196 PMCID: PMC10679643 DOI: 10.4274/dir.2023.232299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 05/30/2023] [Indexed: 06/14/2023]
Abstract
PURPOSE To review imaging findings in chemotherapy-associated liver morphological changes in hepatic metastases (CALMCHeM) on computed tomography (CT)/magnetic resonance imaging (MRI) and its association with tumor burden. METHODS We performed a retrospective chart review to identify patients with hepatic metastases who received chemotherapy and subsequent follow-up imaging where CT or MRI showed morphological changes in the liver. The morphological changes searched for were nodularity, capsular retraction, hypodense fibrotic bands, lobulated outline, atrophy or hypertrophy of segments or lobes, widened fissures, and one or more features of portal hypertension (splenomegaly/venous collaterals/ascites). The inclusion criteria were as follows: a) no known chronic liver disease; b) availability of CT or MRI images before chemotherapy that showed no morphological signs of chronic liver disease; c) at least one follow-up CT or MRI image demonstrating CALMCHeM after chemotherapy. Two radiologists in consensus graded the initial hepatic metastases tumor burden according to number (≤10 and >10), lobe distribution (single or both lobes), and liver parenchyma volume affected (<50%, or ≥50%). Imaging features after treatment were graded according to a pre-defined qualitative assessment scale of "normal," "mild," "moderate," or "severe." Descriptive statistics were performed with binary groups based on the number, lobar distribution, type, and volume of the liver affected. Chi-square and t-tests were used for comparative statistics. The Cox proportional hazard model was used to determine the association between severe CALMCHeM changes and age, sex, tumor burden, and primary carcinoma type. RESULTS A total of 219 patients met the inclusion criteria. The most common primaries were from breast (58.4%), colorectal (14.2%), and neuroendocrine (11.0%) carcinomas. Hepatic metastases were discrete in 54.8% of cases, confluent in 38.8%, and diffuse in 6.4%. The number of metastases was >10 in 64.4% of patients. The volume of liver involved was <50% in 79.8% and ≥50% in 20.2% of cases. The severity of CALMCHeM at the first imaging follow-up was associated with a larger number of metastases (P = 0.002) and volume of the liver affected (P = 0.015). The severity of CALMCHeM had progressed to moderate to severe changes in 85.9% of patients, and 72.5% of patients had one or more features of portal hypertension at the last follow-up. The most common features at the final follow-up were nodularity (95.0%), capsular retraction (93.4%), atrophy (66.2%), and ascites (65.7%). The Cox proportional hazard model showed metastases affected ≥50% of the liver (P = 0.033), and the female gender (P = 0.004) was independently associated with severe CALMCHeM. CONCLUSION CALMCHeM can be observed with a wide variety of malignancies, is progressive in severity, and the severity correlates with the initial metastatic liver disease burden.
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Affiliation(s)
- Matthew C. Pope
- Department of Radiology, Division of Abdominal Imaging, Mayo Clinic, Minnesota, USA
| | - Michael C. Olson
- Department of Radiology, Division of Abdominal Imaging, Mayo Clinic, Minnesota, USA
| | - Kristina T. Flicek
- Department of Radiology, Division of Abdominal Imaging, Mayo Clinic, Minnesota, USA
| | - Neema J. Patel
- Department of Radiology, Division of Abdominal Imaging, Mayo Clinic, Florida, USA
| | - Candice W. Bolan
- Department of Radiology, Division of Abdominal Imaging, Mayo Clinic, Florida, USA
| | - Christine O. Menias
- Department of Radiology, Division of Abdominal Imaging, Mayo Clinic, Arizona, USA
| | - Zhen Wang
- Department of Biostatistics, Mayo Clinic, Minnesota, USA
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19
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Ali YA, Soliman HA, Abdel-Gabbar M, Ahmed NA, Attia KAA, Shalaby FM, El-Nahass ES, Ahmed OM. Rutin and Hesperidin Revoke the Hepatotoxicity Induced by Paclitaxel in Male Wistar Rats via Their Antioxidant, Anti-Inflammatory, and Antiapoptotic Activities. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2023; 2023:2738351. [PMID: 37275575 PMCID: PMC10238143 DOI: 10.1155/2023/2738351] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/09/2022] [Accepted: 09/29/2022] [Indexed: 06/07/2023]
Abstract
Paclitaxel, one of the most effective chemotherapeutic drugs, is used to treat various cancers but it is exceedingly toxic when used long-term and can harm the liver. This study aimed to see if rutin, hesperidin, and their combination could protect male Wistar rats against paclitaxel (Taxol)-induced hepatotoxicity. Adult male Wistar rats were subdivided into 5 groups (each of six rats). The normal group was orally given the equivalent volume of vehicles for 6 weeks. The paclitaxel-administered control group received intraperitoneal injection of paclitaxel at a dose of 2 mg/Kg body weight twice a week for 6 weeks. Treated paclitaxel-administered groups were given paclitaxel similar to the paclitaxel-administered control group together with oral supplementation of rutin, hesperidin, and their combination at a dose of 10 mg/Kg body weight every other day for 6 weeks. The treatment of paclitaxel-administered rats with rutin and hesperidin significantly reduced paclitaxel-induced increases in serum alanine transaminase, aspartate transaminase, lactate dehydrogenase, alkaline phosphatase, and gamma-glutamyl transferase activities as well as total bilirubin level and liver lipid peroxidation. However, the levels of serum albumin, liver glutathione content, and the activities of liver superoxide dismutase and glutathione peroxidase increased. Furthermore, paclitaxel-induced harmful hepatic histological changes (central vein and portal area blood vessel congestion, fatty changes, and moderate necrotic changes with focal nuclear pyknosis, focal mononuclear infiltration, and Kupffer cell proliferation) were remarkably enhanced by rutin and hesperidin treatments. Moreover, the elevated hepatic proapoptotic mediator (caspase-3) and pro-inflammatory cytokine (tumor necrosis factor-α) expressions were decreased by the three treatments in paclitaxel-administered rats. The cotreatment with rutin and hesperidin was the most effective in restoring the majority of liver function and histological integrity. Therefore, rutin, hesperidin, and their combination may exert hepatic protective effects in paclitaxel-administered rats by improving antioxidant defenses and inhibiting inflammation and apoptosis.
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Affiliation(s)
- Yasmine A. Ali
- Biochemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Hanan A. Soliman
- Biochemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Mohamed Abdel-Gabbar
- Biochemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Noha A. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Kandil A. A. Attia
- Clinical Nutrition Department, College of Applied Medical Sciences, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
- Department of Evaluation of Natural Resources, Environmental Studies and Research Institute, El-Sadat City University, El-Sadat City 32897, Egypt
| | - Fatma M. Shalaby
- Biology Department, Faculty of Science, King Khalid University, Abha, Saudi Arabia
- Department of Zoology, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - El-Shaymaa El-Nahass
- Department of Pathology, Faculty of Veterinary Medicine, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Osama M. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
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20
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Patil NS, Larocque N, van der Pol CB, Torres C, Raptis DA, Patlas MN. Chemotherapy-Induced Toxicities: An Imaging Primer. Can Assoc Radiol J 2023; 74:432-445. [PMID: 35968850 DOI: 10.1177/08465371221120263] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The Coronavirus Disease of 2019 (COVID-19) pandemic has caused significant delays in the delivery of cancer treatments in Canada. As cancer treatment and imaging volumes return to normal, radiologists will encounter more cases of chemotherapy-induced toxicities. These toxicities have varied appearances on imaging, and can affect multiple organ systems. The purpose of this review is to offer a unified resource for general radiologists regarding the imaging appearances of chemotherapy-induced toxicities.
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Affiliation(s)
- Nikhil S Patil
- Michael DeGroote School of Medicine, 62703McMaster University, Hamilton, ON, Canada
| | - Natasha Larocque
- Department of Radiology, 3710McMaster University, Hamilton, ON, Canada
| | - Christian B van der Pol
- Department of Diagnostic Imaging, Juravinski Hospital and Cancer Centre, Hamilton Health Sciences, Canada
| | - Carlos Torres
- Department of Radiology, Radiation Oncology and Medical Physics, 6363University of Ottawa, Ottawa, ON, Canada
| | - Demetrios A Raptis
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, USA
| | - Michael N Patlas
- Department of Radiology, 3710McMaster University, Hamilton, ON, Canada
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21
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Ali YA, Ahmed OM, Soliman HA, Abdel-Gabbar M, Al-Dossari M, El-Gawaad NSA, El-Nahass ES, Ahmed NA. Rutin and Hesperidin Alleviate Paclitaxel-Induced Nephrocardiotoxicity in Wistar Rats via Suppressing the Oxidative Stress and Enhancing the Antioxidant Defense Mechanisms. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2023; 2023:5068304. [PMID: 36874615 PMCID: PMC9977529 DOI: 10.1155/2023/5068304] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 10/05/2022] [Accepted: 01/27/2023] [Indexed: 02/24/2023]
Abstract
Paclitaxel is a primary chemotherapy agent that displays antitumor activity against a variety of solid tumors. However, the clinical effectiveness of the drug is hampered by its nephrotoxic and cardiotoxic side effects. Thus, this investigation aimed at assessing the protective effects of rutin, hesperidin, and their combination to alleviate nephrotoxicity caused by paclitaxel (Taxol), cardiotoxicity in male Wistar rats, as well as oxidative stress. Rutin (10 mg/kg body weight), hesperidin (10 mg/kg body weight), and their mixture were given orally every other day for six weeks. Rats received intraperitoneal injections of paclitaxel twice weekly, on the second and fifth days of the week, at a dose of 2 mg/kg body weight. In paclitaxel-treated rats, the treatment of rutin and hesperidin decreased the elevated serum levels of creatinine, urea, and uric acid, indicating a recovery of kidney functions. The cardiac dysfunction in paclitaxel-treated rats that got rutin and hesperidin treatment also diminished, as shown by a substantial reduction in elevated CK-MB and LDH activity. Following paclitaxel administration, the severity of the kidney and the heart's histopathological findings and lesion scores were markedly decreased by rutin and hesperidin administration. Moreover, these treatments significantly reduced renal and cardiac lipid peroxidation while markedly increased GSH content and SOD and GPx activities. Thus, paclitaxel likely induces toxicity in the kidney and the heart by producing oxidative stress. The treatments likely countered renal and cardiac dysfunction and histopathological changes by suppressing oxidative stress and augmenting the antioxidant defenses. Rutin and hesperidin combination was most efficacious in rescuing renal and cardiac function as well as histological integrity in paclitaxel-administered rats.
