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Kumar S, Koseki Y, Tanita K, Shibata A, Mizutani A, Kasai H. SN-38-indoximod conjugate: carrier free nano-prodrug for cancer therapy. Ther Deliv 2025; 16:217-226. [PMID: 39887189 PMCID: PMC11875466 DOI: 10.1080/20415990.2025.2458449] [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: 10/21/2024] [Accepted: 01/22/2025] [Indexed: 02/01/2025] Open
Abstract
BACKGROUND The integration of immunotherapy alongside chemotherapy represents a crucial approach in the treatment of cancer. Herein we report the SN-38-indoximod conjugate nano-prodrug to address the difficulties encountered by individuals. In this prodrug, SN-38 is connected to indoximod through a specific disulfide linker, which enables the release of the components in response to the tumor microenvironment characterized by elevated levels of glutathione, thereby facilitating programmed chemoimmunotherapy. RESULTS SN-38-indoximod conjugate was synthesized and fabricated to nano-prodrug by reprecipitation method. It showed comparable anti-cancer activity against A549 cells than SN-38 (IC50 = 0.24 ± 0.01 µM) with IC50 value 0.32 ± 0.04 µM. It inhibited 90% A549 cell at very lower concentration (IC90 = 6.07 ± 0.41 µM) as compared with SN-38 (IC90 = 24.60 ± 1.24 µM) and mixture of SN-38: indoximod (1:1, IC90 >30 µM). The nano-prodrug showed better size distribution profile and dispersion stability contains nanoparticles in effective size range (80-160 nm) required for the EPR effect. CONCLUSION This research offers valuable insights into the advancement of conjugate nano-prodrugs exhibiting synergistic pharmacological effects, while also presenting novel opportunities for the design of prodrug molecules capable of releasing drugs in response to diverse triggers.
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Affiliation(s)
- Sanjay Kumar
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Japan
| | - Yoshitaka Koseki
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Japan
| | - Keita Tanita
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Japan
| | - Aki Shibata
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Japan
| | - Asuka Mizutani
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Japan
| | - Hitoshi Kasai
- Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Japan
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Krishnamurthy A, Wang H, Rhee JC, Davar D, Moy RH, Ratner L, Christner SM, Holleran JL, Deppas J, Sclafani C, Schmitz JC, Gore S, Chu E, Bakkenist CJ, Beumer JH, Villaruz LC. Phase I trial of ATR inhibitor elimusertib with FOLFIRI in advanced or metastatic gastrointestinal malignancies (ETCTN 10406). Cancer Chemother Pharmacol 2025; 95:27. [PMID: 39841295 DOI: 10.1007/s00280-024-04745-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 12/19/2024] [Indexed: 01/23/2025]
Abstract
BACKGROUND ATR is an apical DDR kinase activated at damaged replication forks. Elimusertib is an oral ATR inhibitor and potentiates irinotecan in human colorectal cancer models. METHODS To establish dose and tolerability of elimusertib with FOLFIRI, a Bayesian Optimal Interval trial design was pursued. Starting elimusertib dose was 20 mg BID days 1, 2, 15 and 16 every 28-day cycle, combined with irinotecan (150 mg/m2) and 5-FU (2000 mg/m2). RESULTS The trial was stopped after 10 accruals, with four DLT across 4 dose levels including grade 3 febrile neutropenia, mucositis, nausea, vomiting and grade 4 neutropenia. The most common grade 3/4 adverse events were neutropenia, leukopenia, lymphopenia and mucositis. Based on significant toxicities the trial was stopped. PK data for 5-FU and irinotecan were unremarkable and did not account for DLTs. Among the six response evaluable patients, four had stable disease as their best response. Median PFS was 7 months. A first case of ATRi chemotherapy combination related AML (t-AML) was observed. CONCLUSIONS The combination of elimusertib with FOLFIRI was associated with intolerable toxicity. Combination of ATR kinases with chemotherapies that target DNA replication may be associated with significant myelotoxicity. Ongoing ATRi trials should monitor for t-AML. CLINICALTRIALS GOV ID NCT04535401.
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Affiliation(s)
- Anuradha Krishnamurthy
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Hong Wang
- Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - John C Rhee
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Diwakar Davar
- Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ryan H Moy
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA
| | - Lee Ratner
- Division of Oncology, Washington University School of Medicine, St Louis, MO, USA
| | - Susan M Christner
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Julianne L Holleran
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Joshua Deppas
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA
| | - Carina Sclafani
- Department of Radiation Oncology, School of Medicine, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - John C Schmitz
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Steve Gore
- Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
| | - Edward Chu
- Montefiore Einstein Cancer Canter, Bronx, NY, USA
| | - Christopher J Bakkenist
- Department of Radiation Oncology, School of Medicine, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jan H Beumer
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
- Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
- University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Room G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA.
| | - Liza C Villaruz
- Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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González NS, Marchese PV, Baraibar I, Ros J, Salvà F, Rodríguez M, Salvà C, Vaghi C, Alcaraz A, García A, Tabernero J, Élez E. Epidermal growth factor receptor antagonists in colorectal cancer: emerging strategies for precision therapy. Expert Opin Investig Drugs 2024; 33:613-625. [PMID: 38775361 DOI: 10.1080/13543784.2024.2349287] [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: 02/23/2024] [Accepted: 04/25/2024] [Indexed: 06/25/2024]
Abstract
INTRODUCTION The global prevalence of colorectal cancer highlights the need to enhance treatment strategies for improved patient outcomes. The pivotal role of epidermal growth factor receptor (EGFR) signaling in regulating cellular processes for this disease pinpoints its value as a therapeutic target, despite the emergence of resistance mechanisms over time. AREAS COVERED This review discusses the clinical evidence supporting the use of EGFR inhibitors in molecularly-selected patients based on molecular characteristics (notably BRAF V600E and KRAS G12C) including combination approaches targeting different points in in the signaling pathway, as well as strategies such as EGFR inhibitor rechallenge. The role of HER2 inhibitors and emerging approaches such as bispecific antibodies are also reviewed. EXPERT OPINION Recently, inhibitors targeting the KRAS G12C variant have emerged, albeit with modest monotherapy activity compared to other tumor types, emphasizing the influence of histologic origins on the EGFR signaling pathway. Integration of EGFR inhibitors into precision medicine has facilitated tailored therapies addressing resistance mechanisms. Patient selection for EGFR inhibitor rechallenge guided by ctDNA findings is crucial, with ongoing investigations exploring novel combinations to enhance EGFR blockade, highlighting the transformative potential of precision medicine in shaping the future of mCRC treatment toward personalized and targeted approaches.
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Affiliation(s)
- Nadia Saoudi González
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | | | - Iosune Baraibar
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Javier Ros
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Francesc Salvà
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Marta Rodríguez
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Clara Salvà
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Caterina Vaghi
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Adriana Alcaraz
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Ariadna García
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Josep Tabernero
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Elena Élez
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
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Gall L, Duckworth C, Jardi F, Lammens L, Parker A, Bianco A, Kimko H, Pritchard DM, Pin C. Homeostasis, injury, and recovery dynamics at multiple scales in a self-organizing mouse intestinal crypt. eLife 2023; 12:e85478. [PMID: 38063302 PMCID: PMC10789491 DOI: 10.7554/elife.85478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 12/07/2023] [Indexed: 01/16/2024] Open
Abstract
The maintenance of the functional integrity of the intestinal epithelium requires a tight coordination between cell production, migration, and shedding along the crypt-villus axis. Dysregulation of these processes may result in loss of the intestinal barrier and disease. With the aim of generating a more complete and integrated understanding of how the epithelium maintains homeostasis and recovers after injury, we have built a multi-scale agent-based model (ABM) of the mouse intestinal epithelium. We demonstrate that stable, self-organizing behaviour in the crypt emerges from the dynamic interaction of multiple signalling pathways, such as Wnt, Notch, BMP, ZNRF3/RNF43, and YAP-Hippo pathways, which regulate proliferation and differentiation, respond to environmental mechanical cues, form feedback mechanisms, and modulate the dynamics of the cell cycle protein network. The model recapitulates the crypt phenotype reported after persistent stem cell ablation and after the inhibition of the CDK1 cycle protein. Moreover, we simulated 5-fluorouracil (5-FU)-induced toxicity at multiple scales starting from DNA and RNA damage, which disrupts the cell cycle, cell signalling, proliferation, differentiation, and migration and leads to loss of barrier integrity. During recovery, our in silico crypt regenerates its structure in a self-organizing, dynamic fashion driven by dedifferentiation and enhanced by negative feedback loops. Thus, the model enables the simulation of xenobiotic-, in particular chemotherapy-, induced mechanisms of intestinal toxicity and epithelial recovery. Overall, we present a systems model able to simulate the disruption of molecular events and its impact across multiple levels of epithelial organization and demonstrate its application to epithelial research and drug development.
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Affiliation(s)
- Louis Gall
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZenecaCambridgeUnited Kingdom
| | - Carrie Duckworth
- Institute of Systems, Molecular and Integrative Biology, University of LiverpoolLiverpoolUnited Kingdom
| | - Ferran Jardi
- Preclinical Sciences and Translational Safety, JanssenBeerseBelgium
| | - Lieve Lammens
- Preclinical Sciences and Translational Safety, JanssenBeerseBelgium
| | - Aimee Parker
- Gut Microbes and Health Programme, Quadram InstituteNorwichUnited Kingdom
| | - Ambra Bianco
- Clinical Pharmacology and Safety Sciences, AstraZenecaCambridgeUnited Kingdom
| | - Holly Kimko
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZenecaCambridgeUnited Kingdom
| | - David Mark Pritchard
- Institute of Systems, Molecular and Integrative Biology, University of LiverpoolLiverpoolUnited Kingdom
| | - Carmen Pin
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZenecaCambridgeUnited Kingdom
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Schmutz C, Will F, Varga E, Jaunecker C, Pahlke G, Berger W, Marko D. In Vitro Inhibitory Potential of Different Anthocyanin-Rich Berry Extracts in Murine CT26 Colon Cancer Cells. Molecules 2023; 28:7684. [PMID: 38067418 PMCID: PMC10707341 DOI: 10.3390/molecules28237684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/15/2023] [Accepted: 11/19/2023] [Indexed: 12/18/2023] Open
Abstract
Anti-oxidant, -inflammatory, and -carcinogenic activities of bioactive plant constituents, such as anthocyanins, have been widely discussed in literature. However, the potential interaction of anthocyanin-rich extracts with routinely used chemotherapeutics is still not fully elucidated. In the present study, anthocyanin-rich polyphenol extracts of blackberry (BB), bilberry (Bil), black currant (BC), elderberry (EB), and their respective main anthocyanins (cyanidin-3-O-glucoside, delphinidin-3-O-glucoside, cyanidin-3-O-rutinoside, and cyanidin-3-O-sambubioside) were investigated concerning their cytotoxic and DNA-damaging properties in murine CT26 cells either alone or in combination with the chemotherapeutic agent SN-38. BB exerted potent cytotoxic effects, while Bil, BC, and EB only had marginal effects on cell viability. Single anthocyanins comprised of the extracts could not induce comparable effects. Even though the BB extract further pronounced SN-38-induced cytotoxicity and inhibited cell adhesion at 100-200 µg/mL, no effect on DNA damage was observed. In conclusion, anti-carcinogenic properties of the extracts on CT26 cells could be ranked BB >> BC ≥ Bil ≈ EB. Mechanisms underlying the potent cytotoxic effects are still to be elucidated since the induction of DNA damage does not play a role.
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Affiliation(s)
- Cornelia Schmutz
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währingerstraße 38-40, 1090 Vienna, Austria; (C.S.); (E.V.); (G.P.)
- Doctoral School in Chemistry, University of Vienna, Währingerstraße 42, 1090 Vienna, Austria
| | - Frank Will
- Department of Beverage Research, Hochschule Geisenheim University, P.O. Box 1154, 65366 Geisenheim, Germany;
| | - Elisabeth Varga
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währingerstraße 38-40, 1090 Vienna, Austria; (C.S.); (E.V.); (G.P.)
| | - Carola Jaunecker
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria; (C.J.); (W.B.)
| | - Gudrun Pahlke
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währingerstraße 38-40, 1090 Vienna, Austria; (C.S.); (E.V.); (G.P.)
| | - Walter Berger
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria; (C.J.); (W.B.)
| | - Doris Marko
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währingerstraße 38-40, 1090 Vienna, Austria; (C.S.); (E.V.); (G.P.)