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Affiliation(s)
- Yasmine A. Ali
- Biochemistry Department, Faculty of Science, Beni-Sued University, P.O. Box 62521, Beni-Suef, Egypt
| | - Osama M. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Hanan A. Soliman
- Biochemistry Department, Faculty of Science, Beni-Sued University, P.O. Box 62521, Beni-Suef, Egypt
| | - Mohamed Abdel-Gabbar
- Biochemistry Department, Faculty of Science, Beni-Sued University, P.O. Box 62521, Beni-Suef, Egypt
| | - M. Al-Dossari
- Research Center for Advanced Materials Science (RCAMS), King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia
| | - N. S. Abd El-Gawaad
- Department of Physics, Faculty of Science, King Khalid University, P.O. Box 9004, Abha 62529, Saudi Arabia
| | - El-Shaymaa El-Nahass
- Department of Pathology, Faculty of Veterinary Medicine, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Noha A. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
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Molehin OR, Idowu KA, Olaoye AB, Fakayode AE, Adesua OO. Influence of Clerodendrum volubile leaf extract on doxorubicin-induced toxicity and inhibition of carbonyl reductase mediated metabolism. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2022; 19:937-946. [PMID: 33977682 DOI: 10.1515/jcim-2020-0231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 02/15/2021] [Indexed: 06/12/2023]
Abstract
OBJECTIVES Doxorubicin (DOX) is a commonly used chemotherapeutic drug. However, its non-target organ toxicities pose a serious problem. This study is to assess the protective role of Clerodendrum volubile leaf extract (CVE) against DOX-induced toxicities in rats. In addition, the inhibitory activities of three phytochemical compounds (Rutin, Gallic acid and Rosmarinic acid) from CVE against Carbonyl reductase 1 (CBR1) were examined. METHODS Rats were randomly divided into 5 groups: (a) Control group rats were given 0.9% NaCl as vehicle, (b) DOX group: A single dose of DOX (25 mg/kg; i.p.) was administered and rats were sacrificed 4 days after DOX injection, while groups (c-e) CVE-treated DOX rat groups were given 125, 250 and 500 mg/kg body weight of extracts orally for 12 consecutive days; 8 days before, and 4 days after the DOX administration. Computational techniques were used to determine the inhibitory activities of the compounds against CBR1. RESULTS DOX intoxication caused a significant increase (p<0.05) in serum marker enzymes: ALT, AST, ALP, LDH, CK activities. The levels of liver and heart tissues antioxidant parameters: GPx, SOD, CAT, and GSH were significantly (p<0.05) decreased in DOX-intoxicated rats with concomitant elevation of malondialdehyde levels. Pretreatment with CVE reversed the above trends. From the structural analysis, Rutin and RSA exhibited the highest binding free energies against CBR1, and also exhibited structural stability when bound with CBR1. CONCLUSIONS Our study indicates the protective effect of CVE when used in combination with doxorubicin thus improving its chemotherapeutic application via inhibition of CBR-mediated metabolism.
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Affiliation(s)
- Olorunfemi R Molehin
- Department of Biochemistry, Faculty of Science, Ekiti State University, Ado-Ekiti, Nigeria
| | - Kehinde A Idowu
- Department of Medical Biochemistry, College of Medicine, Ekiti State University, Ado-Ekiti, Nigeria
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Medical Campus, Durban, South Africa
| | - Ayonposi B Olaoye
- Department of Science Technology, The Federal Polytechnic Ado-Ekiti, Ado-Ekiti, Nigeria
| | - Aderonke E Fakayode
- Department of Biochemistry and Molecular Biology, Faculty of Science, Obafemi Awolowo University, Ile-Ife, Nigeria
| | - Oluwatumininu O Adesua
- Department of Biochemistry, Faculty of Science, Ekiti State University, Ado-Ekiti, Nigeria
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23
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Wang Y, Li J, do Vale GD, Chaudhary J, Anwar A, McDonald JG, Qin T, Zhang H, Corbin IR. Repeated trans-arterial treatments of LDL-DHA nanoparticles induce multiple pathways of tumor cell death in hepatocellular carcinoma bearing rats. Front Oncol 2022; 12:1052221. [PMID: 36505796 PMCID: PMC9730405 DOI: 10.3389/fonc.2022.1052221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 11/07/2022] [Indexed: 11/27/2022] Open
Abstract
Introduction Repeated hepatic arterial delivery of therapeutic agents to the liver by percutaneously implanted port-catheter systems has been widely used to treat unresectable liver cancer. This approach is applied to assess the therapeutic efficacy of repeated low-density lipoprotein-docosahexaenoic acid (LDL-DHA) nanoparticle treatments in a rat model of hepatocellular carcinoma. Methods N1S1 hepatoma bearing rats underwent placement of a percutaneously implanted hepatic artery port-catheter system and were allocated to untreated, control LDL-triolein (LDL-TO) or LDL-DHA nanoparticle infusions groups. Treatments were performed every three days over a nine day study period. MRI was performed at baseline and throughout the study. At the end of the study tissue samples were collected for analyses. Results and Discussion Implantation of the port catheters was successful in all rats. MRI showed that repeated infusions of LDL-DHA nanoparticles significantly impaired the growth of the rat hepatomas eventually leading to tumor regression. The tumors in the LDL-TO treated group showed delayed growth, while the untreated tumors grew steadily throughout the study. Histopathology and MRI support these findings demonstrating extensive tumor necrosis in LDL-DHA treated groups while the control groups displayed minor necrosis. Molecular and biochemical analyses also revealed that LDL-DHA treated tumors had increased levels of nuclear factor-kappa B and lipid peroxidation and depletion of glutathione peroxidase 4 relative to the control groups. Evidence of both ferroptosis and apoptosis tumor cell death was observed following LDL-DHA treatments. In conclusion repeated transarterial infusions of LDL-DHA nanoparticles provides sustained repression of tumor growth in a rat hepatoma model.
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Affiliation(s)
- Yuzhu Wang
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou, Henan, China
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
| | - Junjie Li
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
| | - Goncalo Dias do Vale
- Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
| | - Jaideep Chaudhary
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
| | - Arnida Anwar
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
| | - Jeffrey G. McDonald
- Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
| | - Tao Qin
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou, Henan, China
| | - Hongwei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Henan University People’s Hospital, Zhengzhou, Henan, China
| | - Ian R. Corbin
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
- Internal Medicine Division of Liver and Digestive Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
- Radiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United States
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24
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Moghtaderi M, Sedaghatnia K, Bourbour M, Fatemizadeh M, Salehi Moghaddam Z, Hejabi F, Heidari F, Quazi S, Farasati Far B. Niosomes: a novel targeted drug delivery system for cancer. Med Oncol 2022; 39:240. [PMID: 36175809 DOI: 10.1007/s12032-022-01836-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 08/27/2022] [Indexed: 10/25/2022]
Abstract
Recently, nanotechnology is involved in various fields of science, of which medicine is one of the most obvious. The use of nanoparticles in the process of treating and diagnosing diseases has created a novel way of therapeutic strategies with effective mechanisms of action. Also, due to the remarkable progress of personalized medicine, the effort is to reduce the side effects of treatment paths as much as possible and to provide targeted treatments. Therefore, the targeted delivery of drugs is important in different diseases, especially in patients who receive combined drugs, because the delivery of different drug structures requires different systems so that there is no change in the drug and its effectiveness. Niosomes are polymeric nanoparticles that show favorable characteristics in drug delivery. In addition to biocompatibility and high absorption, these nanoparticles also provide the possibility of reducing the drug dosage and targeting the release of drugs, as well as the delivery of both hydrophilic and lipophilic drugs by Niosome vesicles. Since various factors such as components, preparation, and optimization methods are effective in the size and formation of niosomal structures, in this review, the characteristics related to niosome vesicles were first examined and then the in silico tools for designing, prediction, and optimization were explained. Finally, anticancer drugs delivered by niosomes were compared and discussed to be a suitable model for designing therapeutic strategies. In this research, it has been tried to examine all the aspects required for drug delivery engineering using niosomes and finally, by presenting clinical examples of the use of these nanocarriers in cancer, its clinical characteristics were also expressed.
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Affiliation(s)
- Maryam Moghtaderi
- Department of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran
| | - Kamand Sedaghatnia
- Department of Applied Chemistry, Azad University of Tehran South Branch, Tehran, Iran
| | - Mahsa Bourbour
- Department of Biotechnology, Alzahra University, Tehran, Iran
| | - Mahdi Fatemizadeh
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Salehi Moghaddam
- Department of Microbial Biotechnology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Faranak Hejabi
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Fatemeh Heidari
- Department of Cellular and Molecular Biology, Islamic Azad University, Tehran Medical Branch, Tehran, Iran
| | - Sameer Quazi
- GenLab Biosolutions Private Limited, Bangalore, Karnataka, India.
- Department of Biomedical Sciences, School of Life Sciences, Anglia Ruskin University, Cambridge, UK.
- Clinical Bioinformatics, School of Health Sciences, The University of Manchester, Manchester, UK.
| | - Bahareh Farasati Far
- Department of Chemistry, Iran University of Science and Technology, Tehran, Iran
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25
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Chowdhury P, Bhusetty Nagesh PK, Hollingsworth TJ, Jaggi M, Chauhan SC, Yallapu MM. Coating a Self-Assembly Nanoconstruct with a Neutrophil Cell Membrane Enables High Specificity for Triple Negative Breast Cancer Treatment. ACS APPLIED BIO MATERIALS 2022; 5:4554-4566. [PMID: 35976626 DOI: 10.1021/acsabm.2c00614] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Breast cancer is one of the most commonly diagnosed cancers in American women. Triple negative breast cancer is among the most advanced and aggressive forms of breast cancer. Treatment options are limited for such cancers, making chemotherapy a convenient and effective treatment. Although these therapies can reduce morbidity and mortality, it is often followed by systemic side effects or relapse. Nanoparticles (NPs) have been considered for drug delivery approaches due to their ability to target various disease sites. Herein, we aim to develop a biomimetic NP construct (cell membrane-cloaked NPs) that exhibits specific affinity with triple negative breast cancer cells. In this regard, we designed biomimetic supramolecular nanoconstructs composed of a poly(vinyl pyrrolidone)-tannic acid (PVP-TA NPs/ PVT NPs) core and biofunctionalized with neutrophil cell membranes (PVT-NEU NPs). In this study, we have synthesized a PVT-NEU NP construct, characterized it, and evaluated it for improved targeting and therapeutic benefits in in vitro and in vivo models. Analysis of PVT-NEU NPs confirms the presence of the core of PVP-TA NPs coated with activated human neutrophil membranes. The study results confirmed that PVT-NEU NPs demonstrated an enhanced interaction and targeting with the tumor cells, thus improving the therapeutic activity of a model therapeutic agent (paclitaxel). Altogether, this study suggests the potential of biomimetic NPs as a promising therapeutic option for targeted drug delivery for advanced-stage breast cancer and other similar diseased conditions.
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Affiliation(s)
- Pallabita Chowdhury
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Prashanth Kumar Bhusetty Nagesh
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
- Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, United States
| | - T J Hollingsworth
- Department of Ophthalmology, Hamilton Eye Institute, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Meena Jaggi
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, United States
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, United States
| | - Subhash Chand Chauhan
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, United States
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, United States
| | - Murali Mohan Yallapu
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, United States
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas 78504, United States
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Menon J, Rammohan A, Vij M, Shanmugam N, Rela M. Current perspectives on the role of liver transplantation for Langerhans cell histiocytosis: A narrative review. World J Gastroenterol 2022; 28:4044-4052. [PMID: 36157108 PMCID: PMC9403430 DOI: 10.3748/wjg.v28.i30.4044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 03/30/2022] [Accepted: 07/19/2022] [Indexed: 02/06/2023] Open
Abstract
Langerhans cell histiocytosis (LCH) is a malignant disease of the histiocytes involving various organ systems. The spectrum of liver involvement in LCH ranges from mild transaminitis to end-stage liver disease. The hallmark of hepatic LCH is secondary sclerosing cholangitis, which manifests due to a progressive destruction of the biliary tree by malignant histiocytes. Chemotherapy remains the mainstay of treatment for active LCH. Early recognition, diagnosis and a systematic approach to the management of LCH can ameliorate the disease process. Nonetheless, the liver involvement in these patients may progress despite the LCH being in remission. Liver transplantation (LT) remains central in the management of such patients. Various facets of the management of LCH, especially those with liver involvement remain unclear. Furthermore, aspects of LT in LCH with regards to the indication, timing and post-LT management, including immunosuppression and adjuvant therapy, remain undefined. This review summarises the current evidence and discusses the practical aspects of the role of LT in the management of LCH.
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Affiliation(s)
- Jagadeesh Menon
- Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai 600044, India
| | - Ashwin Rammohan
- Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai 600044, India
| | - Mukul Vij
- Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai 600044, India
| | - Naresh Shanmugam
- Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai 600044, India
| | - Mohamed Rela
- Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai 600044, India
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Evaluation of liver function tests to identify hepatotoxicity among acute lymphoblastic leukemia patients who are receiving chemotherapy induction. Sci Rep 2022; 12:13215. [PMID: 35918381 PMCID: PMC9346124 DOI: 10.1038/s41598-022-17618-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 07/28/2022] [Indexed: 11/27/2022] Open
Abstract
The effect of induction chemotherapy on liver function in patients with acute lymphoblastic leukemia is not well documented in Ethiopia. This study assessed hepatotoxicity in patients with acute lymphoblastic leukemia who were undergoing induction chemotherapy in Ethiopia. A 1-month cohort study was undertaken in forty patients with acute lymphoblastic leukemia, with measurements taken at the baseline, second, and fourth weeks. A Log 10 transformation was done because of the skewed distribution of liver function tests. Descriptive statistics such as mean and proportion were calculated. A mixed model ANOVA and Bonferroni post hoc test were computed. A p value < 0.05 was declared to determine statistical significance. Clinically significant hepatotoxicity was observed in 15% of patients. Mild liver injury occurred in 5% of patients. The mean of all liver function tests increased significantly from pre-induction to post-induction. ALT levels were significantly higher in patients who received blood transfusions, but not in those who did not. Regardless of other factors, ALP level in children is significantly higher than in adults, although total bilirubin in adults is higher than in children. A significant proportion of patients had hepatotoxicity. During chemotherapy induction, the mean of all liver function tests rose significantly, but this elevation of serum liver function tests may be transient. Chemotherapy drugs should be given without causing a significant alteration in serum liver function tests. Continuous monitoring of patients should be required.
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Serum protein and electrolyte imbalances are associated with chemotherapy induced neutropenia. Heliyon 2022; 8:e09949. [PMID: 35865973 PMCID: PMC9293742 DOI: 10.1016/j.heliyon.2022.e09949] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 01/23/2022] [Accepted: 07/08/2022] [Indexed: 11/29/2022] Open
Abstract
Introduction Cancer and its treatment using various chemotherapeutic agents can have many adverse side effects. These side effects often result in significant changes in haematological and biochemical composition of blood. As a result, the regular monitoring of serum biochemical and haematological changes plays an important role in management of disease. The present study aimed to determine the relationship between haematological and biochemical changes in neutropenic cancer patients following chemotherapy. Specifically we evaluated the association between neutrophil count and serum proteins and electrolytes. Methods For this purpose we analysed retrospectively collected laboratory results from two independent patient cohorts. Each cohort was divided into a control group consisting of patients with normal haematological parameters and a study group which included patients with reduced neutrophil counts. Neutropenic patients (study group) were cancer patients on chemotherapy. Results and conclusion Blood samples of cancer patients in study group showed reduction in haemoglobin, neutrophils and platelets. Neutropenic group showed a significant reduction in serum albumin, total protein, calcium, and potassium. Our results show that patients with severe neutropenia had pronounced changes in serum protein and electrolytes and increased incidence of abnormal serum protein and electrolyte level. The changes in the neutrophil counts showed a positive correlation with the changes in serum protein and electrolyte levels. A similar trend was seen in both the patient cohorts: the discovery set (176 patients) and the validation set (200 patients). Taken together our results suggest that chemotherapy-induced neutropenia is associated with dysregulation in haemoglobin, platelets, serum proteins and electrolytes.
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Cerqueira M, Belmonte-Reche E, Gallo J, Baltazar F, Bañobre-López M. Magnetic Solid Nanoparticles and Their Counterparts: Recent Advances towards Cancer Theranostics. Pharmaceutics 2022; 14:pharmaceutics14030506. [PMID: 35335882 PMCID: PMC8950239 DOI: 10.3390/pharmaceutics14030506] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 02/20/2022] [Accepted: 02/22/2022] [Indexed: 02/01/2023] Open
Abstract
Cancer is currently a leading cause of death worldwide. The World Health Organization estimates an increase of 60% in the global cancer incidence in the next two decades. The inefficiency of the currently available therapies has prompted an urgent effort to develop new strategies that enable early diagnosis and improve response to treatment. Nanomedicine formulations can improve the pharmacokinetics and pharmacodynamics of conventional therapies and result in optimized cancer treatments. In particular, theranostic formulations aim at addressing the high heterogeneity of tumors and metastases by integrating imaging properties that enable a non-invasive and quantitative assessment of tumor targeting efficiency, drug delivery, and eventually the monitoring of the response to treatment. However, in order to exploit their full potential, the promising results observed in preclinical stages need to achieve clinical translation. Despite the significant number of available functionalization strategies, targeting efficiency is currently one of the major limitations of advanced nanomedicines in the oncology area, highlighting the need for more efficient nanoformulation designs that provide them with selectivity for precise cancer types and tumoral tissue. Under this current need, this review provides an overview of the strategies currently applied in the cancer theranostics field using magnetic nanoparticles (MNPs) and solid lipid nanoparticles (SLNs), where both nanocarriers have recently entered the clinical trials stage. The integration of these formulations into magnetic solid lipid nanoparticles—with different composition and phenotypic activity—constitutes a new generation of theranostic nanomedicines with great potential for the selective, controlled, and safe delivery of chemotherapy.