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Gall L, Jardi F, Lammens L, Piñero J, Souza TM, Rodrigues D, Jennen DGJ, de Kok TM, Coyle L, Chung S, Ferreira S, Jo H, Beattie KA, Kelly C, Duckworth CA, Pritchard DM, Pin C. A dynamic model of the intestinal epithelium integrates multiple sources of preclinical data and enables clinical translation of drug-induced toxicity. CPT Pharmacometrics Syst Pharmacol 2023; 12:1511-1528. [PMID: 37621010 PMCID: PMC10583244 DOI: 10.1002/psp4.13029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 07/13/2023] [Accepted: 07/17/2023] [Indexed: 08/26/2023] Open
Abstract
We have built a quantitative systems toxicology modeling framework focused on the early prediction of oncotherapeutic-induced clinical intestinal adverse effects. The model describes stem and progenitor cell dynamics in the small intestinal epithelium and integrates heterogeneous epithelial-related processes, such as transcriptional profiles, citrulline kinetics, and probability of diarrhea. We fitted a mouse-specific version of the model to quantify doxorubicin and 5-fluorouracil (5-FU)-induced toxicity, which included pharmacokinetics and 5-FU metabolism and assumed that both drugs led to cell cycle arrest and apoptosis in stem cells and proliferative progenitors. The model successfully recapitulated observations in mice regarding dose-dependent disruption of proliferation which could lead to villus shortening, decrease of circulating citrulline, increased diarrhea risk, and transcriptional induction of the p53 pathway. Using a human-specific epithelial model, we translated the cytotoxic activity of doxorubicin and 5-FU quantified in mice into human intestinal injury and predicted with accuracy clinical diarrhea incidence. However, for gefitinib, a specific-molecularly targeted therapy, the mice failed to reproduce epithelial toxicity at exposures much higher than those associated with clinical diarrhea. This indicates that, regardless of the translational modeling approach, preclinical experimental settings have to be suitable to quantify drug-induced clinical toxicity with precision at the structural scale of the model. Our work demonstrates the usefulness of translational models at early stages of the drug development pipeline to predict clinical toxicity and highlights the importance of understanding cross-settings differences in toxicity when building these approaches.
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Affiliation(s)
- Louis Gall
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&DAstraZenecaCambridgeUK
| | - Ferran Jardi
- Preclinical Sciences & Translational SafetyJanssen Pharmaceutica NVBeerseBelgium
| | - Lieve Lammens
- Preclinical Sciences & Translational SafetyJanssen Pharmaceutica NVBeerseBelgium
| | - Janet Piñero
- Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM)UPFBarcelonaSpain
| | - Terezinha M. Souza
- Department of Toxicogenomics, GROW School for Oncology and Developmental BiologyMaastricht UniversityMaastrichtThe Netherlands
| | - Daniela Rodrigues
- Department of Toxicogenomics, GROW School for Oncology and Developmental BiologyMaastricht UniversityMaastrichtThe Netherlands
| | - Danyel G. J. Jennen
- Department of Toxicogenomics, GROW School for Oncology and Developmental BiologyMaastricht UniversityMaastrichtThe Netherlands
| | - Theo M. de Kok
- Department of Toxicogenomics, GROW School for Oncology and Developmental BiologyMaastricht UniversityMaastrichtThe Netherlands
| | - Luke Coyle
- Boehringer Ingelheim International GmbHRidgefieldConnecticutUSA
| | | | | | - Heeseung Jo
- Simcyp DivisionCertara UK LimitedSheffieldUK
| | - Kylie A. Beattie
- Target and Systems Safety, Non‐Clinical Safety, In Vivo/In Vitro TranslationGSKStevenageUK
| | - Colette Kelly
- Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Carrie A. Duckworth
- Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - D. Mark Pritchard
- Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Carmen Pin
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&DAstraZenecaCambridgeUK
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Bré J, Dickson AL, Read OJ, Zhang Y, McKissock FG, Mullen P, Tang P, Zickuhr GM, Czekster CM, Harrison DJ. The novel anti-cancer fluoropyrimidine NUC-3373 is a potent inhibitor of thymidylate synthase and an effective DNA-damaging agent. Cancer Chemother Pharmacol 2023; 91:401-412. [PMID: 37000221 PMCID: PMC10156769 DOI: 10.1007/s00280-023-04528-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 03/17/2023] [Indexed: 04/01/2023]
Abstract
INTRODUCTION Fluoropyrimidines, principally 5-fluorouracil (5-FU), remain a key component of chemotherapy regimens for multiple cancer types, in particular colorectal and other gastrointestinal malignancies. To overcome key limitations and pharmacologic challenges that hinder the clinical utility of 5-FU, NUC-3373, a phosphoramidate transformation of 5-fluorodeoxyuridine, was designed to improve the efficacy and safety profile as well as the administration challenges associated with 5-FU. METHODS Human colorectal cancer cell lines HCT116 and SW480 were treated with sub-IC50 doses of NUC-3373 or 5-FU. Intracellular activation was measured by LC-MS. Western blot was performed to determine binding of the active anti-cancer metabolite FdUMP to thymidylate synthase (TS) and DNA damage. RESULTS We demonstrated that NUC-3373 generates more FdUMP than 5-FU, resulting in a more potent inhibition of TS, DNA misincorporation and subsequent cell cycle arrest and DNA damage in vitro. Unlike 5-FU, the thymineless death induced by NUC-3373 was rescued by the concurrent addition of exogenous thymidine. 5-FU cytotoxicity, however, was only reversed by supplementation with uridine, a treatment used to reduce 5-FU-induced toxicities in the clinic. This is in line with our findings that 5-FU generates FUTP which is incorporated into RNA, a mechanism known to underlie the myelosuppression and gastrointestinal inflammation associated with 5-FU. CONCLUSION Taken together, these results highlight key differences between NUC-3373 and 5-FU that are driven by the anti-cancer metabolites generated. NUC-3373 is a potent inhibitor of TS that also causes DNA-directed damage. These data support the preliminary clinical evidence that suggest NUC-3373 has a favorable safety profile in patients.
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Affiliation(s)
- Jennifer Bré
- School of Medicine, University of St Andrews, North Haugh, St Andrews, KY16 9TF, UK.
- NuCana Plc, 3 Lochside Way, Edinburgh, EH12 9DT, UK.
| | - Alison L Dickson
- School of Medicine, University of St Andrews, North Haugh, St Andrews, KY16 9TF, UK
- NuCana Plc, 3 Lochside Way, Edinburgh, EH12 9DT, UK
| | - Oliver J Read
- School of Medicine, University of St Andrews, North Haugh, St Andrews, KY16 9TF, UK
- NuCana Plc, 3 Lochside Way, Edinburgh, EH12 9DT, UK
| | - Ying Zhang
- School of Medicine, University of St Andrews, North Haugh, St Andrews, KY16 9TF, UK
| | | | - Peter Mullen
- School of Medicine, University of St Andrews, North Haugh, St Andrews, KY16 9TF, UK
| | - Peijun Tang
- School of Biology, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK
| | - Greice M Zickuhr
- School of Biology, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK
| | - Clarissa M Czekster
- School of Biology, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK
| | - David J Harrison
- School of Medicine, University of St Andrews, North Haugh, St Andrews, KY16 9TF, UK
- NuCana Plc, 3 Lochside Way, Edinburgh, EH12 9DT, UK
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Okunaka M, Kano D, Uesawa Y. Nuclear Receptor and Stress Response Pathways Associated with Antineoplastic Agent-Induced Diarrhea. Int J Mol Sci 2022; 23:12407. [PMID: 36293277 PMCID: PMC9604027 DOI: 10.3390/ijms232012407] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/09/2022] [Accepted: 10/12/2022] [Indexed: 12/06/2023] Open
Abstract
In severe cases, antineoplastic agent-induced diarrhea may be life-threatening; therefore, it is necessary to determine the mechanism of toxicity and identify the optimal management. The mechanism of antineoplastic agent-induced diarrhea is still unclear but is often considered to be multifactorial. The aim of this study was to determine the molecular initiating event (MIE), which is the initial interaction between molecules and biomolecules or biosystems, and to evaluate the MIE specific to antineoplastic agents that induce diarrhea. We detected diarrhea-inducing drug signals based on adjusted odds ratios using the Food and Drug Administration Adverse Event Reporting System. We then used the quantitative structure-activity relationship platform of Toxicity Predictor to identify potential MIEs that are specific to diarrhea-inducing antineoplastic agents. We found that progesterone receptor antagonists were potential MIEs associated with diarrhea. The findings of this study may help improve the prediction and management of antineoplastic agent-induced diarrhea.
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Affiliation(s)
- Mashiro Okunaka
- Department of Medical Molecular Informatics, Meiji Pharmaceutical University, Kiyose 204-8588, Japan
- Department of Pharmacy, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
| | - Daisuke Kano
- Department of Pharmacy, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
| | - Yoshihiro Uesawa
- Department of Medical Molecular Informatics, Meiji Pharmaceutical University, Kiyose 204-8588, Japan
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Jiang W, Liu Q, Yang D, Yang SB. The efficacy of irinotecan supplementation for colorectal cancer: A meta-analysis of randomized controlled studies. Medicine (Baltimore) 2022; 101:e28090. [PMID: 36254072 PMCID: PMC9575722 DOI: 10.1097/md.0000000000028090] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND The efficacy of irinotecan as the adjunctive therapy to fluorouracil and leucovorin remains controversial in patients with colorectal cancer. We conduct this meta-analysis to explore the efficacy of irinotecan supplementation for colorectal cancer. METHODS We have searched PubMed, EMBASE, Web of science, EBSCO, and Cochrane library databases through March 19, 2020, and included randomized controlled trials assessing the efficacy of irinotecan plus fluorouracil and leucovorin for colorectal cancer. RESULTS Five randomized controlled trials were included in the meta-analysis. Compared with fluorouracil and leucovorin for colorectal cancer, irinotecan supplementation could significantly improve progression-free survival rate (hazard ratio = 0.72; 95% confidence interval [CI] = 0.58-0.90; P = .003), median progression-free survival (standard mean difference = -0.30; 95% CI = -0.44 to -0.15; P < .0001), overall survival rate (hazard ratio = 0.77; 95% CI = 0.66-0.90; P = .001), and objective response (risk ratio [RR] = 0.57; 95% CI = 0.49-0.66; P < .00001) and decrease progressive disease (RR = 2.10; 95% CI = 1.40-3.14; P = .0003), but revealed no obvious effect on complete response (RR = 0.88; 95% CI = 0.33-2.29; P = .79). The incidence of grade ≥3 adverse events in irinotecan supplementation group was increased compared to control group (RR = 0.67; 95% CI = 0.57-0.79; P < .00001). CONCLUSIONS Irinotecan as the adjunctive therapy to fluorouracil and leucovorin can increase the survival and objective response of patients with colorectal cancer, but the incidence of grade ≥3 adverse events is found to be increased after irinotecan supplementation.
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Affiliation(s)
- Wei Jiang
- Rehabilitation Medicine Department, The Affiliated Hospital of Southwest Medical University, Lu zhou, 646000, Sichuan, People’s Republic of China
| | - Qiying Liu
- Rehabilitation Medicine Department, The Affiliated Hospital of Southwest Medical University, Lu zhou, 646000, Sichuan, People’s Republic of China
| | - Donglin Yang
- Rehabilitation Medicine Department, The Affiliated Hospital of Southwest Medical University, Lu zhou, 646000, Sichuan, People’s Republic of China
| | - Shi-bin Yang
- Rehabilitation Medicine Department, The Affiliated Hospital of Southwest Medical University, Lu zhou, 646000, Sichuan, People’s Republic of China
- *Correspondence: Shi-bin Yang, Rehabilitation Medicine Department, The Affiliated Hospital of Southwest Medical University, Lu zhou, 646000, Sichuan, People’s Republic of China; (e-mail: )
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10
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Sun Y, Fry CM, Shieh A, Cai X, Reardon TJ, Parquette JR. Self-assembly of a 5-fluorouracil and camptothecin dual drug dipeptide conjugate. Org Biomol Chem 2022; 20:5254-5258. [PMID: 35734894 DOI: 10.1039/d2ob00762b] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Nano-formulated, combinatory therapeutics that control the spatiotemporal aspects of drug release have potential to overcome many of the challenges faced in cancer therapy. Herein, we describe a peptide nanotube functionalized with two anticancer drugs, 5-fluoruracil (5-FU) and camptothecin (CPT). The nanotube was formed via peptide self-assembly, which positioned 5-FU on the surface at the aqueous interface; whereas, CPT was sequestered within the hydrophobic walls. Thus, two different release profiles were observed: rapid release of 5-FU, followed by slower, sustained production of CPT. This profile emerged from the rapid hydrolytic cleavage of 5-FU at the aqueous/nanotube interface, which produced a smaller nanotube comprised of the peptide fragment.