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Affiliation(s)
- Mónica Cerqueira
- Life and Health Sciences Research Institute (ICVS), Campus of Gualtar, University of Minho, 4710-057 Braga, Portugal;
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
- Advanced (Magnetic) Theranostic Nanostructures Lab, Nanomedicine Unit, International Iberian Nanotechnology Laboratory, Avenida Mestre José Veiga, 4715-330 Braga, Portugal; (E.B.-R.); (J.G.)
| | - Efres Belmonte-Reche
- Advanced (Magnetic) Theranostic Nanostructures Lab, Nanomedicine Unit, International Iberian Nanotechnology Laboratory, Avenida Mestre José Veiga, 4715-330 Braga, Portugal; (E.B.-R.); (J.G.)
| | - Juan Gallo
- Advanced (Magnetic) Theranostic Nanostructures Lab, Nanomedicine Unit, International Iberian Nanotechnology Laboratory, Avenida Mestre José Veiga, 4715-330 Braga, Portugal; (E.B.-R.); (J.G.)
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), Campus of Gualtar, University of Minho, 4710-057 Braga, Portugal;
- ICVS/3B’s—PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
- Correspondence: (F.B.); (M.B.-L.)
| | - Manuel Bañobre-López
- Advanced (Magnetic) Theranostic Nanostructures Lab, Nanomedicine Unit, International Iberian Nanotechnology Laboratory, Avenida Mestre José Veiga, 4715-330 Braga, Portugal; (E.B.-R.); (J.G.)
- Correspondence: (F.B.); (M.B.-L.)
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Szpakowski JL, Tucker LY, Baer DM, Pauly MP. Hepatotoxicity during legacy cancer chemotherapy in patients infected with hepatitis C virus: A retrospective cohort study. CANADIAN LIVER JOURNAL 2022; 5:43-60. [PMID: 35990784 PMCID: PMC9231429 DOI: 10.3138/canlivj-2021-0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 08/13/2021] [Indexed: 11/04/2023]
Abstract
BACKGROUND The rates and causes of significant hepatotoxicity with cancer chemotherapy (CCT) in patients infected with hepatitis C virus (HCV) are incompletely characterized. METHODS We compared rates of grade 3 or 4 hepatotoxicity, defined as elevated transaminases, during CCT in patients who are mono-infected with HCV compared with rates in controls matched on demographics, diagnosis, and rituximab use. We excluded patients with hepatobiliary cancers, hepatitis B virus or human immunodeficiency virus infection. Hepatotoxicity was attributed to a medical cause, cancer progression, or CCT, including HCV flare. RESULTS Patients with HCV (n = 196) had a higher rate of cirrhosis than the 1,130 matched controls (21.9% versus 4%; P <0.001). Their higher rate of overall hepatotoxicity (8.7% versus 4.5% of controls, P = 0.01) was due to higher rate of CCT-related hepatotoxicity (4.1% versus 1.2%, P = 0.01). On multivariable analysis, the largest risk factor for overall hepatotoxicity was cirrhosis, and the only risk factor for CCT-related hepatotoxicity was HCV infection. Among those with HCV, the only significant risk factor for hepatotoxicity was rituximab use. Hepatotoxicity caused by CCT delayed or altered treatment in only 3 HCV patients and 1 control (1.5% versus 0.1%, P = 0.01). CONCLUSIONS Most patients with HCV can safely be treated with cancer chemotherapy. Cirrhosis and HCV infection contributed to increased hepatotoxicity in subjects on CCT. Among HCV patients, rituximab use was the major risk factor for increased hepatotoxicity. Hepatotoxicity due to CCT itself rarely altered or delayed CCT. Nonetheless, HCV-positive patients should be monitored carefully during CCT.
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Affiliation(s)
| | - Lue-Yen Tucker
- Division of Research, Kaiser Permanente, Oakland, California, USA
| | - David M Baer
- Kaiser Permanente Medical Center, Oakland, California, USA
| | - Mary Pat Pauly
- Kaiser Permanente Medical Center, Sacramento, California, USA
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H. Alhowai A, Almogbel Y, A.H. Abdel A, A. Aldubay M, Alfheeaid HA, Felemban SG, Chigurupat S, F. Alharbi I, S. Alharbi H. Metformin Induced Cognitive Impairment and Neuroinflammation in CMF-Treated Rats. INT J PHARMACOL 2022. [DOI: 10.3923/ijp.2022.228.235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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van den Boogaard WMC, Komninos DSJ, Vermeij WP. Chemotherapy Side-Effects: Not All DNA Damage Is Equal. Cancers (Basel) 2022; 14:627. [PMID: 35158895 PMCID: PMC8833520 DOI: 10.3390/cancers14030627] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 02/04/2023] Open
Abstract
Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment and later in life they are frequently confronted with the severe negative side-effects of their life-saving treatment. The occurrence of numerous features of accelerated aging, seriously affecting quality of life, has now become one of the most pressing problems associated with (pediatric) cancer treatment. Chemotherapies frequently target and damage the DNA, causing mutations or genome instability, a major hallmark of both cancer and aging. However, there are numerous types of chemotherapeutic drugs that are genotoxic and interfere with DNA metabolism in different ways, each with their own biodistribution, kinetics, and biological fate. Depending on the type of DNA lesion produced (e.g., interference with DNA replication or RNA transcription), the organ or cell type inflicted (e.g., cell cycle or differentiation status, metabolic state, activity of clearance and detoxification mechanisms, the cellular condition or micro-environment), and the degree of exposure, outcomes of cancer treatment can largely differ. These considerations provide a conceptual framework in which different classes of chemotherapeutics contribute to the development of toxicities and accelerated aging of different organ systems. Here, we summarize frequently observed side-effects in (pediatric) ex-cancer patients and discuss which types of DNA damage might be responsible.
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Affiliation(s)
- Winnie M. C. van den Boogaard
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (W.M.C.v.d.B.); (D.S.J.K.)
- Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, The Netherlands
| | - Daphne S. J. Komninos
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (W.M.C.v.d.B.); (D.S.J.K.)
- Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, The Netherlands
| | - Wilbert P. Vermeij
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (W.M.C.v.d.B.); (D.S.J.K.)
- Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, The Netherlands
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Pondugula SR, Salamat JM, Abbott KL, Flannery PC, Majrashi M, Almaghrabi M, Govindarajulu M, Ramesh S, Sandey M, Onteru SK, Huang CCJ, Iwaki Y, Gill K, Narayanan N, McElroy E, Desai D, Nadar R, Moore T, Dhanasekaran M. A clinically relevant combination treatment with doxorubicin and cyclophosphamide does not induce hepatotoxicity in C57BL/6J mice. LIVER RESEARCH 2021; 5:239-242. [PMID: 34900377 PMCID: PMC8663913 DOI: 10.1016/j.livres.2021.04.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND AND AIM Chronic exposure to chemotherapeutics can lead to severe adverse events including hepatotoxicity. A combination chemotherapy regimen of doxorubicin (DOX) and cyclophosphamide (CPS) is employed in treatment of several cancers such as leukemia, lymphoma, and breast cancer. It is not well understood whether a combination therapy of DOX and CPS can induce hepatotoxicity. We therefore sought to determine whether co-administration of DOX and CPS at their clinically relevant doses and frequency results in hepatotoxicity. METHODS Male C57BL/6J mice received one intraperitoneal injection of saline or DOX-2mg /kg and CPS-50mg/kg once a week for 4 weeks. After the treatment period, liver histology and various serum biomarkers of hepatotoxicity were assessed. RESULTS Co-treatment of DOX and CPS did not alter the serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, albumin, globulin, or total protein. Similarly, co-administration of DOX and CPS did not result in a noticeable change in liver histology. However, it was notable that the concomitant treatment with DOX and CPS resulted in a significant increase in serum levels of aspartate aminotransferase (AST). Elevated serum AST levels were also associated with increased serum creatinine kinase (CK) levels, suggesting that the elevated serum AST levels are likely due to muscle injury following the co-administration of DOX and CPS. CONCLUSION Taken together, our results, for the first time, suggest that co-administration of DOX and CPS, at their clinically relevant doses and frequency does not induce a significant hepatotoxicity in the mice.