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Affiliation(s)
- Yuan Sun
- Department of Chemistry and Biochemistry, The Ohio State University, 100 W. 18th Ave., Columbus, Ohio 43210, USA.
| | - Cathleen M Fry
- Department of Chemistry and Biochemistry, The Ohio State University, 100 W. 18th Ave., Columbus, Ohio 43210, USA.
| | - Aileen Shieh
- Department of Chemistry and Biochemistry, The Ohio State University, 100 W. 18th Ave., Columbus, Ohio 43210, USA.
| | - Xiangchen Cai
- Department of Chemistry and Biochemistry, The Ohio State University, 100 W. 18th Ave., Columbus, Ohio 43210, USA.
| | - Thomas J Reardon
- Department of Chemistry and Biochemistry, The Ohio State University, 100 W. 18th Ave., Columbus, Ohio 43210, USA.
| | - Jon R Parquette
- Department of Chemistry and Biochemistry, The Ohio State University, 100 W. 18th Ave., Columbus, Ohio 43210, USA.
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11
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Ranasinghe R, Mathai M, Zulli A. A synopsis of modern - day colorectal cancer: Where we stand. Biochim Biophys Acta Rev Cancer 2022; 1877:188699. [DOI: 10.1016/j.bbcan.2022.188699] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/30/2022] [Accepted: 02/14/2022] [Indexed: 02/07/2023]
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Ando T, Sakumura M, Mihara H, Fujinami H, Yasuda I. A Review of Potential Role of Capsule Endoscopy in the Work-Up for Chemotherapy-Induced Diarrhea. Healthcare (Basel) 2022; 10:healthcare10020218. [PMID: 35206833 PMCID: PMC8871585 DOI: 10.3390/healthcare10020218] [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: 11/27/2021] [Revised: 01/13/2022] [Accepted: 01/21/2022] [Indexed: 11/29/2022] Open
Abstract
Chemotherapy-induced diarrhea (CID) is a common, severe side effect of chemotherapy, immunotherapy, and targeted therapy. Because patients are more prone to continuing chemotherapy if they do not suffer from CID, appropriate diagnosis and monitoring of this disease are essential. However, suitable monitoring methods are yet to be developed. To date, several studies have shown that small-bowel capsule endoscopy (SBCE) is useful in visualizing the entire small intestinal mucosa and detecting small intestinal abnormalities, including bleeding, malignant tumors, and mucosal injury, associated with the use of nonsteroidal anti-inflammatory drugs and low-dose aspirin. Currently, limited studies have evaluated the small intestinal mucosa using SBCE in patients receiving fluoropyrimidine-based chemotherapy or immune checkpoint inhibitors. These studies have reported that small intestinal mucosal injury is common in patients with severe fluoropyrimidine-induced diarrhea. SBCE might be a useful screening method for the early detection of enterocolitis induced by immune checkpoint inhibitors. SBCE may be a powerful tool for the diagnosis and monitoring of CID, and understanding its indication, contraindication, and capsule-retention risk for each patient is important for clinicians.
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Affiliation(s)
- Takayuki Ando
- Correspondence: ; Tel.: +81-76-434-7300; Fax: +81-76-434-5027
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Hamed RA, Marks S, Mcelligott H, Kalachand R, Ibrahim H, Atyani S, Korpanty G, Osman N. Inoperable de novo metastatic colorectal cancer with primary tumour in situ: Evaluating discordant responses to upfront systemic therapy of the primary tumours and metastatic sites and complications arising from primary tumours (experiences from an Irish Cancer Centre). Mol Clin Oncol 2022; 16:40. [PMID: 35003738 PMCID: PMC8739439 DOI: 10.3892/mco.2021.2472] [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: 03/25/2021] [Accepted: 11/22/2021] [Indexed: 12/24/2022] Open
Abstract
Systemic therapy is the mainstay of treatment for de novo metastatic colorectal cancer (mCRC). Heterogeneity between primary tumours and metastases may lead to discordant responses to systemic therapy at these sites. The aim of the present study was to examine these discrepancies and to evaluate the rates of complications arising from the primary tumour and the strategies employed to manage these complications. Electronic medical records were screened for patients eligible for data analysis between January 1st, 2014 and December 31st, 2019. All patients diagnosed with de novo mCRC with primary tumour in situ at the time of initial systemic therapy were included in data analysis. Responses in primary tumour and metastatic sites (according to the Response Evaluation Criteria In Solid Tumours v1.1), discrepancies in these responses and rates of complications arising from primary tumours were assessed along with patient, pathological or molecular factors that may be associated with these discrepant responses or primary tumour complications. A total of 50 patients were identified (median age, 62 years). Right-colon, left-colon and rectal primary tumours comprised 34, 44 and 22% of CRC cases, respectively. All patients received 5-fluorouracil-based chemotherapy (either alone or in combination with oxaliplatin or irinotecan). Disease response (DR), stable disease (SD) and progressive disease (PD) were observed as the first response to systemic therapy in 24, 62 and 12% of primary tumours and in 36, 18 and 44% of metastatic sites, respectively. Only 36% of patients demonstrated concordant responses between the primary tumours and metastases, while the remaining 62% demonstrated discordant responses between the primary tumour and distant metastases (22% had DR with SD; 36% had DR or SD with PD; and 4% had PD with SD in the primary tumour and metastases, respectively). Restaging images were not available for 2% of the patients. Approximately 30% of patients developed complications from primary tumours, including bowel obstruction (6.12%), perforation (6%), rectal pain (6%) and rectal bleeding (10%). Approximately 10% of patients underwent palliative stoma creation. Additionally, 12% required palliative radiotherapy to the primary tumour (due to localized complications arising from the tumour). Discordant responses to systemic therapy between primary tumours and metastases occurred in 60% of patients with de novo mCRC (with primary tumour in situ at the time of first systemic therapy). The observations of the present study have potential implications for molecular tissue analysis to help guide systemic therapy. Tissue from metastatic sites may be preferable to confirm biomarker status in mCRC based on this study.
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Affiliation(s)
- Ruba A Hamed
- Department of Oncology, Mid-Western Cancer Centre, University Hospital Limerick, Limerick V94 F858, Ireland
| | - Sam Marks
- Department of Oncology, Mid-Western Cancer Centre, University Hospital Limerick, Limerick V94 F858, Ireland
| | - Helen Mcelligott
- Department of Oncology, Mid-Western Cancer Centre, University Hospital Limerick, Limerick V94 F858, Ireland
| | - Roshni Kalachand
- Department of Oncology, Mid-Western Cancer Centre, University Hospital Limerick, Limerick V94 F858, Ireland
| | - Hawa Ibrahim
- Palliative Department, St. Francis Hospice, Dublin 5 D05 T9K8, Ireland
| | - Said Atyani
- Radiology Department, University Hospital Limerick, Limerick V94 F858, Ireland
| | - Greg Korpanty
- Department of Oncology, Mid-Western Cancer Centre, University Hospital Limerick, Limerick V94 F858, Ireland
| | - Nemer Osman
- Department of Oncology, Mid-Western Cancer Centre, University Hospital Limerick, Limerick V94 F858, Ireland
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Xu Z, Peng X, Kong Y, Cui Y, Li Y, Guo Y. The best strategy for metastatic colorectal cancer (mCRC) patients in second-line treatment: A network meta-analysis. Cancer Treat Res Commun 2021; 29:100455. [PMID: 34619647 DOI: 10.1016/j.ctarc.2021.100455] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 09/07/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Varieties of systemic treatments in second-line treatment for metastatic colorectal cancer (mCRC) patients have showed an improvement on survival. In this study, we performed a systematic review with a pairwise and bayesian network meta-analysis to rank the best strategy for mCRC patients in second-line treatment. METHODS A systematic literature search through 2007 was performed to evaluate the association between several treatment combinations and overall survival (OS), progression-free survival (PFS) and disease control rate (DCR) in mCRC patients. Data were carried out and pooled into a statistical indirect comparison with Bayesian network meta-analysis (NMA). RESULTS 10 trials totally comprised 4183 patients were included in our study. In NMA, For PFS, Doublet+Bev showed benefits in comparing with Doublet, Doulblet+placebo and Doublet+Ramucirumab. Also, Doublet+Aflibercept demonstrated its superiority in comparing with Doulblet+placebo. For OS, Doublet+Bev represented its superiority when comparing with Double and Doublet+placebo. Doublet+Aflibercept and Doublet+Ramucirumab also done well when opposed to Doublet+placebo. For DCR, Doublet+bev showed unique superiority when compared with Doublet, And Doublet+targeted agent did not represent benefits to each other in DCR. Doublet+bev ranked highest in terms of PFS, OS and DCR followed by Doublet+panitumumab, Doublet+placebo was the lowest in terms of PFS and OS. CONCLUSIONS Our study shows that Doublet+Bev has the major probability to provide an improvement of survival in patients with mCRC.
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Affiliation(s)
- Zhili Xu
- First Clinical Medical College, Zhejiang Chinese Medical University, Zhejiang 310053, China
| | - Xinyi Peng
- First Clinical Medical College, Zhejiang Chinese Medical University, Zhejiang 310053, China
| | - Yanni Kong
- First Clinical Medical College, Zhejiang Chinese Medical University, Zhejiang 310053, China
| | - Yiyi Cui
- First Clinical Medical College, Zhejiang Chinese Medical University, Zhejiang 310053, China; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, 310000, China
| | - Yan Li
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, 310006, China.
| | - Yong Guo
- First Clinical Medical College, Zhejiang Chinese Medical University, Zhejiang 310053, China; The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, 310006, China.
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15
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Kacew AJ, Strohbehn GW, Saulsberry L, Laiteerapong N, Cipriani NA, Kather JN, Pearson AT. Artificial Intelligence Can Cut Costs While Maintaining Accuracy in Colorectal Cancer Genotyping. Front Oncol 2021; 11:630953. [PMID: 34168975 PMCID: PMC8217761 DOI: 10.3389/fonc.2021.630953] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 05/13/2021] [Indexed: 12/22/2022] Open
Abstract
Rising cancer care costs impose financial burdens on health systems. Applying artificial intelligence to diagnostic algorithms may reduce testing costs and avoid wasteful therapy-related expenditures. To evaluate the financial and clinical impact of incorporating artificial intelligence-based determination of mismatch repair/microsatellite instability status into the first-line metastatic colorectal carcinoma setting, we developed a deterministic model to compare eight testing strategies: A) next-generation sequencing alone, B) high-sensitivity polymerase chain reaction or immunohistochemistry panel alone, C) high-specificity panel alone, D) high-specificity artificial intelligence alone, E) high-sensitivity artificial intelligence followed by next generation sequencing, F) high-specificity artificial intelligence followed by next-generation sequencing, G) high-sensitivity artificial intelligence and high-sensitivity panel, and H) high-sensitivity artificial intelligence and high-specificity panel. We used a hypothetical, nationally representative, population-based sample of individuals receiving first-line treatment for de novo metastatic colorectal cancer (N = 32,549) in the United States. Model inputs were derived from secondary research (peer-reviewed literature and Medicare data). We estimated the population-level diagnostic costs and clinical implications for each testing strategy. The testing strategy that resulted in the greatest project cost savings (including testing and first-line drug cost) compared to next-generation sequencing alone in newly-diagnosed metastatic colorectal cancer was using high-sensitivity artificial intelligence followed by confirmatory high-specificity polymerase chain reaction or immunohistochemistry panel for patients testing negative by artificial intelligence ($400 million, 12.9%). The high-specificity artificial intelligence-only strategy resulted in the most favorable clinical impact, with 97% diagnostic accuracy in guiding genotype-directed treatment and average time to treatment initiation of less than one day. Artificial intelligence has the potential to reduce both time to treatment initiation and costs in the metastatic colorectal cancer setting without meaningfully sacrificing diagnostic accuracy. We expect the artificial intelligence value proposition to improve in coming years, with increasing diagnostic accuracy and decreasing costs of processing power. To extract maximal value from the technology, health systems should evaluate integrating diagnostic histopathologic artificial intelligence into institutional protocols, perhaps in place of other genotyping methodologies.