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Affiliation(s)
- Satyanarayana R Pondugula
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA,Corresponding Authors: Satyanarayana R. Pondugula, DVM, PhD, Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, Phone: 334-844-8505, Fax: 334-844-4542, , Muralikrishnan Dhanasekaran, M.Pharm., PG. DPM & IR, Ph.D, Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, , Phone: 334-844-8327
| | - Julia M Salamat
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Kodye L Abbott
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Patrick C Flannery
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Mohammed Majrashi
- Department of Pharmacology, Faculty of Medicine, University of Jeddah, Jeddah, Saudi Arabia,Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Mohammed Almaghrabi
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Manoj Govindarajulu
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Sindhu Ramesh
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Maninder Sandey
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL 36849, USA
| | - Suneel K Onteru
- Animal Biochemistry Division, National Dairy Research Institute, ICAR-NDRI, Karnal, Haryana 132001, India
| | - Chen-Che J Huang
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Yoshimi Iwaki
- Department of Clinical Science, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Kristina Gill
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Natasha Narayanan
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Edwin McElroy
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Darshini Desai
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Rishi Nadar
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Timothy Moore
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Muralikrishnan Dhanasekaran
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA,Corresponding Authors: Satyanarayana R. Pondugula, DVM, PhD, Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, Phone: 334-844-8505, Fax: 334-844-4542, , Muralikrishnan Dhanasekaran, M.Pharm., PG. DPM & IR, Ph.D, Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, , Phone: 334-844-8327
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Fuchs J, Murtha-Lemekhova A, Kessler M, Günther P, Fichtner A, Pfeiffenberger J, Probst P, Hoffmann K. Biliary Rhabdomyosarcoma in Pediatric Patients: A Systematic Review and Meta-Analysis of Individual Patient Data. Front Oncol 2021; 11:701400. [PMID: 34660271 PMCID: PMC8515851 DOI: 10.3389/fonc.2021.701400] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 09/14/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The biliary tree is a rare location of pediatric rhabdomyosarcoma. Due to the low incidence, there is a lack of evidence concerning therapeutic guidelines for this tumor location. In particular, the impact of surgery is discussed controversially. PURPOSE Objective is to generate evidence-based treatment guidelines for pediatric biliary rhabdomyosarcoma (BRMS). All available published data on therapeutic regimens and important prognostic factors are investigated with a focus on the role of surgery. METHODS A systematic literature search of MEDLINE, Web of Science, and CENTRAL was performed. Patient data were entered individually. Data was pooled and qualitative and quantitative analyses of demographic data, therapy, postoperative/interventional outcomes, relapse, and survival were conducted. In an individual patient data analysis, cox regression was applied to identify key factors predicting the outcome of patients with BRMS. RESULTS 65 studies met the inclusion criteria, providing data on 176 patients with BRMS. Individual patient data analysis showed a 5-year overall survival and progression-free survival of 51% and 50% for the total study population. For patients treated after 2000, 5-year OS and PFS was 65% and 59%, respectively. Absence of surgical tumor resection was an independent risk factor for death (Hazard ratio 8.9, 95%-CI 1.8-43.6, p = 0.007) and significantly associated with recurrent disease and disease-related death. CONCLUSION This analysis provides comprehensive information on the largest number of patients hitherto reported in the literature. BRMS is still associated with high morbidity and mortality. Surgical tumor resection is essential for appropriate oncological treatment of BRMS. International cooperation studies are needed to enhance evidence and improve the outcome of this orphan disease. PROTOCOL REGISTRATION PROSPERO (CRD42021228911) https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021228911.
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Affiliation(s)
- Juri Fuchs
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Anastasia Murtha-Lemekhova
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Markus Kessler
- Department of General, Visceral and Transplantation Surgery, Division of Pediatric Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Patrick Günther
- Department of General, Visceral and Transplantation Surgery, Division of Pediatric Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Alexander Fichtner
- Department of Pediatrics I, Division of Pediatric Gastroenterology, University Children's Hospital Heidelberg, Heidelberg, Germany
| | - Jan Pfeiffenberger
- Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Pascal Probst
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
- Study Center of the German Surgical Society (SDGC), University of Heidelberg, Heidelberg, Germany
| | - Katrin Hoffmann
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
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Kim J, Randhawa H, Sands D, Lambe S, Puglia M, Serrano PE, Pinthus JH. Muscle-Invasive Bladder Cancer in Patients with Liver Cirrhosis: A Review of Pertinent Considerations. Bladder Cancer 2021; 7:261-278. [PMID: 38993608 PMCID: PMC11181825 DOI: 10.3233/blc-211536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/09/2021] [Indexed: 11/15/2022]
Abstract
The incidence of liver cirrhosis is increasing worldwide. Patients with cirrhosis are generally at a higher risk of harbouring hepatic and non-hepatic malignancies, including bladder cancer, likely due to the presence of related risk factors such as smoking. Cirrhosis can complicate both the operative and non-surgical management of bladder cancer. For example, cirrhotic patients undergoing abdominal surgery generally demonstrate worse postoperative outcomes, and chemotherapy in patients with cirrhosis often requires dose reduction due to its direct hepatotoxic effects and reduced hepatic clearance. Multiple other considerations in the peri-operative management for cirrhosis patients with muscle-invasive bladder cancer must be taken into account to optimize outcomes in these patients. Unfortunately, the current literature specifically related to the treatment of cirrhotic bladder cancer patients remains sparse. We aim to review the literature on treatment considerations for this patient population with respect to perioperative, surgical, and adjuvant management.
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Affiliation(s)
- John Kim
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
| | | | - David Sands
- Division of Urology, McMaster University, Hamilton, ON, Canada
| | - Shahid Lambe
- Division of Urology, McMaster University, Hamilton, ON, Canada
- McMaster Institute of Urology, St. Joseph’s Hospital, Hamilton, ON, Canada
| | - Marco Puglia
- Juravinski Hospital and Cancer Centre, Hamilton, ON, Canada
| | | | - Jehonathan H. Pinthus
- Division of Urology, McMaster University, Hamilton, ON, Canada
- Juravinski Hospital and Cancer Centre, Hamilton, ON, Canada
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Nanocarriers as a Tool for the Treatment of Colorectal Cancer. Pharmaceutics 2021; 13:pharmaceutics13081321. [PMID: 34452282 PMCID: PMC8399070 DOI: 10.3390/pharmaceutics13081321] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/13/2021] [Accepted: 07/20/2021] [Indexed: 12/13/2022] Open
Abstract
Nanotechnology is a promising tool for the treatment of cancer. In the past decades, major steps have been made to bring nanotechnology into the clinic in the form of nanoparticle-based drug delivery systems. The great hope of drug delivery systems is to reduce the side effects of chemotherapeutics while simultaneously increasing the efficiency of the therapy. An increased treatment efficiency would greatly benefit the quality of life as well as the life expectancy of cancer patients. However, besides its many advantages, nanomedicines have to face several challenges and hurdles before they can be used for the effective treatment of tumors. Here, we give an overview of the hallmarks of cancer, especially colorectal cancer, and discuss biological barriers as well as how drug delivery systems can be utilized for the effective treatment of tumors and metastases.
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Mudd TW, Guddati AK. Management of hepatotoxicity of chemotherapy and targeted agents. Am J Cancer Res 2021; 11:3461-3474. [PMID: 34354855 PMCID: PMC8332851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/13/2021] [Indexed: 06/13/2023] Open
Abstract
Hepatotoxicity of chemotherapeutic agents such as methotrexate, oxaliplatin, and irinotecan have been well documented and characterized allowing for careful management by oncologists during administration. However, the rapid advance of the field of oncology and introduction of new classes of therapies such as small molecule inhibitors and immunotherapies have introduced new hepatotoxicity challenges and management strategies. This work is a compilation of the hepatotoxicity and recommended management of various chemotherapies and targeted agents, with a focus on the newer classes of targeted anticancer agents.
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Affiliation(s)
- Todd William Mudd
- Division of Hematology/Oncology, Georgia Cancer Center, Augusta University Augusta, GA 30912, USA
| | - Achuta Kumar Guddati
- Division of Hematology/Oncology, Georgia Cancer Center, Augusta University Augusta, GA 30912, USA
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Palmieri C, Macpherson IR. A review of the evidence base for utilizing Child-Pugh criteria for guiding dosing of anticancer drugs in patients with cancer and liver impairment. ESMO Open 2021; 6:100162. [PMID: 34098229 PMCID: PMC8190488 DOI: 10.1016/j.esmoop.2021.100162] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 04/12/2021] [Accepted: 05/05/2021] [Indexed: 12/24/2022] Open
Abstract
As the liver is vital for the metabolism of many anticancer drugs, determining the correct starting doses in cancer patients with liver impairment is key to safe prescription and prevention of unnecessary adverse effects. Clinicians typically use liver function tests when evaluating patients; however, prescribing information and summaries of product characteristics often suggest dosing of anticancer drugs in patients with liver impairment based on the Child-Pugh criteria, even though the criteria were not developed for this purpose. In this review, we assessed all the oncological small molecule and cytotoxic drugs approved by the United States Food and Drug Administration (FDA) over a 5-year period from 2014 to 2018. The various entry criteria related to these drugs—with respect to hepatic function—in key pivotal studies were compared with their approved dosing recommendations found in prescribing information and summaries of product characteristics. We found that 46% of drugs have dosing recommendations based on Child-Pugh criteria alone, despite the fact that only 8% of these drugs were tested within studies that used the Child-Pugh criteria as entry criteria. Moreover, we note that the data used to make recommendations based on Child-Pugh criteria are typically from small studies that may lack an appropriate patient population. We propose that these findings, along with details surrounding the development of the Child-Pugh criteria, call into question the validity and appropriateness of using Child-Pugh criteria for dosing recommendations of anticancer drugs.
Dosing information for anticancer drugs in patients with liver impairment is often based on the Child-Pugh criteria. Clinical trials and clinicians typically use liver function tests when evaluating patients. Of the 39 oncologic drugs examined, almost half (46%) had dosing recommendations based on Child-Pugh criteria alone. We question whether using Child-Pugh criteria for dosing recommendations of anticancer drugs is the best approach.