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Affiliation(s)
- Alec J Kacew
- Pritzker School of Medicine, University of Chicago, Chicago, IL, United States
| | - Garth W Strohbehn
- Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Loren Saulsberry
- Department of Public Health Sciences, University of Chicago, Chicago, IL, United States
| | - Neda Laiteerapong
- Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Nicole A Cipriani
- Department of Pathology, University of Chicago, Chicago, IL, United States
| | - Jakob N Kather
- Department of Medicine, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany
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16
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Ghani MA, Fereydooni A, Chen E, Letzen B, Laage-Gaupp F, Nezami N, Deng Y, Gan G, Thakur V, Lin M, Papademetris X, Schernthaner RE, Huber S, Chapiro J, Hong K, Georgiades C. Identifying enhancement-based staging markers on baseline MRI in patients with colorectal cancer liver metastases undergoing intra-arterial tumor therapy. Eur Radiol 2021; 31:8858-8867. [PMID: 34061209 DOI: 10.1007/s00330-021-08058-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/07/2021] [Accepted: 05/06/2021] [Indexed: 12/17/2022]
Abstract
OBJECTIVES To determine if three-dimensional whole liver and baseline tumor enhancement features on MRI can serve as staging biomarkers and help predict survival of patients with colorectal cancer liver metastases (CRCLM) more accurately than one-dimensional and non-enhancement-based features. METHODS This retrospective study included 88 patients with CRCLM, treated with transarterial chemoembolization or Y90 transarterial radioembolization between 2001 and 2014. Semi-automated segmentations of up to three dominant lesions were performed on pre-treatment MRI to calculate total tumor volume (TTV) and total liver volumes (TLV). Quantitative 3D analysis was performed to calculate enhancing tumor volume (ETV), enhancing tumor burden (ETB, calculated as ETV/TLV), enhancing liver volume (ELV), and enhancing liver burden (ELB, calculated as ELV/TLV). Overall and enhancing tumor diameters were also measured. A modified Kaplan-Meier method was used to determine appropriate cutoff values for each metric. The predictive value of each parameter was assessed by Kaplan-Meier survival curves and univariable and multivariable cox proportional hazard models. RESULTS All methods except whole liver (ELB, ELV) and one-dimensional/non-enhancement-based methods were independent predictors of survival. Multivariable analysis showed a HR of 2.1 (95% CI 1.3-3.4, p = 0.004) for enhancing tumor diameter, HR 1.7 (95% CI 1.1-2.8, p = 0.04) for TTV, HR 2.3 (95% CI 1.4-3.9, p < 0.001) for ETV, and HR 2.4 (95% CI 1.4-4.0, p = 0.001) for ETB. CONCLUSIONS Tumor enhancement of CRCLM on baseline MRI is strongly associated with patient survival after intra-arterial therapy, suggesting that enhancing tumor volume and enhancing tumor burden are better prognostic indicators than non-enhancement-based and one-dimensional-based markers. KEY POINTS • Tumor enhancement of colorectal cancer liver metastases on MRI prior to treatment with intra-arterial therapies is strongly associated with patient survival. • Three-dimensional, enhancement-based imaging biomarkers such as enhancing tumor volume and enhancing tumor burden may serve as the basis of a novel prognostic staging system for patients with liver-dominant colorectal cancer metastases.
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Affiliation(s)
- Mansur A Ghani
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Arash Fereydooni
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Evan Chen
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Brian Letzen
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Fabian Laage-Gaupp
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Nariman Nezami
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA.,Russel H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Baltimore, MD, USA.,Interventional Radiology and Image-Guided Medicine, Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Yanhong Deng
- Yale Center for Analytical Science, Yale School of Public Health, New Haven, CT, USA
| | - Geliang Gan
- Yale Center for Analytical Science, Yale School of Public Health, New Haven, CT, USA
| | - Vinayak Thakur
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - MingDe Lin
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Xenophon Papademetris
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA.,Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Ruediger E Schernthaner
- Russel H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Baltimore, MD, USA.,Department of Diagnostic and Interventional Radiology, Hospital Landstraße, Vienna, Austria
| | - Steffen Huber
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA
| | - Julius Chapiro
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, 333 Cedar St, New Haven, CT, USA. .,Russel H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Baltimore, MD, USA.
| | - Kelvin Hong
- Russel H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Christos Georgiades
- Russel H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Baltimore, MD, USA
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IL15RA and SMAD3 Genetic Variants Predict Overall Survival in Metastatic Colorectal Cancer Patients Treated with FOLFIRI Therapy: A New Paradigm. Cancers (Basel) 2021; 13:cancers13071705. [PMID: 33916844 PMCID: PMC8038482 DOI: 10.3390/cancers13071705] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/25/2021] [Accepted: 04/01/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary There is an increasing scientific interest in the study of the interaction between the immune system and drugs in cancer that can affect the efficacy of an anti-cancer treatment. This study was undertaken to better understand if the genetic characteristic of a cancer patient’s immune system can predict the tumor response to the treatment and the duration of survival. The topic was studied on 335 metastatic colorectal cancer patients treated with a first-line chemotherapy (FOLFIRI regimen, irinotecan-5-fluorouracil-leucovorin). The research highlighted two markers, IL15RA-rs7910212 and SMAD3-rs7179840, significantly associated with the patient’s survival. When considering IL15RA-rs7910212 and SMAD3-rs7179840 in combination with other two genetic markers previously investigated (NR1I2-rs1054190, VDR-rs7299460), we built up a highly predictive genetic score of survival. The herein identified markers must be further validated, but still represent good candidates to understand how much a patient with a metastatic colorectal cancer can benefit from a chemotherapy with FOLFIRI regimen. Abstract A new paradigm in cancer chemotherapy derives from the interaction between chemotherapeutics, including irinotecan and 5-fluorouracil (5-FU), and the immune system. The patient’s immune response can modulate chemotherapy effectiveness, and, on the other hand, chemotherapeutic agents can foster tumor cell immunogenicity. On these grounds, the analysis of the cancer patients’ immunogenetic characteristics and their effect on survival after chemotherapy represent a new frontier. This study aims to identify genetic determinants in the immuno-related pathways predictive of overall survival (OS) after FOLFIRI (irinotecan, 5-FU, leucovorin) therapy. Two independent cohorts comprising a total of 335 patients with metastatic colorectal cancer (mCRC) homogeneously treated with first-line FOLFIRI were included in the study. The prognostic effect of 192 tagging genetic polymorphisms in 34 immune-related genes was evaluated using the bead array technology. The IL15RA rs7910212-C allele was associated with worse OS in both discovery (HR: 1.57, p = 0.0327, Bootstrap p-value = 0.0280) and replication (HR: 1.71, p = 0.0411) cohorts. Conversely, SMAD3 rs7179840-C allele was associated with better OS in both discovery (HR: 0.65, p = 0.0202, Bootstrap p-value = 0.0203) and replication (HR: 0.61, p = 0.0216) cohorts. A genetic prognostic score was generated integrating IL15RA-rs7910212 and SMAD3-rs7179840 markers with inflammation-related prognostic polymorphisms we previously identified in the same study population (i.e., PXR [NR1I2]-rs1054190, VDR-rs7299460). The calculated genetic score successfully discriminated patients with different survival probabilities (p < 0.0001 log-rank test). These findings provide new insight on the prognostic value of genetic determinants, such as IL15RA and SMAD3 markers, and could offer a new decision tool to improve the clinical management of patients with mCRC receiving FOLFIRI.
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Peri-operative chemotherapy for resectable colorectal lung metastasis: a systematic review and meta-analysis. J Cancer Res Clin Oncol 2020; 146:545-553. [PMID: 32036456 PMCID: PMC7039839 DOI: 10.1007/s00432-020-03142-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 01/30/2020] [Indexed: 12/13/2022]
Abstract
Purpose Several studies have evaluated surgical resection of pulmonary metastases as a standard treatment option for colorectal cancer (CRC) patients with resectable pulmonary metastases. However, the role of peri-operative chemotherapy after complete resection of pulmonary metastases from CRC patients is still controversial. This systematic review and meta-analysis is aimed to investigate the clinical efficacy of peri-operative chemotherapy after resection of CRC pulmonary metastases. Methods PubMed, the Cochrane Library databases, and Embase were searched for studies evaluating the effect of peri-operative chemotherapy on the survival of patients with CRC after pulmonary metastasectomy. The hazard ratio (HR) was used for analyzing overall survival (OS) and progression-free survival (PFS)/recurrence-free survival (RFS)/disease-free survival (DFS). Results Eight studies were included in the final analysis. The outcome showed that peri-operative chemotherapy had a significant favourable effect on OS (HR 0.83, 95% CI 0.75–0.92, p < 0.05) and PFS/RFS/DFS (HR 0.67, 95% CI 0.53–0.86, p < 0.05) in patients who received pulmonary metastasectomy. Multivariate analysis also validated this result (OS: HR 0.56, 95% CI 0.36–0.86, p < 0.05; PFS/RFS/DFS: HR 0.64, 95% CI 0.46–0.87, p < 0.05). There was a significant benefit in peri-operative group on OS and PFS/RFS/DFS in studies with R0 resection of pulmonary metastases (OS: HR 0.72, 95% CI 0.53–0.97, p < 0.05; PFS/RFS/DFS: HR 0.72, 95% CI 0.54–0.95, p < 0.05) and metachronous pulmonary metastases (OS: HR 0.40, 95% CI 0.22–0.75, p < 0.05; PFS/RFS/DFS: HR 0.67, 95% CI 0.49–0.92, p < 0.05). Conclusion Our meta-analysis demonstrated a significant difference in favor of peri-operative chemotherapy in CRC patients who underwent resection of pulmonary metastases. More clinical data and studies are needed to validate the findings of our study. Electronic supplementary material The online version of this article (10.1007/s00432-020-03142-9) contains supplementary material, which is available to authorized users.
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Sun H, Li Y, Su Y, Wu X, Zhou X, Han J, Li J. Efficacy and safety of anti-EGFR monoclonal antibodies combined with different chemotherapy regimens in patients with RAS wild-type metastatic colorectal cancer: A meta-analysis. J Evid Based Med 2019; 12:300-312. [PMID: 31596544 DOI: 10.1111/jebm.12360] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Accepted: 05/27/2019] [Indexed: 02/05/2023]
Abstract
OBJECTIVES To investigate the efficacy and safety of adding anti-epidermal growth factor receptor [EGFR] MoAbs to various chemotherapy regimens in patients with RAS wild-type metastasized colorectal cancer (RAS WT metastatic colorectal cancer [mCRC]) and to identify the optimal combination regimens. METHODS We searched MEDLINE, EMBASE, and CENTRAL from the inception date to 20th May 2019. Randomized clinical trials investigating chemotherapy with or without anti-EGFR MoAbs in treatment of patients with RAS WT mCRC were included. RESULTS Eighteen studies involving 8848 participants were eligible. Comparing with oxaliplatin-based chemotherapy, adding anti-EGFR MoAbs benefited only in progression-free survival (PFS) (hazard ratio [HR] = 0.80, 95% confidence interval [CI]: 0.67 to 0.94), but not in overall survival (OS) (HR = 0.89, 95% CI: 0.78 to 1.02). Further sensitivity analysis indicated that adding anti-EGFR MoAbs to FOLFOLX regimen as a first-line treatment showed benefits in both PFS and OS (PFS: HR = 0.74, 95% CI: 0.64 to 0.84; OS: HR = 0.83, 95% CI: 0.73 to 0.95, respectively). Comparing with irinotecan-based chemotherapy or best supportive care, adding anti-EGFR MoAbs revealed an improvement in both PFS (HR = 0.77, 95% CI: 0.69 to 0.86; HR = 0.46, 95% CI: 0.40 to 0.54, respectively) and OS (HR = 0.89, 95% CI: 0.80 to 0.98; HR = 0.65, 95% CI: 0.54 to 0.78, respectively). CONCLUSION Anti-EGFR MoAbs as a monotherapy or in combination with either irinotecan-based chemotherapy or FOLFOX in patients with RAS wild-type mCRC have better response and survival outcome, whereas OS does not benefit from adding anti-EGFR MoAbs to another oxaliplatin-based regimen. Anti-EGFR MoAbs have increased the risk of adverse effects than chemotherapy alone. More high-quality randomized controlled trials for RAS wild type are necessary.
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Affiliation(s)
- Huan Sun
- Department of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yonghong Li
- Department of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yana Su
- Department of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xinyu Wu
- Chengdu Fifth People's Hospital, Chengdu, Sichuan, China
| | - Xiaoqin Zhou
- Department of Clinical Research Management, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jin Han
- School of Life Science and Technology, Shanghai Jiaotong University, Shanghai, China
| | - Jing Li
- Department of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Ziemann C, Roller J, Malter MM, Keller K, Kollmar O, Glanemann M, Menger MD, Sperling J. Intra-arterial EmboCept S® and DC Bead® effectively inhibit tumor growth of colorectal rat liver metastases. BMC Cancer 2019; 19:938. [PMID: 31601175 PMCID: PMC6785845 DOI: 10.1186/s12885-019-6135-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 09/04/2019] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Intra-arterial therapy with embolics is established for the treatment of malignancies of the liver. However, there are no studies comparing the different effects of various embolics used in clinical practice. Herein, we analyzed the effect of 3 different embolics on tumor growth in a rat model of colorectal liver metastases. METHODS Eight days after subcapsular implantation of 5 × 105 colorectal cancer cells (CC531) in the left liver lobe of WAG/Rij rats were randomized into 4 groups (n = 8) and underwent intra-arterial hepatic therapy. Animals received either EmboCept S®, DC Bead® or Lipiodol® Ultra-Fluid. Animals of the control group received a comparable amount of saline. Tumor growth was measured on day 8 and 11 using a three-dimensional 40 MHz ultrasound device. On day 11 tumor and liver tissue were removed for histological and immunohistochemical analyses. RESULTS On day 11 animals of the control group showed a tumor growth of ~ 60% compared to day 8. Application of Lipiodol Ultra-Fluid® did not significantly influence tumor growth (~ 40%). In contrast, treatment with EmboCept S® or DC Bead® completely inhibited tumor growth. Of interest, application of EmboCept S® did not only completely inhibit tumor growth but even decreased tumor size. Immunohistochemical analysis showed a significant increase of necrotic areas within the tumors after application of EmboCept S® and DC Bead® compared to Lipiodol® Ultra-Fluid. CONCLUSION The present study demonstrates that an intra-arterial therapy with EmboCept S® and DC Bead®, but not Lipiodol® Ultra-Fluid, results in a complete inhibition of rat colorectal liver metastatic growth.