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Affiliation(s)
- C Palmieri
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK; Academic Department of Medical Oncology, The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK.
| | - I R Macpherson
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
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Corrias G, Erta M, Sini M, Sardu C, Saba L, Mahmood U, Huicochea Castellanos S, Bates D, Mondanelli N, Thomsen B, Carollo G, Sawan P, Mannelli L. Comparison of Multimaterial Decomposition Fat Fraction with DECT and Proton Density Fat Fraction with IDEAL IQ MRI for Quantification of Liver Steatosis in a Population Exposed to Chemotherapy. Dose Response 2021; 19:1559325820984938. [PMID: 33958978 PMCID: PMC8060765 DOI: 10.1177/1559325820984938] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/20/2020] [Accepted: 12/07/2020] [Indexed: 12/25/2022] Open
Abstract
INTRODUCTION Oncologic patients who develop chemotherapy-associated liver injury (CALI) secondary to chemotherapy treatment tend to have worse outcomes. Biopsy remains the gold standard for the diagnosis of hepatic steatosis. The purpose of this article is to compare 2 alternatives: Proton-Density-Fat-Fraction (PDFF) MRI and MultiMaterial-Decomposition (MMD) DECT. MATERIALS AND METHODS 49 consecutive oncologic patients treated with Chemotherapy underwent abdominal DECT and abdominal MRI within 2 weeks of each other. Two radiologists tracked Regions of Interest independently both in the PDFF fat maps and in the MMD DECT fat maps. Non-parametric exact Wilcoxon signed rank test and Cohen's K were used to compare the 2 sequences and to evaluate the agreement. RESULTS There was no statistically significant difference in the fat fraction measured as a continuous value between PDFF and DECT between 2 readers. Within the same imaging method (PDFF) the degree of agreement based on the k coefficient between reader 1 and reader 2 is 0.88 (p-value < 0.05). Similarly, for single-source DECT(ssDECT) the degree of agreement based on the k coefficient between reader 1 and reader 2 is 0.97 (p-value < 0.05). CONCLUSIONS The results of this study demonstrate that the hepatic fat fraction of ssDECT with MMD are not significantly different from PDFF. This could be an advantage in an oncological population that undergoes serial CT scans for follow up of chemotherapy response.
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Affiliation(s)
- Giuseppe Corrias
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Radiology, University of Cagliari, Italy
| | - Marco Erta
- Department of Radiology, University of Cagliari, Italy
| | - Marcello Sini
- Department of Radiology, University of Cagliari, Italy
| | - Claudia Sardu
- Department of Medical Science, University of Cagliari, Italy
| | - Luca Saba
- Department of Radiology, University of Cagliari, Italy
| | - Usman Mahmood
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - David Bates
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | | | | | - Peter Sawan
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- * Peter Sawan and Lorenzo Mannelli have contributed equally
| | - Lorenzo Mannelli
- IRCCS SDN, Napoli, Italy
- * Peter Sawan and Lorenzo Mannelli have contributed equally
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Patel R, Roberson J, Prakash D, Meyer R, Hogan L, Azmy C, Suprenant V, Ryu S, Stessin A. Potential alternative treatment approach for pediatric patient with diffusely infiltrative primary rhabdomyosarcoma of the liver. Rep Pract Oncol Radiother 2021; 26:143-148. [PMID: 34046225 PMCID: PMC8149128 DOI: 10.5603/rpor.a2021.0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 12/24/2020] [Indexed: 11/25/2022] Open
Abstract
Primary hepatic rhabdomyosarcoma is rare, making decisions regarding locoregional management with resection and/or conventional radiation difficult. We present a novel treatment approach for a pediatric patient diagnosed with rhabdomyosarcoma diffusely involving the liver. This patient underwent treatment with yttrium-90 (Y-90) microspheres followed by external beam radiation therapy (EBRT ) to residual disease, interdigitated with systemic chemotherapy. Initial post-radiation imaging showed significant response to treatment, and she experienced minimal acute toxicities and no long-term toxicities. She developed recurrent PET-avid disease 23 months after Y-90 treatment, necessitating further local and continued systemic therapies. We report on the tumor control following Y-90 and EBRT treatment.
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Affiliation(s)
- Rushil Patel
- Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, United States
| | - John Roberson
- Department of Radiation Oncology, Stony Brook University Hospital, Stony Brook, NY, United States
| | - Devina Prakash
- Division of Pediatric Hematology Oncology, Stony Brook Children’s Hospital, Stony Brook, NY, United States
| | - Rina Meyer
- Division of Pediatric Hematology Oncology, Stony Brook Children’s Hospital, Stony Brook, NY, United States
| | - Laura Hogan
- Division of Pediatric Hematology Oncology, Stony Brook Children’s Hospital, Stony Brook, NY, United States
| | - Christeen Azmy
- Division of Pediatric Hematology Oncology, Stony Brook Children’s Hospital, Stony Brook, NY, United States
| | - Valmore Suprenant
- Department of Radiology, Stony Brook University Hospital, Stony Brook, NY, United States
| | - Samuel Ryu
- Department of Radiation Oncology, Stony Brook University Hospital, Stony Brook, NY, United States
| | - Alexander Stessin
- Department of Radiation Oncology, Stony Brook University Hospital, Stony Brook, NY, United States
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Benedicto A, Sanz E, Márquez J. Ocoxin as a complement to first line treatments in cancer. Int J Med Sci 2021; 18:835-845. [PMID: 33437220 PMCID: PMC7797552 DOI: 10.7150/ijms.50122] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 11/25/2020] [Indexed: 12/18/2022] Open
Abstract
Chemotherapy and radiotherapy are the most frequent treatment for patients suffering from malignant progression of cancer. Even though new treatments are now being implemented, administration of these chemotherapeutic agents remains as the first line option in many tumor types. However, the secondary effects of these compounds represent one of the main reasons cancer patients lose life quality during disease progression. Recent data suggests that Ocoxin, a plant extract and natural compound based nutritional complement rich in antioxidants and anti-inflammatory mediators exerts a positive effect in patients receiving chemotherapy and radiotherapy. This mixture attenuates the chemotherapy and radiotherapy-related side effects such as radiation-induced skin burns and mucositis, chemotherapy-related diarrhea, hepatic toxicity and blood-infection. Moreover, it has been proven to be effective as anticancer agent in different tumor models both in vitro and in vivo, potentiating the cytotoxic effect of several chemotherapy compounds such as Lapatinib, Gemcitabine, Paclitaxel, Sorafenib and Irinotecan. The aim of this review is to put some light on the potential of this nutritional mixture as an anticancer agent and complement for the standard chemotherapy routine.
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Affiliation(s)
- Aitor Benedicto
- Department of Cellular Biology and Histology, School of Medicine and Nursing, University of the Basque Country, 48940, Leioa, Bizkaia, Spain
| | | | - Joana Márquez
- Department of Cellular Biology and Histology, School of Medicine and Nursing, University of the Basque Country, 48940, Leioa, Bizkaia, Spain
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Elmeliegy M, Yang DZ, Salama E, Parivar K, Wang DD. Discordance Between Child-Pugh and National Cancer Institute Classifications for Hepatic Dysfunction: Implications on Dosing Recommendations for Oncology Compounds. J Clin Pharmacol 2021; 61:105-115. [PMID: 32691438 PMCID: PMC7754409 DOI: 10.1002/jcph.1702] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 06/24/2020] [Indexed: 12/23/2022]
Abstract
Guidance from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency recommends using Child-Pugh classification for pharmacokinetic evaluation in noncancer subjects with hepatic impairment (HI). Therefore, dosing recommendations for oncology compounds for patients with HI are commonly based on Child-Pugh classification. In oncology clinical practice, National Cancer Institute classification (NCIc), is commonly used for evaluating hepatic function and dosing decisions for oncology patients. This work evaluated the discordance between the 2 systems and the impact on dosing recommendations. The classification system in HI studies was reviewed for FDA-approved oncology compounds. Discordance between Child-Pugh and NCIc was evaluated for sunitinib, dacomitinib, palbociclib, bosutinib, and axitinib. Pharmacokinetic (PK) analyses were conducted based on Child-Pugh classification and NCIc. Review of 117 approved oncology compounds showed prevalent use of Child-Pugh classification for dedicated HI studies in noncancer subjects. NCIc is commonly used in cancer patient studies. NCIc tended to classify subjects as less impaired versus Child-Pugh (64.9%, 73.7%, and 61.5% of subjects with mild, moderate, and severe HI, respectively, via Child-Pugh were classified as at least 1 category less impaired via NCIc). PK analyses by NCIc were consistent with Child-Pugh for sunitinib, dacomitinib, and palbociclib. For bosutinib, NCIc showed less impact of HI than Child-Pugh; an opposite trend was observed for axitinib. The impact of this considerable discordance between the 2 systems on dosing decisions bears consideration. When Child-Pugh is used for HI study enrollment, exploratory PK analyses based on NCIc should be conducted. Prescribers should attempt to use the same classification system in the product label for dosing decisions.