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Affiliation(s)
- Christian Ziemann
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany.
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany.
- Present address: Department of Cardiovascular Surgery, University Heart Center, University Medical Center, University of Freiburg, Hugstetter Str. 55, 79104, Freiburg, Germany.
| | - Jonas Roller
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany
| | - Markus M Malter
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Kira Keller
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Otto Kollmar
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
- Present address: Department of General and Visceral Surgery, Helios Dr. Horst Schmidt Kliniken, Wiesbaden, Germany
| | - Matthias Glanemann
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany
| | - Michael D Menger
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Jens Sperling
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
- Present address: Department of General and Visceral Surgery, University Medical Center Göttingen, Göttingen, Germany
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21
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Diaz-Mercedes S, Archilla I, Camps J, de Lacy A, Gorostiaga I, Momblan D, Ibarzabal A, Maurel J, Chic N, Bombí JA, Balaguer F, Castells A, Aldecoa I, Borras JM, Cuatrecasas M. Budget Impact Analysis of Molecular Lymph Node Staging Versus Conventional Histopathology Staging in Colorectal Carcinoma. APPLIED HEALTH ECONOMICS AND HEALTH POLICY 2019; 17:655-667. [PMID: 31115896 PMCID: PMC6748889 DOI: 10.1007/s40258-019-00482-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
BACKGROUND The presence of lymph node (LN) metastasis is a critical prognostic factor in colorectal cancer (CRC) patients and is also an indicator for adjuvant chemotherapy. The gold standard (GS) technique for LN diagnosis and staging is based on the analysis of haematoxylin and eosin (H&E)-stained slides, but its sensitivity is low. As a result, patients may not be properly diagnosed and some may have local recurrence or distant metastases after curative-intent surgery. Many of these diagnostic and treatment problems could be avoided if the one-step nucleic acid amplification assay (OSNA) was used rather than the GS technique. OSNA is a fast, automated, standardised, highly sensitive, quantitative technique for detecting LN metastases. OBJECTIVES The aim of this study was to assess the budget impact of introducing OSNA LN analysis in early-stage CRC patients in the Spanish National Health System (NHS). METHODS A budget impact analysis comparing two scenarios (GS vs. OSNA) was developed within the Spanish NHS framework over a 3-year time frame (2017-2019). The patient population consisted of newly diagnosed CRC patients undergoing surgical treatment, and the following costs were included: initial surgery, pathological diagnosis, staging, follow-up expenses, systemic treatment and surgery after recurrence. One- and two-way sensitivity analyses were performed. RESULTS Using OSNA instead of the GS would have saved €1,509,182, €6,854,501 and €10,814,082 during the first, second and third years of the analysis, respectively, because patients incur additional costs in later years, leading to savings of more than €19 million for the NHS over the 3-year time horizon. CONCLUSIONS Introducing OSNA in CRC LN analysis may represent not only an economic benefit for the NHS but also a clinical benefit for CRC patients since a more accurate staging could be performed, thus avoiding unnecessary treatments.
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Affiliation(s)
- Sherley Diaz-Mercedes
- Pathology Department-Center of Biomedical Diagnosis (CDB), Hospital Clínic, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain
| | - Ivan Archilla
- Pathology Department-Center of Biomedical Diagnosis (CDB), Hospital Clínic, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain
| | - Jordi Camps
- Gastroenterology Department, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
- CIBERehd and Banc de Tumors-Biobanc Clinic-IDIBAPS-XBTC, Hospital Clinic, Barcelona, Spain
| | | | - Iñigo Gorostiaga
- Pathology Department, Araba University Hospital, Vitoria-Gasteiz, Spain
| | - Dulce Momblan
- Surgical Department, Hospital Clinic, Barcelona, Spain
| | | | - Joan Maurel
- Medical Oncology Department, Hospital Clinic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Nuria Chic
- Medical Oncology Department, Hospital Clinic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Josep Antoni Bombí
- Pathology Department-Center of Biomedical Diagnosis (CDB), Hospital Clínic, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain
| | - Francesc Balaguer
- Gastroenterology Department, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
- CIBERehd and Banc de Tumors-Biobanc Clinic-IDIBAPS-XBTC, Hospital Clinic, Barcelona, Spain
| | - Antoni Castells
- Gastroenterology Department, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
- CIBERehd and Banc de Tumors-Biobanc Clinic-IDIBAPS-XBTC, Hospital Clinic, Barcelona, Spain
| | - Iban Aldecoa
- Pathology Department-Center of Biomedical Diagnosis (CDB), Hospital Clínic, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain
- Neurological Tissue Bank of the Biobank Clinic-IDIBAPS-XBTC, Hospital Clinic, Barcelona, Spain
| | - Josep Maria Borras
- Department of Clinical Sciences and Bellvitge Biomedical Research Institute (IDIBELL), Universitat de Barcelona, Barcelona, Spain
| | - Miriam Cuatrecasas
- Pathology Department-Center of Biomedical Diagnosis (CDB), Hospital Clínic, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain.
- Pathology Department, Araba University Hospital, Vitoria-Gasteiz, Spain.
- CIBERehd and Banc de Tumors-Biobanc Clinic-IDIBAPS-XBTC, Hospital Clinic, Barcelona, Spain.
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22
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Population pharmacokinetic model of irinotecan and its metabolites in patients with metastatic colorectal cancer. Eur J Clin Pharmacol 2019; 75:529-542. [DOI: 10.1007/s00228-018-02609-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 12/07/2018] [Indexed: 01/11/2023]
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23
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Irinotecan-Eluting 75–150-μm Embolics Lobar Chemoembolization in Patients with Colorectal Cancer Liver Metastases: A Prospective Single-Center Phase I Study. J Vasc Interv Radiol 2018; 29:1646-1653.e5. [DOI: 10.1016/j.jvir.2018.08.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 08/08/2018] [Accepted: 08/12/2018] [Indexed: 12/30/2022] Open
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24
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Hubert C, Lucidi V, Weerts J, Dili A, Demetter P, Massart B, Komuta M, Navez J, Reding R, Gigot JF, Sempoux C. Impact of biological agents on the prevalence of chemotherapy associated liver injury (CALI): Multicentric study of patients operated for colorectal liver metastases. Eur J Surg Oncol 2018; 44:1532-1538. [DOI: 10.1016/j.ejso.2018.07.050] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 06/27/2018] [Accepted: 07/18/2018] [Indexed: 01/10/2023] Open
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25
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Sun L, Huang Y, Liu Y, Zhao Y, He X, Zhang L, Wang F, Zhang Y. Ipatasertib, a novel Akt inhibitor, induces transcription factor FoxO3a and NF-κB directly regulates PUMA-dependent apoptosis. Cell Death Dis 2018; 9:911. [PMID: 30185800 PMCID: PMC6125489 DOI: 10.1038/s41419-018-0943-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 07/27/2018] [Accepted: 07/30/2018] [Indexed: 12/27/2022]
Abstract
Colon cancer is one of the three common malignant tumors, with a lower survival rate. Ipatasertib, a novel highly selective ATP-competitive pan-Akt inhibitor, shows a strong antitumor effect in a variety of carcinoma, including colon cancer. However, there is a lack of knowledge about the precise underlying mechanism of clinical therapy for colon cancer. We conducted this study to determine that ipatasertib prevented colon cancer growth through PUMA-dependent apoptosis. Ipatasertib led to p53-independent PUMA activation by inhibiting Akt, thereby activating both FoxO3a and NF-κB synchronously that will directly bind to PUMA promoter, up-regulating PUMA transcription and Bax-mediated intrinsic mitochondrial apoptosis. Remarkably, Akt/FoxO3a/PUMA is the major pathway while Akt/NF-κB/PUMA is the secondary pathway of PUMA activation induced by ipatasertib in colon cancer. Knocking out PUMA eliminated ipatasertib-induced apoptosis both in vitro and in vivo (xenografts). Furthermore, PUMA is also indispensable in combinational therapies of ipatasertib with some conventional or novel drugs. Collectively, our study demonstrated that PUMA induction by FoxO3a and NF-κB is a critical step to suppress the growth of colon cancer under the therapy with ipatasertib, which provides some theoretical basis for clinical assessment.
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Affiliation(s)
- Li Sun
- College of Biology, Hunan University, Changsha, 410082, China.,Department of Out-patient, Affiliated Hospital of Hebei University of Engineering, Handan, 056002, China
| | - Yuan Huang
- College of Biology, Hunan University, Changsha, 410082, China
| | - Yeying Liu
- College of Biology, Hunan University, Changsha, 410082, China
| | - Yujie Zhao
- College of Biology, Hunan University, Changsha, 410082, China
| | - Xiaoxiao He
- College of Biology, Hunan University, Changsha, 410082, China
| | - Lingling Zhang
- Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, 410013, China.
| | - Feng Wang
- Department of Gastroenterology, The Tenth People's Hospital of Shanghai, Tongji University, Shanghai, 200072, China. .,Shenzhen Institute, Hunan University, Shenzhen, China.
| | - Yingjie Zhang
- College of Biology, Hunan University, Changsha, 410082, China. .,Shenzhen Institute, Hunan University, Shenzhen, China.
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26
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Ruihua H, Mengyi Z, Chong Z, Meng Q, Xin M, Qiulin T, Feng B, Ming L. RhoA regulates resistance to irinotecan by regulating membrane transporter and apoptosis signaling in colorectal cancer. Oncotarget 2018; 7:87136-87146. [PMID: 27888624 PMCID: PMC5349977 DOI: 10.18632/oncotarget.13548] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 11/08/2016] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. While surgery remains the mainstay of treatment in early stage CRC, chemotherapy is usually given to prolong the overall survival and improve the quality of life for metastatic colorectal cancer (mCRC). But drug resistance is one of the major hurdles of mCRC treatment, and the underlying mechanisms are still largely unknown. In this study, we show that, compared with parental cells, RhoA is up-regulated in irinotecan (CPT-11)-resistant CRC cells. Furthermore, inhibition of RhoA in drug resistant cells, at least partially, rescues the resistance against irinotecan and increases the sensitivity to other chemotherapeutic drug by inhibiting expression of MDR1, MRP1and GSTP1, promotes apoptosis by suppressing the expression of BCL-XL and Bcl-2 and increasing Bax expression, and significantly decreases side population cells. Our results suggest that, in addition to survival, proliferation, migration, adhesion, cell cycle and gene transcription, RhoA is also involved in chemoresistance by regulating the expression of membrane transporter and apoptosis protein in colorectal cancer. They raise an interesting possibility that the expression of RhoA may indicate a poor prognosis due to the high probability to therapy resistance and, on the other hand, inhibition of RhoA activity and function may overcome chemoresistance and improve the effectiveness of clinical treatment of CRC.
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Affiliation(s)
- Huang Ruihua
- Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhang Mengyi
- Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhao Chong
- Department of Radiotherapy, The Tumor Hospital of Chengdu/The Seventh Peoples's Hospital of Chengdu, Chengdu, Sichuan Province, China
| | - Qiu Meng
- Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Ma Xin
- Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tang Qiulin
- Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Bi Feng
- Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Liu Ming
- Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
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27
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Leelakanok N, Geary S, Salem A. Fabrication and Use of Poly(d,l-lactide-co-glycolide)-Based Formulations Designed for Modified Release of 5-Fluorouracil. J Pharm Sci 2017; 107:513-528. [PMID: 29045885 DOI: 10.1016/j.xphs.2017.10.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Revised: 10/03/2017] [Accepted: 10/06/2017] [Indexed: 12/14/2022]
Abstract
5-fluorouracil (5-FU) is a chemotherapeutic agent that has been used for the treatment of a variety of malignancies since its initial introduction to the clinic in 1957. Owing to its short biological half-life, multiple dosings are generally required to maintain effective 5-FU plasma concentrations throughout the therapeutic period. Clinical studies have shown that continuous 5-FU administration is generally superior to bolus injection as exhibited by lower toxicities and increased therapeutic efficacy. Optimal therapeutic efficacy, however, is often compromised by the limiting therapeutic index. Whilst oral formulations are also used, these suffer from the drawbacks of variable bioavailability and first-pass metabolism. As a result, sustained release formulations of 5-FU have been investigated in an effort to mimic the kinetics of continuous infusion particularly for situations where local delivery is considered appropriate. The biocompatible, biodegradable, and highly tunable synthetic polymer, poly(d,l-lactide-co-glycolide) (PLGA), is widely used as a vector for sustained drug delivery, however, issues such as insufficient loading and inappropriate burst release kinetics have dogged progress into the clinic for small hydrophilic drugs such as 5-FU. This review provides introductory information about the mechanism of action, pharmacokinetic and physicochemical properties, and clinical use of 5-FU that have contributed to the development of PLGA-based 5-FU release platforms. In addition, this review provides information on fabrication methods used for a range of 5-FU-loaded PLGA formulations and discusses factors affecting the release kinetics of 5-FU as well as the in vitro and in vivo antitumor or antiproliferative efficacy of these platforms.
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Affiliation(s)
- Nattawut Leelakanok
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, Iowa City, Iowa 52242
| | - Sean Geary
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, Iowa City, Iowa 52242
| | - Aliasger Salem
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, Iowa City, Iowa 52242.
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28
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A Novel Derivation Predicting Survival After Primary Tumor Resection in Stage IV Colorectal Cancer: Validation of a Prognostic Scoring Model and an Online Calculator to Provide Individualized Survival Estimation. Dis Colon Rectum 2017; 60:895-904. [PMID: 28796727 DOI: 10.1097/dcr.0000000000000821] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND A prognostic scoring model has been devised previously to predict survival following primary tumor resection in patients with metastatic colorectal cancer and unresectable metastases. This has yet to be validated. OBJECTIVE The main objectives of this study are to validate the proposed prognostic scoring model and create an interactive online calculator to estimate an individual's survival after primary tumor resection. DESIGN Clinical data and survival outcomes of patients were extracted from a prospectively maintained database. Patients were categorized into good, moderate, or poor survivor groups based on the previously proposed scoring algorithm. Discrimination was assessed and recalibration was performed, with the recalibrated model implemented as an interactive Web application to provide individualized survival probability. SETTINGS This study was conducted at a tertiary referral center. PATIENTS The study included 324 consecutive patients with metastatic colorectal carcinoma and unresectable metastases who underwent primary tumor resection between January 2008 and December 2013. MAIN OUTCOME MEASURES The primary outcome measured was overall survival. RESULTS Three hundred twenty-four patients were included in the study. Median survival in the good, moderate, and poor prognostic groups was 56.8, 25.7, and 19.9 months (log rank test, p = 0.003). The κ statistic was 0.638 and RD was 0.101. Significant differences in survival were found between the moderate and good prognostic groups (HR, 2.79; 95% CI, 1.51-5.15; p = 0.001) and between poor and good prognostic groups (HR, 4.12; 95% CI, 1.98-8.55; p < 0.001). The model was implemented as an interactive online calculator to provide individualized survival estimation after primary tumor resection (http://bit.ly/Stage4PrognosticScore). LIMITATIONS Selection bias and single-center data preclude the generalizability of the proposed model. Information regarding the severity or likelihood of developing symptoms from the primary tumor were also not accounted for in the prognostic scoring model proposed. CONCLUSIONS The prognostic scoring model provides good prognostic stratification of survival after primary tumor resection and may be a useful tool to predict survival after primary tumor resection. See Video Abstract at http://links.lww.com/DCR/A330.
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29
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Abalo R, Uranga JA, Pérez-García I, de Andrés R, Girón R, Vera G, López-Pérez AE, Martín-Fontelles MI. May cannabinoids prevent the development of chemotherapy-induced diarrhea and intestinal mucositis? Experimental study in the rat. Neurogastroenterol Motil 2017; 29. [PMID: 27686064 DOI: 10.1111/nmo.12952] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Accepted: 08/24/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND The antineoplastic drug 5-fluoruracil (5-FU) is a pirimidine analog, which frequently induces potentially fatal diarrhea and mucositis. Cannabinoids reduce gastrointestinal motility and secretion and might prevent 5-FU-induced gut adverse effects. Here, we asked whether cannabinoids may prevent diarrhea and mucositis induced by 5-FU in the rat. METHODS Male Wistar rats received vehicle or the non-selective cannabinoid agonist WIN 55,212-2 (WIN; 0.5 mg kg-1 injection-1 , 1 injection day-1 , 4 consecutive days) by intraperitoneal (ip) route; on the first 2 days, animals received also saline or 5-FU (150 mg kg-1 injection-1 , cumulative dose of 300 mg kg-1 ). Gastrointestinal motor function was radiographically studied after barium contrast intragastric administration on experimental days 1 and 4. Structural alterations of the stomach, small intestine and colon were histologically studied on day 4. PAS staining and immunohistochemistry for Ki67, chromogranin A and CD163 were used to detect secretory, proliferating, and endocrine cells, and activated macrophages respectively. KEY RESULTS As shown radiographically, 5-FU induced significant gastric emptying delay (on days 1 and 4) and diarrhea (on day 4). WIN did not significantly alter the motility curves obtained for either control or 5-FU-treated animals but tended to reduce the severity of 5-FU-induced diarrhea and increased permanence of barium from day 1 to the beginning of day 4 in 5-FU-treated animals. 5-FU-induced mucositis was severe and not counteracted by WIN. CONCLUSIONS AND INFERENCES 5-FU-induced diarrhea, but not mucositis, was partly prevented by WIN at a low dose. Cannabinoids might be useful to prevent chemotherapy-induced diarrhea.
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Affiliation(s)
- R Abalo
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Alcorcón, Spain.,Unidad Asociada I+D+i al Instituto de Investigación en Ciencias de la Alimentación, CIAL (CSIC), Madrid, Spain.,Unidad Asociada I+D+i al Instituto de Química Médica, IQM (CSIC), Madrid, Spain.,Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Madrid, Spain
| | - J A Uranga
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Alcorcón, Spain.,Unidad Asociada I+D+i al Instituto de Investigación en Ciencias de la Alimentación, CIAL (CSIC), Madrid, Spain.,Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Madrid, Spain
| | - I Pérez-García
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Alcorcón, Spain
| | - R de Andrés
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Alcorcón, Spain
| | - R Girón
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Alcorcón, Spain.,Unidad Asociada I+D+i al Instituto de Investigación en Ciencias de la Alimentación, CIAL (CSIC), Madrid, Spain.,Unidad Asociada I+D+i al Instituto de Química Médica, IQM (CSIC), Madrid, Spain.,Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Madrid, Spain
| | - G Vera
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Alcorcón, Spain.,Unidad Asociada I+D+i al Instituto de Investigación en Ciencias de la Alimentación, CIAL (CSIC), Madrid, Spain.,Unidad Asociada I+D+i al Instituto de Química Médica, IQM (CSIC), Madrid, Spain.,Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Madrid, Spain
| | - A E López-Pérez
- Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Madrid, Spain.,Unidad del Dolor, Servicio de Anestesiología, Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain
| | - M I Martín-Fontelles
- Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Alcorcón, Spain.,Unidad Asociada I+D+i al Instituto de Investigación en Ciencias de la Alimentación, CIAL (CSIC), Madrid, Spain.,Unidad Asociada I+D+i al Instituto de Química Médica, IQM (CSIC), Madrid, Spain.,Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo Multidisciplinar de Investigación y Tratamiento del Dolor (i+DOL), Madrid, Spain
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30
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Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives. Cancer Chemother Pharmacol 2016; 78:881-893. [PMID: 27590709 DOI: 10.1007/s00280-016-3139-y] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 08/23/2016] [Indexed: 12/20/2022]
Abstract
PURPOSE Intestinal mucositis and diarrhea are common manifestations of anticancer regimens that include irinotecan, 5-fluorouracil (5-FU), and other cytotoxic drugs. These side effects negatively impact therapeutic outcomes and delay subsequent cycles of chemotherapy, resulting in dose reductions and treatment discontinuation. Here, we aimed to review the experimental evidence regarding possible new targets for the management of irinotecan- and 5-FU-related intestinal mucositis. METHODS A literature search was performed using the PubMed and MEDLINE databases. No publication time limit was set for article inclusion. RESULTS Here, we found that clinical management of intestinal mucositis and diarrhea is somewhat ineffective at reducing symptoms, possibly due to a lack of specific targets for modulation. We observed that IL-1β contributes to the apoptosis of enterocytes in mucositis induced by 5-FU. However, 5-FU-related mucositis is far less thoroughly investigated with regard to specific molecular targets when compared to irinotecan-related disease. Several studies have proposed that a correlation exists between the intestinal microbiota, the enterohepatic recirculation of active metabolites of irinotecan, and the establishment of mucositis. However, as reviewed here, this association seems to be controversial. In addition, the pathogenesis of irinotecan-induced mucositis appears to be orchestrated by interleukin-1/Toll-like receptor family members, leading to epithelial cell apoptosis. CONCLUSIONS IL-1β, IL-18, and IL-33 and the receptors IL-1R, IL-18R, ST2, and TLR-2 are potential therapeutic targets that can be modulated to minimize anticancer agent-associated toxicity, optimize cancer treatment dosing, and improve clinical outcomes. In this context, the pathogenesis of mucositis caused by other anticancer agents should be further investigated.
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Roder D, Karapetis CS, Wattchow D, Moore J, Singhal N, Joshi R, Keefe D, Fusco K, Buranyi-Trevarton D, Sharplin G, Price TJ. Metastatic Colorectal Cancer Treatment and Survival: the Experience of Major Public Hospitals in South Australia Over Three Decades. Asian Pac J Cancer Prev 2016; 16:5923-31. [PMID: 26320474 DOI: 10.7314/apjcp.2015.16.14.5923] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Registry data from four major public hospitals indicate trends over three decades from 1980 to 2010 in treatment and survival from colorectal cancer with distant metastases at diagnosis (TNM stage IV). MATERIALS AND METHODS Kaplan-Meier product-limit estimates and Cox proportional hazards models for investigating disease-specific survival and multiple logistic regression analyses for indicating first-round treatment trends. RESULTS Two-year survivals increased from 10% for 1980-84 to 35% for 2005-10 diagnoses. Corresponding increases in five-year survivals were from 3% to 16%. Time-to-event risk of colorectal cancer death approximately halved (hazards ratio: 0.48 (0.40, 0.59) after adjusting for demographic factors, tumour differentiation, and primary sub-site. Survivals were not found to differ by place of residence, suggesting reasonable equity in service provision. About 74% of cases were treated surgically and this proportion increased over time. Proportions having systemic therapy and/or radiotherapy increased from 12% in 1980-84 to 61% for 2005-10. Radiotherapy was more common for rectal than colonic cases (39% vs 7% in 2005-10). Of the cases diagnosed in 2005-10 when less than 70 years of age, the percentage having radiotherapy and/or systemic therapy was 79% for colorectal, 74% for colon and 86% for rectum (and RS)) cancers. Corresponding proportions having: systemic therapies were 75%, 71% and 81% respectively; radiotherapy were 24%, 10% and 46% respectively; and surgery were 75%, 78% and 71% respectively. Based on survey data on uptake of offered therapies, it is likely that of these younger cases, 85% would have been offered systemic treatment and among rectum (and RS) cases, about 63% would have been offered radiotherapy. CONCLUSIONS Pronounced increases in survivals from metastatic colorectal cancer have occurred, in keeping with improved systemic therapies and surgical interventions. Use of radiotherapy and/or systemic therapy has increased markedly and patterns of change accord with clinical guideline recommendations.
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Affiliation(s)
- David Roder
- Centre for Population Health Research, University of South Australia, South Australia E-mail :
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Shao J, Xu Z, Peng X, Chen M, Zhu Y, Xu L, Zhu H, Yang B, Luo P, He Q. Gefitinib Synergizes with Irinotecan to Suppress Hepatocellular Carcinoma via Antagonizing Rad51-Mediated DNA-Repair. PLoS One 2016; 11:e0146968. [PMID: 26752698 PMCID: PMC4709237 DOI: 10.1371/journal.pone.0146968] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 12/23/2015] [Indexed: 11/24/2022] Open
Abstract
Chemotherapy is the only choice for most of the advanced hepatocellular carcinoma (HCC) patients, while few agents were available, making it an urgent need to develop new chemotherapy strategies. A phase II clinical trial suggested that the efficacy of irinotecan in HCC was limited due to dose-dependent toxicities. Here, we found that gefitinib exhibited synergistic activity in combination with SN-38, an active metabolite of irinotecan, in HCC cell lines. And the enhanced apoptosis induced by gefitinib plus SN-38 was a result from caspase pathway activation. Mechanistically, gefitinib dramatically promoted the ubiquitin–proteasome-dependent degradation of Rad51 protein, suppressed the DNA repair, gave rise to more DNA damages, and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of gefitinib combined with irinotecan was further validated in a HepG2 xenograft mice model. Taken together, our data demonstrated for the first time that the combination of irinotecan and gefitinib showed potential benefit in HCC, which suggests that Rad51 is a promising target and provides a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and gefitinib in HCC.