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Affiliation(s)
| | - Derek Z. Yang
- Global Product DevelopmentPfizer Inc.San DiegoCaliforniaUSA
- Skaggs School of Pharmacy & Pharmaceutical SciencesUniversity of California San DiegoSan DiegoCaliforniaUSA
| | - Engie Salama
- Global Product DevelopmentPfizer Inc.San DiegoCaliforniaUSA
- Skaggs School of Pharmacy & Pharmaceutical SciencesUniversity of California San DiegoSan DiegoCaliforniaUSA
| | | | - Diane D. Wang
- Global Product DevelopmentPfizer Inc.San DiegoCaliforniaUSA
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Martin J, Petrillo A, Smyth EC, Shaida N, Khwaja S, Cheow HK, Duckworth A, Heister P, Praseedom R, Jah A, Balakrishnan A, Harper S, Liau S, Kosmoliaptsis V, Huguet E. Colorectal liver metastases: Current management and future perspectives. World J Clin Oncol 2020; 11:761-808. [PMID: 33200074 PMCID: PMC7643190 DOI: 10.5306/wjco.v11.i10.761] [Citation(s) in RCA: 135] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/14/2020] [Accepted: 08/31/2020] [Indexed: 02/06/2023] Open
Abstract
The liver is the commonest site of metastatic disease for patients with colorectal cancer, with at least 25% developing colorectal liver metastases (CRLM) during the course of their illness. The management of CRLM has evolved into a complex field requiring input from experienced members of a multi-disciplinary team involving radiology (cross sectional, nuclear medicine and interventional), Oncology, Liver surgery, Colorectal surgery, and Histopathology. Patient management is based on assessment of sophisticated clinical, radiological and biomarker information. Despite incomplete evidence in this very heterogeneous patient group, maximising resection of CRLM using all available techniques remains a key objective and provides the best chance of long-term survival and cure. To this end, liver resection is maximised by the use of downsizing chemotherapy, optimisation of liver remnant by portal vein embolization, associating liver partition and portal vein ligation for staged hepatectomy, and combining resection with ablation, in the context of improvements in the functional assessment of the future remnant liver. Liver resection may safely be carried out laparoscopically or open, and synchronously with, or before, colorectal surgery in selected patients. For unresectable patients, treatment options including systemic chemotherapy, targeted biological agents, intra-arterial infusion or bead delivered chemotherapy, tumour ablation, stereotactic radiotherapy, and selective internal radiotherapy contribute to improve survival and may convert initially unresectable patients to operability. Currently evolving areas include biomarker characterisation of tumours, the development of novel systemic agents targeting specific oncogenic pathways, and the potential re-emergence of radical surgical options such as liver transplantation.
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Affiliation(s)
- Jack Martin
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Angelica Petrillo
- Department of Precision Medicine, Division of Medical Oncology, University of Campania "L. Vanvitelli", Napoli 80131, Italy, & Medical Oncology Unit, Ospedale del Mare, 80147 Napoli Italy
| | - Elizabeth C Smyth
- Department of Oncology, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Nadeem Shaida
- Department of Radiology, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB22 0QQ, United Kingdom
| | - Samir Khwaja
- Department of Radiology, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB22 0QQ, United Kingdom
| | - HK Cheow
- Department of Nuclear Medicine, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Adam Duckworth
- Department of Pathology, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Paula Heister
- Department of Pathology, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Raaj Praseedom
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Asif Jah
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Anita Balakrishnan
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Siong Liau
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Vasilis Kosmoliaptsis
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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Amaral RG, Gomes SVF, Andrade LN, dos Santos SA, Severino P, de Albuquerque Júnior RLC, Souto EB, Brandão GC, Santos SL, David JM, Carvalho AA. Cytotoxic, Antitumor and Toxicological Profile of Passiflora alata Leaf Extract. Molecules 2020; 25:molecules25204814. [PMID: 33092066 PMCID: PMC7587945 DOI: 10.3390/molecules25204814] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/08/2020] [Accepted: 10/15/2020] [Indexed: 12/14/2022] Open
Abstract
Passiflora alata or passion fruit is a native flowering plant from Amazon, geographically spread from Peru to Brazil. The plant has long been used in folks medicine for its pharmacological properties and is included in the Brazilian Pharmacopoeia since 1929. The aim of this study was to evaluate the potential cytotoxic and antitumor activities of Passiflora alata leaf extract (PaLE) in S180-tumor bearing mice. The percentage of cell proliferation inhibition (% CPI) and IC50 in relation to 4 tumor cell lines were determined in PC3, K-562, HepG2 and S180 cell lines using the MTT assay. PaLE showed a CPI > 75% and greater potency (IC50 < 30 µg/mL) against PC3 and S180 cell lines. PaLE showed antitumor activity in treatments intraperitoneally (36.75% and 44.99% at doses of 100 and 150 mg/kg/day, respectively). Toxicological changes were shown in the reduced body mass associated with reduced food consumption, increased spleen mass associated with histopathological increase in the white pulp of the spleen and increased number of total leukocytes with changes in the percentage relationship between lymphocytes and neutrophils. Our outcomes corroborate the conclusion that PaLE has antitumor activity in vitro and in vivo with low toxicity.
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Affiliation(s)
- Ricardo G. Amaral
- Department of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe 49100-000, Brazil; (R.G.A.); (S.A.d.S.); (S.L.S.)
| | - Silvana V. F. Gomes
- Institute of Technology and Research, University of Tiradentes, Aracaju, Sergipe 49032-490, Brazil; (S.V.F.G.); (P.S.); (R.L.C.d.A.J.)
| | - Luciana N. Andrade
- Department of Medicine, Federal University of Sergipe (UFS), Avenida Governador Marcelo Déda, Lagarto-SE 49400-000, Brazil
- Correspondence: (L.N.A.); (E.B.S.); (A.A.C.)
| | - Sara A. dos Santos
- Department of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe 49100-000, Brazil; (R.G.A.); (S.A.d.S.); (S.L.S.)
| | - Patrícia Severino
- Institute of Technology and Research, University of Tiradentes, Aracaju, Sergipe 49032-490, Brazil; (S.V.F.G.); (P.S.); (R.L.C.d.A.J.)
- Center for Biomedical Engineering, Department of Medicine, Brigham and Women′s Hospital, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA
- Tiradentes Institute, 150 Mt Vernon St, Dorchester, MA 02125, USA
| | | | - Eliana B. Souto
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
- CEB—Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
- Correspondence: (L.N.A.); (E.B.S.); (A.A.C.)
| | - Geraldo C. Brandão
- Department of Pharmacy, Federal University of Ouro Preto, Ouro Preto 78950-000, Brazil;
| | - Sandra L. Santos
- Department of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe 49100-000, Brazil; (R.G.A.); (S.A.d.S.); (S.L.S.)
| | - Jorge M. David
- Institute of Chemistry, Federal University of Bahia, Salvador 40000-000, Brazil;
| | - Adriana A. Carvalho
- Department of Medicine, Federal University of Sergipe (UFS), Avenida Governador Marcelo Déda, Lagarto-SE 49400-000, Brazil
- Correspondence: (L.N.A.); (E.B.S.); (A.A.C.)
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Stankovic JSK, Selakovic D, Mihailovic V, Rosic G. Antioxidant Supplementation in the Treatment of Neurotoxicity Induced by Platinum-Based Chemotherapeutics-A Review. Int J Mol Sci 2020; 21:E7753. [PMID: 33092125 PMCID: PMC7589133 DOI: 10.3390/ijms21207753] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 10/10/2020] [Accepted: 10/16/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer represents one of the most pernicious public health problems with a high mortality rate among patients worldwide. Chemotherapy is one of the major therapeutic approaches for the treatment of various malignancies. Platinum-based drugs (cisplatin, oxaliplatin, carboplatin, etc.) are highly effective chemotherapeutic drugs used for the treatment of several types of malignancies, but their application and dosage are limited by their toxic effects on various systems, including neurotoxicity. Simultaneously, researchers have tried to improve the survival rate and quality of life of cancer patients and decrease the toxicity of platinum-containing drugs by combining them with non-chemotherapy-based drugs, dietary supplements and/or antioxidants. Additionally, recent studies have shown that the root cause for the many side effects of platinum chemotherapeutics involves the production of reactive oxygen species (ROS) in naive cells. Therefore, suppression of ROS generation and their inactivation with antioxidants represents an appropriate approach for platinum drug-induced toxicities. The aim of this paper is to present an updated review of the protective effects of different antioxidant agents (vitamins, dietary antioxidants and supplements, medicaments, medicinal plants and their bioactive compounds) against the neurotoxicity induced by platinum-based chemotherapeutics. This review highlights the high potential of plant antioxidants as adjuvant strategies in chemotherapy with platinum drugs.
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Affiliation(s)
- Jelena S. Katanic Stankovic
- Institute for Information Technologies Kragujevac, Department of Science, University of Kragujevac, Jovana Cvijica bb, 34000 Kragujevac, Serbia;
| | - Dragica Selakovic
- Faculty of Medical Sciences, Department of Physiology, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia;
| | - Vladimir Mihailovic
- Faculty of Science, Department of Chemistry, University of Kragujevac, Radoja Domanovica 12, 34000 Kragujevac, Serbia
| | - Gvozden Rosic
- Faculty of Medical Sciences, Department of Physiology, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia;
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Kanji S, MacLean E, Rashid FJ, Pittman M, Trinacty M, Allan D, Rosenberg E. Chemotherapy in the Intensive Care Unit: An Evaluation of Context and Outcomes. Can J Hosp Pharm 2020; 73:279-287. [PMID: 33100360 PMCID: PMC7556399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
BACKGROUND Administration of chemotherapy to highly vulnerable, critically ill patients in the intensive care unit (ICU) is becoming more common, but the process requires significantly more resources than chemotherapy administration in specialized oncology settings. OBJECTIVE To describe the context, complications, and outcomes of chemotherapy administration for cancer-related indications in ICU patients. METHODS For this retrospective observational study, consecutive patients receiving parenteral chemotherapy in the ICU at the General Campus of The Ottawa Hospital between January 1, 2014, and December 31, 2017, were identified using pharmacy records. The clinical characteristics of these patients, details of their chemotherapy regimens, and outcomes were analyzed. RESULTS A total of 32 patients were included in the study. Of these, 27 patients (84%) had a hematological malignancy, 16 (50%) had a documented infection at the time of chemotherapy administration, and 29 (91%) received their first cycle of chemotherapy on an urgent basis during the ICU admission rather than as a scheduled or planned treatment. Severity of illness was high both at ICU admission and at the time of chemotherapy treatment; regimen modifications, drug interactions, and adverse events were common. Remission and survival data were available for 28 patients at 12 months. Eighteen (56%) of the 32 patients survived to hospital discharge, and 12 (38%) survived to 6 months; at 12 months, survival was 25% (7 of 28 patients with available data). About one-quarter of the patients were in remission at 6 and 12 months. CONCLUSION Administering chemotherapy in the ICU is feasible, but the process is resource-intensive. Patients with aggressive hematological cancers who require treatment on an urgent basis represent the most commonly observed scenario. This study highlights the complexity of management and the importance of multidisciplinary care teams for this patient population.