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Affiliation(s)
- Jinjin Shao
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Zhifei Xu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xueming Peng
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Min Chen
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yuanrun Zhu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Li Xu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Hong Zhu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Bo Yang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Peihua Luo
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- * E-mail: (PL); (QH)
| | - Qiaojun He
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- * E-mail: (PL); (QH)
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A new animal model of intestinal mucositis induced by the combination of irinotecan and 5-fluorouracil in mice. Cancer Chemother Pharmacol 2015; 77:323-32. [PMID: 26666645 DOI: 10.1007/s00280-015-2938-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 12/01/2015] [Indexed: 12/30/2022]
Abstract
PURPOSE Intestinal mucositis (IM) is a common side effect of anticancer agents. Despite polychemotherapy use in clinical practice, the pathogenesis of IM has been investigated in single drug injection animal models. However, the progression of IM could vary according to drug regimens. Thus, we aimed to develop a new experimental mucositis model induced by combining irinotecan and 5-fluorouracil (5-FU) treatments. METHODS IM was induced in male C57BL/6 mice by the intraperitoneal administration of either 0.9 % saline (5 mL/kg), irinotecan (IRI, 30 or 45 mg/kg), 5-FU (25, 37.5, or 50 mg/kg), or the combination of these doses (IRI + 5-FU) for 4 days. Animal survival, body mass variation, and diarrhea scores were evaluated daily. On the 7th day, the mice were euthanized, and intestinal samples were collected for histopathology and morphometric analysis, as well as for the determination of myeloperoxidase activity and cytokine dosage (TNF-α and IL-6). RESULTS The optimal dose combination that induced IM and presented no substantial mortality on the 7th day was IRI (45 mg/kg) + 5-FU (37.5 mg/kg), which was used for subsequent studies. IRI and 5-FU in combination induced significant diarrhea, body weight loss, intestinal damage, inflammatory cell infiltration, and increased levels of cytokines when compared with other groups (P < 0.05). Neither IRI nor 5-FU alone induced IM. CONCLUSIONS We developed a new experimental model of IM induced by combining irinotecan and 5-FU treatments, which will allow us to gain a better knowledge concerning the pathogenesis of this disease through the pharmacological modulation of key inflammatory mediators.
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Milinis K, Thornton M, Montazeri A, Rooney PS. Adjuvant chemotherapy for rectal cancer: Is it needed? World J Clin Oncol 2015; 6:225-236. [PMID: 26677436 PMCID: PMC4675908 DOI: 10.5306/wjco.v6.i6.225] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 08/01/2015] [Accepted: 09/08/2015] [Indexed: 02/06/2023] Open
Abstract
Adjuvant chemotherapy has become a standard treatment of advanced rectal cancer in the West. The benefits of adjuvant chemotherapy after surgery alone have been well established. However, controversy surrounds the use adjuvant chemotherapy in patients who received preoperative chemoradiotherapy, despite it being recommended by a number of international guidelines. Results of recent multicentre randomised control trials showed no benefit of adjuvant chemotherapy in terms of survival and rates of distant metastases. However, concerns exist regarding the quality of the studies including inadequate staging modalities, out-dated chemotherapeutic regimens and surgical approaches and small sample sizes. It has become evident that not all the patients respond to adjuvant chemotherapy and more personalised approach should be employed when considering the benefits of adjuvant chemotherapy. The present review discusses the strengths and weaknesses of the current evidence-base and suggests improvements for future studies.
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Exploring Different Strategies for Efficient Delivery of Colorectal Cancer Therapy. Int J Mol Sci 2015; 16:26936-52. [PMID: 26569228 PMCID: PMC4661854 DOI: 10.3390/ijms161125995] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 10/29/2015] [Accepted: 10/30/2015] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death in the world. Currently available chemotherapy of CRC usually delivers the drug to both normal as well as cancerous tissues, thus leading to numerous undesirable effects. Much emphasis is being laid on the development of effective drug delivery systems for achieving selective delivery of the active moiety at the anticipated site of action with minimized unwanted side effects. Researchers have employed various techniques (dependent on pH, time, pressure and/or bacteria) for targeting drugs directly to the colonic region. On the other hand, systemic drug delivery strategies to specific molecular targets (such as FGFR, EGFR, CD44, EpCAM, CA IX, PPARγ and COX-2) overexpressed by cancerous cells have also been shown to be effective. This review aims to put forth an overview of drug delivery technologies that have been, and may be developed, for the treatment of CRC.
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Hsieh YT, Lin HP, Chen BM, Huang PT, Roffler SR. Effect of Cellular Location of Human Carboxylesterase 2 on CPT-11 Hydrolysis and Anticancer Activity. PLoS One 2015; 10:e0141088. [PMID: 26509550 PMCID: PMC4624787 DOI: 10.1371/journal.pone.0141088] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 10/03/2015] [Indexed: 01/08/2023] Open
Abstract
CPT-11 is an anticancer prodrug that is clinically used for the treatment of metastatic colorectal cancer. Hydrolysis of CPT-11 by human carboxylesterase 2 (CE2) generates SN-38, a topoisomerase I inhibitor that is the active anti-tumor agent. Expression of CE2 in cancer cells is under investigation for the tumor-localized activation of CPT-11. CE2 is normally expressed in the endoplasmic reticulum of cells but can be engineered to direct expression of active enzyme on the plasma membrane or as a secreted form. Although previous studies have investigated different locations of CE2 expression in cancer cells, it remains unclear if CE2 cellular location affects CPT-11 anticancer activity. In the present study, we directly compared the influence of CE2 cellular location on substrate hydrolysis and CPT-11 cytotoxicity. We linked expression of CE2 and enhanced green fluorescence protein (eGFP) via a foot-and-mouth disease virus 2A (F2A) peptide to facilitate fluorescence-activated cell sorting to achieve similar expression levels of ER-located, secreted or membrane-anchored CE2. Soluble CE2 was detected in the medium of cells that expressed secreted and membrane-anchored CE2, but not in cells that expressed ER-retained CE2. Cancer cells that expressed all three forms of CE2 were more sensitive to CPT-11 as compared to unmodified cancer cells, but the membrane-anchored and ER-retained forms of CE2 were consistently more effective than secreted CE2. We conclude that expression of CE2 in the ER or on the membrane of cancer cells is suitable for enhancing CPT-11 anticancer activity.
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Affiliation(s)
- Yuan-Ting Hsieh
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Hsuan-Pei Lin
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Bing-Mae Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Ping-Ting Huang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Steve R. Roffler
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- * E-mail:
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Mallarkey G, Mangoni AA. Targeting precision medicine toxicity: recent developments. Ther Adv Drug Saf 2015; 6:4-14. [PMID: 25642318 DOI: 10.1177/2042098614560737] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Affiliation(s)
- Gordon Mallarkey
- Sage Publications Ltd, 1 Oliver's Yard, 55 City Road, London, EC1Y 1SP, London, UK
| | - Arduino A Mangoni
- Department of Clinical Pharmacology, School of Medicine, Flinders University and Flinders Medical Centre, Bedford Park, SA 5042, Australia
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Abstract
Diarrhoea induced by chemotherapy in cancer patients is common, causes notable morbidity and mortality, and is managed inconsistently. Previous management guidelines were based on poor evidence and neglect physiological causes of chemotherapy-induced diarrhoea. In the absence of level 1 evidence from randomised controlled trials, we developed practical guidance for clinicians based on a literature review by a multidisciplinary team of clinical oncologists, dietitians, gastroenterologists, medical oncologists, nurses, pharmacist, and a surgeon. Education of patients and their carers about the risks associated with, and management of, chemotherapy-induced diarrhoea is the foundation for optimum treatment of toxic effects. Adequate--and, if necessary, repeated--assessment, appropriate use of loperamide, and knowledge of fluid resuscitation requirements of affected patients is the second crucial step. Use of octreotide and seeking specialist advice early for patients who do not respond to treatment will reduce morbidity and mortality. In view of the burden of chemotherapy-induced diarrhoea, appropriate multidisciplinary research to assess meaningful endpoints is urgently required.
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Costi R, Leonardi F, Zanoni D, Violi V, Roncoroni L. Palliative care and end-stage colorectal cancer management: The surgeon meets the oncologist. World J Gastroenterol 2014; 20:7602-7621. [PMID: 24976699 PMCID: PMC4069290 DOI: 10.3748/wjg.v20.i24.7602] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Accepted: 04/09/2014] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is a common neoplasia in the Western countries, with considerable morbidity and mortality. Every fifth patient with CRC presents with metastatic disease, which is not curable with radical intent in roughly 80% of cases. Traditionally approached surgically, by resection of the primitive tumor or stoma, the management to incurable stage IV CRC patients has significantly changed over the last three decades and is nowadays multidisciplinary, with a pivotal role played by chemotherapy (CHT). This latter have allowed for a dramatic increase in survival, whereas the role of colonic and liver surgery is nowadays matter of debate. Although any generalization is difficult, two main situations are considered, asymptomatic (or minimally symptomatic) and severely symptomatic patients needing aggressive management, including emergency cases. In asymptomatic patients, new CHT regimens allow today long survival in selected patients, also exceeding two years. The role of colonic resection in this group has been challenged in recent years, as it is not clear whether the resection of primary CRC may imply a further increase in survival, thus justifying surgery-related morbidity/mortality in such a class of short-living patients. Secondary surgery of liver metastasis is gaining acceptance since, under new generation CHT regimens, an increasing amount of patients with distant metastasis initially considered non resectable become resectable, with a significant increase in long term survival. The management of CRC emergency patients still represents a major issue in Western countries, and is associated to high morbidity/mortality. Obstruction is traditionally approached surgically by colonic resection, stoma or internal by-pass, although nowadays CRC stenting is a feasible option. Nevertheless, CRC stent has peculiar contraindications and complications, and its long-term cost-effectiveness is questionable, especially in the light of recently increased survival. Perforation is associated with the highest mortality and remains mostly matter for surgeons, by abdominal lavage/drainage, colonic resection and/or stoma. Bleeding and other CRC-related symptoms (pain, tenesmus, etc.) may be managed by several mini-invasive approaches, including radiotherapy, laser therapy and other transanal procedures.
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Bester L, Meteling B, Boshell D, Saxena A, Morris DL. Current role of transarterial chemoembolization and radioembolization in the treatment of metastatic colorectal cancer. Hepat Oncol 2014; 1:215-228. [PMID: 30190956 DOI: 10.2217/hep.13.21] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
In this article, we review two liver-directed therapies that are currently used for the palliative treatment of primary and secondary hepatic malignancies, transcatheter arterial chemoembolization (TACE), including a new type of TACE with drug-eluting beads, and radioembolization. Important developments and administration techniques for all therapies are discussed, as well as their integration into the current routine clinical care for management of metastatic colorectal cancer. According to published data from clinical trials, as presented in this review, both radioembolization and TACE/TACE with drug-eluting beads have been proven to be safe and effective in selected patients with chemorefractory liver metastases from colorectal cancer. For patients with unresectable liver-only or liver-dominant disease who have failed standard chemotherapy options or for whom chemotherapy is contraindicated, new modalities, such as those discussed, are particularly valid and promising if clinical guidelines for patient selection and treatment administration are followed.
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Affiliation(s)
- Lourens Bester
- Department of Interventional Radiology, University of New South Wales, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.,Department of Interventional Radiology, University of New South Wales, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia
| | - Baerbel Meteling
- Department of Interventional Radiology, University of New South Wales, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.,Department of Interventional Radiology, University of New South Wales, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia
| | - David Boshell
- Department of Interventional Radiology, University of New South Wales, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.,Department of Interventional Radiology, University of New South Wales, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia
| | - Akshat Saxena
- Department of Surgery, University of New South Wales, St. George Hospital, Kogarah, New South Wales 2217, Australia.,Department of Surgery, University of New South Wales, St. George Hospital, Kogarah, New South Wales 2217, Australia
| | - David L Morris
- Department of Surgery, University of New South Wales, St. George Hospital, Kogarah, New South Wales 2217, Australia.,Department of Surgery, University of New South Wales, St. George Hospital, Kogarah, New South Wales 2217, Australia
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Abstract
Most hepatotoxicity secondary to chemotherapy is idiosyncratic and, therefore, neither dose dependent nor predictable. Some chemotherapy is cleared by the liver and requires dose adjustment in the face of significant liver dysfunction. In addition, preexisting abnormal liver function has been shown to increase the risk of hepatotoxicity. In addition to typical hepatocellular injury, other presentations, including cholestasis and hepatic sinusoidal obstruction syndrome, also commonly occur. The outcomes can range from asymptomatic liver function test abnormalities, which resolve spontaneously, to cirrhosis, which occurs despite discontinuation of the chemotherapeutic agent.