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Affiliation(s)
- Salmaan Kanji
- , PharmD, is with The Ottawa Hospital and the Ottawa Hospital Research Institute, Ottawa, Ontario
| | - Erica MacLean
- , BScPharm, is with The Ottawa Hospital, Ottawa, Ontario
| | | | | | | | - David Allan
- , MD, FRCPC, is with The Ottawa Hospital and the Ottawa Hospital Research Institute, Ottawa, Ontario
| | - Erin Rosenberg
- , MD, MHA, FRCPC, is with The Ottawa Hospital, Ottawa, Ontario
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Abstract
Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.
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Durymanov M, Permyakova A, Reineke J. Pre-treatment With PLGA/Silibinin Nanoparticles Mitigates Dacarbazine-Induced Hepatotoxicity. Front Bioeng Biotechnol 2020; 8:495. [PMID: 32671024 PMCID: PMC7332747 DOI: 10.3389/fbioe.2020.00495] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 04/28/2020] [Indexed: 12/02/2022] Open
Abstract
Drug-induced hepatotoxicity is one of the major barriers limiting application of current pharmaceuticals as well as clinical translation of novel and perspective drugs. In this context, numerous hepatoprotective molecules have been proposed to prevent or mitigate drug-induced hepatotoxicity. To date, silibinin (SBN) is a one the most studied hepatoprotective plant-derived agents for prevention/alleviation of drug-induced liver injury. Hepatoprotective mechanisms of SBN include scavenging of free radicals, upregulation of detoxifying enzymes via Nrf2 activation and inhibition of inflammatory activation of resident macrophages. However, low solubility of this phytochemical in water prevents its intravenous administration and constrains its bioavailability and efficacy. Here, we developed SBN-loaded poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles for intravenous administration aiming at mitigation of drug-induced hepatotoxicity. Obtained nanoparticles demonstrated a slow drug release profile in vitro and caused upregulation of antioxidant and phase II enzymes in AML12 hepatocytes including superoxide dismutase 2, glutathione-S-transferase P1, and glutathione-reductase. Intravenous administration of PLGA nanoparticles to mice led to their fast liver accumulation. In vivo analysis of hepatoprotective effects of PLGA/SBN nanoparticles was carried out on melanoma tumor-bearing syngeneic mouse model treated with the antineoplastic drug dacarbazine (DTIC), which often causes severe hepatotoxicity including development of veno-occlusive disease. It was found that PLGA/SBN caused effective induction of detoxifying liver enzymes. Moreover, pre-treatment with PLGA/SBN nanoparticles reduced elevated transaminase and bilirubin levels in blood, caspase 3 activation, and morphological histology changes in liver tissue upon DTIC treatment. Treatment with PLGA/SBN nanoparticles did not interfere with therapeutic efficacy of DTIC.
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Affiliation(s)
- Mikhail Durymanov
- Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD, United States.,Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Anastasia Permyakova
- Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD, United States
| | - Joshua Reineke
- Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD, United States
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Cavalcanti ID, Costa DT, de Aguiar Silva AT, Peres AL, de Oliveira Coimbra CG. Importance of Pharmacist in Oxaliplatin Hepatotoxicity Associated with Inadequate Nutritional Diet: Case Report. CURRENT NUTRITION & FOOD SCIENCE 2020. [DOI: 10.2174/1573401316666200120110632] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
A 40 years old male with colorectal cancer, with an unbalanced hypercaloric diet, attempted, on his own initiative, to gain weight, without nutritional follow-up, during chemotherapy treatment with oxaliplatin protocols, without pharmaceutical guidance. When initiating the new protocol, with oxaliplatin/irinotecan combination therapy, he presented symptomatology suggestive of hepatic injury during the administration of oxaliplatin. When performing a Magnetic Resonance Imaging of the total abdomen, hepatic nodules were identified indicating lesions resulting from the chemotherapy treatment, and blood tests indicated Aspartate aminotransferase levels in 55 U/L and Alanine aminotransferase in 68 U/L. The patient underwent partial hepatectomy for the removal of the nodules and was currently in clinical care, presenting a frame stable but non-therapeutic possibility. This case highlights the importance of interaction among health professionals, reinforcing the need for multiprofessional approaches to better patient response to antineoplastic treatment.
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Affiliation(s)
- Iago D.L. Cavalcanti
- Resident Pharmacist at the University Center Tabosa de Almeida, ASCES/UNITA, Caruaru, Pernambuco, Brazil
| | - Diogo T. Costa
- Resident Nurse at the University Center Tabosa de Almeida, ASCES/UNITA, Caruaru, Pernambuco, Brazil
| | - Andreza T. de Aguiar Silva
- Resident Nutritionist at the University Center Tabosa de Almeida, ASCES/UNITA, Caruaru, Pernambuco, Brazil
| | - Adrya L. Peres
- Lecturer at the University Center Tabosa de Almeida, ASCES/UNITA, Caruaru, Pernambuco, Brazil
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Quagliariello V, Vecchione R, De Capua A, Lagreca E, Iaffaioli RV, Botti G, Netti PA, Maurea N. Nano-Encapsulation of Coenzyme Q10 in Secondary and Tertiary Nano-Emulsions for Enhanced Cardioprotection and Hepatoprotection in Human Cardiomyocytes and Hepatocytes During Exposure to Anthracyclines and Trastuzumab. Int J Nanomedicine 2020; 15:4859-4876. [PMID: 32764923 PMCID: PMC7359894 DOI: 10.2147/ijn.s245170] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 04/18/2020] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION CoenzymeQ10 (CoQ10) is a well-known antioxidant and anti-inflammatory agent with cardioprotective properties. However, clinical trials based on its oral administration have failed to provide significant effect on cardiac functionality. The main limitation of CoQ10 is based on its very low oral bioavailability and instability that limit dramatically its effects as a cardioprotective agent. Herein, we loaded CoQ10 in high bioavailable nano-emulsions (NEs) coated with chitosan or chitosan and hyaluronic acid in order to improve its performance. METHODS We tested cardioprotective and hepatoprotective effects of CoQ10-loaded nano-carriers against Doxorubicin and Trastuzumab toxicities in cardiomyocytes and liver cells through analysis of cell viability, lipid peroxidation, expression of leukotrienes, p65/NF-kB and pro-inflammatory cytokines involved in anticancer-induced cardio and hepatotoxicity. RESULTS Nano-carriers showed high stability and loading ability and increased cell viability both in hepatocytes and cardiomyocytes during anticancer treatments. We observed that these effects are mediated by the inhibition of lipid peroxidation and reduction of the inflammation. CoQ10-loaded nano-emulsions showed also strong anti-inflammatory effects reducing leukotriene B4 and p65/NF-κB expression and Interleukin 1β and 6 production during anticancer treatments. DISCUSSION Anthracyclines and Human epidermal growth factor receptor (HER2) inhibitors have shown significant anticancer effects in clinical practice but their use is characterized by cardiotoxicity and hepatotoxicity. Nano-carriers loaded with CoQ10 showed cardio and hepatoprotective properties mediated by reduction of oxidative damages and pro-inflammatory mediators. These results set the stage for preclinical studies of cardio and hepatoprotection in HER2+ breast cancer-bearing mice treated with Doxorubicin and Trastuzumab.
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Affiliation(s)
- Vincenzo Quagliariello
- Division of Cardiology, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, Napoli, Italia
| | - Raffaele Vecchione
- Center for Advanced Biomaterial for Health Care (CABHC), Istituto Italiano di Tecnologia, Largo Barsanti e Matteucci 53, Naples, Italy
| | - Alberta De Capua
- Center for Advanced Biomaterial for Health Care (CABHC), Istituto Italiano di Tecnologia, Largo Barsanti e Matteucci 53, Naples, Italy
| | - Elena Lagreca
- Center for Advanced Biomaterial for Health Care (CABHC), Istituto Italiano di Tecnologia, Largo Barsanti e Matteucci 53, Naples, Italy
| | | | - Gerardo Botti
- Scientific Direction, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, Napoli, Italia
| | - Paolo A Netti
- Center for Advanced Biomaterial for Health Care (CABHC), Istituto Italiano di Tecnologia, Largo Barsanti e Matteucci 53, Naples, Italy
| | - Nicola Maurea
- Division of Cardiology, Istituto Nazionale Tumori- IRCCS- Fondazione G. Pascale, Napoli, Italia
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