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Affiliation(s)
- Ameet V Thatishetty
- Department of Medicine, Memorial Health, University Medical Center, 4700 Waters Avenue, Savannah, GA 31403, USA
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Moreno Loaíza Ó, Neira Rojas D. Primary duodenal adenocarcinoma: case report of an infrequent tumor. Medwave 2013. [DOI: 10.5867/medwave.2013.09.5821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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[What is the contribution of tumor response in colorectal cancer?]. Bull Cancer 2013; 100:743-55. [PMID: 23831844 DOI: 10.1684/bdc.2013.1780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Tumor size reduction after cancer treatment is evaluated by tumor response. It is often the primary objective of phase II clinical trials. The WHO and RECIST criteria are now internationally recognized for the quantification of tumor response in clinical trials. This literature review article focuses on the interest of measuring tumor response according to these criteria in terms of clinical benefit for patients with metastatic colorectal cancer (mCRC): metastasis resection, survival and improving quality of life. In patients with mCRC and initially resectable metastases, tumor response following preoperative chemotherapy is an independent prognosis factor for survival and a way of testing tumor sensitivity to the chemotherapy regime; it allows and/or facilitates metastases resection. In patients with mCRC and potentially resectable metastases, obtaining an objective tumor response to allow secondary metastasis resection is one of the primary objectives of chemotherapy. In patients with mCRC and non-resectable metastases, tumor response may provide individual benefit in terms of control of symptoms and quality of life and may favor a survival benefit. Despite the limitations of the RECIST criteria, no other morphological or functional radiological criterion has to date achieved consensus up in terms of availability, reproducibility, sensitivity, specificity, clinical relevance and cost. Finally, although there is no high-level of evidence, tumor response has prognostic value for metastases resection in mCRC and is a therapeutic objective in patients with potentially resectable metastases or symptomatic advanced disease.
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Hare JI, Neijzen RW, Anantha M, Dos Santos N, Harasym N, Webb MS, Allen TM, Bally MB, Waterhouse DN. Treatment of colorectal cancer using a combination of liposomal irinotecan (Irinophore C™) and 5-fluorouracil. PLoS One 2013; 8:e62349. [PMID: 23626804 PMCID: PMC3633892 DOI: 10.1371/journal.pone.0062349] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Accepted: 03/22/2013] [Indexed: 01/09/2023] Open
Abstract
Purpose To investigate the use of liposomal irinotecan (Irinophore C™) plus or minus 5-fluorouracil (5-FU) for the treatment of colorectal cancer. Experimental Design The effect of irinotecan (IRI) and/or 5-FU exposure times on cytotoxicity was assessed in vitro against HT-29 or LS174T human colon carcinoma cells. The pharmacokinetics and biodistribution of Irinophore C™ (IrC™) and 5-FU, administered alone or in combination, were compared in vivo. A subcutaneous model of HT-29 human colorectal cancer in Rag2-M mice was utilized to assess the efficacy of IrC™ alone, and in combination with 5-FU. Results The cytotoxicity of IRI and 5-FU were strongly dependent on exposure time. Synergistic interactions were observed following prolonged exposure to IRI/5-FU combinations. Pharmacokinetics/biodistribution studies demonstrated that the 5-FU elimination rate was decreased significantly when 5-FU was co-administered intravenously with IrC™, versus alone. Significant decreases in 5-FU elimination were also observed in plasma, with an associated increase of 5-FU in some tissues when 5-FU was given by intraperitoneal injection and IrC™ was given intravenously. The elimination of IrC™ was not significantly different when administered alone or in combination with 5-FU. Therapeutic studies demonstrated that single agent IrC™ was significantly more effective than the combination of IRI/5-FU; surprisingly, IrC™/5-FU combinations were no more effective than IrC™ alone. The administration of combinations of 5-FU (16 mg/kg) and IrC™ (60 mg IRI/kg) showed increased toxicity when compared to IrC™ alone. Treatment with IrC™ alone (60 mg IRI/kg) delayed the time required for a 5-fold increase in initial tumor volume to day 49, compared to day 23 for controls. When IrC™ (40 mg IRI/kg) was used in combination with 5-FU (16 mg/kg), the time to increase tumor volume 5-fold was 43 days, which was comparable to that achieved when using IrC™ alone (40 mg IRI/kg). Conclusions Single agent IrC™ was well tolerated and has significant therapeutic potential. IrC™ may be a suitable replacement for IRI treatment, but its use with free 5-FU is complicated by IrC™-engendered changes in 5-FU pharmacokinetics/biodistribution which are associated with increased toxicity when using the combination.
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Affiliation(s)
- Jennifer I. Hare
- Department of Pharmacology, University of Alberta, Edmonton, Canada
| | - Robert W. Neijzen
- Department of Pharmaceutical Science, Universiteit Utrecht, Utrecht, Netherlands
| | - Malathi Anantha
- Experimental Therapeutics, BC Cancer Agency, Vancouver, Canada
| | | | | | - Murray S. Webb
- Centre for Drug Research and Development, Vancouver, Canada
| | - Theresa M. Allen
- Department of Pharmacology, University of Alberta, Edmonton, Canada
- Centre for Drug Research and Development, Vancouver, Canada
| | - Marcel B. Bally
- Experimental Therapeutics, BC Cancer Agency, Vancouver, Canada
- Centre for Drug Research and Development, Vancouver, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada
| | - Dawn N. Waterhouse
- Experimental Therapeutics, BC Cancer Agency, Vancouver, Canada
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada
- * E-mail:
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Messori A, Santarlasci B, Trippoli S. Guadagno di sopravvivenza dei nuovi farmaci. ACTA ACUST UNITED AC 2013. [DOI: 10.1007/bf03320627] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Solbiati L, Ahmed M, Cova L, Ierace T, Brioschi M, Goldberg SN. Small liver colorectal metastases treated with percutaneous radiofrequency ablation: local response rate and long-term survival with up to 10-year follow-up. Radiology 2012; 265:958-968. [PMID: 23091175 DOI: 10.1148/radiol.12111851] [Citation(s) in RCA: 260] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE To determine the long-term (10-year) survival of patients with colorectal liver metastases treated with radiofrequency (RF) ablation and systemic chemotherapy with intention to treat. MATERIALS AND METHODS Institutional review board approval was obtained for this study. From 1997 to 2006, 99 consecutive patients with 202 small (0.8-4.0 cm; mean: 2.2 cm ± 1.1) metachronous colorectal liver metastases underwent ultrasonography-guided percutaneous RF ablation with internally-cooled electrodes in association with systemic chemotherapy. Patients ineligible for surgery (n = 80) or whose lesions were potentially resectable and who refused surgery (n = 19) were included. Patients were followed up with contrast agent-enhanced computed tomography and/or magnetic resonance imaging for a minimum of 3 years to more than 10 years after RF ablation (n = 99, 67, 49, and 25 for 3, 5, 7, and 10 or more years, respectively). Overall local response rates and long-term survival rates were assessed. For each of these primary endpoints, Kaplan-Meier curves were generated and log-rank tests were used to assess for statistically significant differences. RESULTS Primary and secondary technical success rates were 93.1% (188 of 202) and 100% (14 of 14), respectively. Local tumor progression occurred in 11.9% (24 of 202) metastases, and 54.2% (13 of 24) of these were re-treated. Patient survival rates increased with re-treatment versus no re-treatment (P < .001). At follow-up, 125 new liver metastases were found, and of these 32.8% (41 of 125) were treated with RF ablation. Overall survival rates were 98.0%, 69.3%, 47.8%, 25.0%, and 18.0% (median: 53.2 months) at 1, 3, 5, 7, and 10 years, respectively. The major complication rate was 1.3% (two of 156), and there were no procedure-related deaths. At the time this article was written, 32.3% (32 of 99) of the patients were alive, and 67.7% (67 of 99) were deceased, with a median follow-up of 72 months. CONCLUSION Adding RF ablation to systemic chemotherapy achieved local control in a large majority of metachronous colorectal liver metastases. The 3- to 10-year survival rates of this relatively large series of patients were essentially equivalent to those of most surgical series reported in the literature.
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Affiliation(s)
- Luigi Solbiati
- Department of Interventional Oncologic Radiology, General Hospital of Busto Arsizio, Busto Arsizio, Italy
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Yeung Y, Tebbutt NC. Bevacizumab in colorectal cancer: current and future directions. Expert Rev Anticancer Ther 2012; 12:1263-73. [PMID: 23113577 DOI: 10.1586/era.12.104] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Bevacizumab is a humanized monoclonal antibody to VEGF-A, an important therapeutic target through its proangiogenic effects on a variety of tumors. Bevacizumab has demonstrated clinically meaningful benefit in conjunction with chemotherapy for patients with metastatic colorectal cancer as well as other tumor types. Bevacizumab is a well-tolerated therapy with regard to toxicity, in keeping with its biological vascular effect. In this era of personalized medicine, current Phase II and III trials are further defining its role at various stages of metastatic disease and the optimal sequencing with cytotoxic and other targeted agents to achieve further improvements in patient outcome. Translational research for biomarker discovery and validation and further study into mechanisms of resistance are essential for future development and sustained benefit with this class of therapeutic agents.
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Affiliation(s)
- Yvonne Yeung
- Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Heidelberg, Australia
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48
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Integrating Radioembolization (90Y Microspheres) Into Current Treatment Options for Liver Tumors. Am J Clin Oncol 2012; 35:81-90. [DOI: 10.1097/coc.0b013e3181ec60b8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Rottlaender D, Reda S, Motloch LJ, Hoppe UC. [New tyrosine kinase and EGFR inhibitors in cancer therapy. Cardiac and skin toxicity as relevant side effects. Part A: heart]. Internist (Berl) 2011; 52:1245-55. [PMID: 21792599 DOI: 10.1007/s00108-011-2895-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Cardiotoxicity is a serious side effect of targeted molecular therapies in cancer treatment. Monoclonal antibodies and tyrosine kinase inhibitors are known to be potent therapies in various neoplastic diseases due to inhibition of specific signal transduction pathways. Although targeted therapies are considered to be less toxic and better tolerated than common chemotherapies certain cardiac side effects have been observed. Cardiac toxicity may range from asymptomatic reduction of left ventricular function to life-threatening events like heart failure and acute coronary syndrome. Further side effects are arterial hypertension, thrombosis and arrhythmias. Cardiovascular side effects are common for anti-HER2 therapy in combination with anthracyclines and for inhibitors of angiogenesis. In these patients careful cardiac monitoring is warranted. Because of missing randomized long-term follow-ups, information about cardiac side effects is limited in newly developed targeted molecular therapies. In case of cardiac side effects or preexisting cardiac disease before therapy initiation, assessments by a cardiologist throughout the course of treatment are important. For patients with severe cardiac side effects, discontinuation of treatment is warranted; in case of asymptomatic cardiac side effects symptom-specific therapy should be performed.
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Affiliation(s)
- D Rottlaender
- Klinik III für Innere Medizin, Universität zu Köln, Kerpener-Straße 62, 50937, Köln, Deutschland
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Cao S, Durrani FA, Toth K, Rustum YM, Seshadri M. Bevacizumab enhances the therapeutic efficacy of Irinotecan against human head and neck squamous cell carcinoma xenografts. Oral Oncol 2011; 47:459-66. [PMID: 21530364 PMCID: PMC3109241 DOI: 10.1016/j.oraloncology.2011.04.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Revised: 03/31/2011] [Accepted: 04/01/2011] [Indexed: 12/30/2022]
Abstract
Combining antiangiogenic agents with traditional cytotoxic chemotherapy offers the potential to target both vascular and cellular components of a growing tumor mass. Here, we examined the antitumor activity of the vascular endothelial growth factor antibody, Bevacizumab (Avastin®) in combination with the topoisomerase I inhibitor, Irinotecan (CPT-11) against human head and neck squamous cell carcinoma (HNSCC) xenografts. Bevacizumab was administered daily (at 5 or 20mg/kg) to nude mice bearing FaDu HNSCC xenografts for 28days with the first dose beginning seven days prior to Irinotecan (100mg/kg, weekly × 4). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and immunohistochemical (IHC) methods were employed to study the antiangiogenic effects of Bevacizumab in vivo. Kinetics of tumor response to treatment was studied by monitoring tumor volume over a 60-day period. DCE-MRI detected a significant reduction in vascular permeability following treatment with Bevacizumab (5mg/kg) while high dose Bevacizumab (20mg/kg) induced significant microvascular damage and tumor necrosis, confirmed by immunohistochemistry (IHC). Irinotecan alone resulted in complete tumor regression (cures) in ∼40% of animals while Bevacizumab alone did not result in any cures. Treatment with Bevacizumab (5mg/kg/day×28days) in combination with Irinotecan (100mg/kg, weekly × 4) was highly effective in inhibiting FaDu tumor growth and resulted in complete tumor regression in 80% of animals. These results demonstrate that long term administration of Bevacizumab effectively modulates chemotherapeutic efficacy against HNSCC xenografts. Further investigation into the therapeutic potential of this combination strategy against HNSCC is warranted.
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Affiliation(s)
- Shousong Cao
- Department of Cancer Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York, USA
- Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York, USA
| | - Farukh A. Durrani
- Department of Cancer Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York, USA
| | - Karoly Toth
- Department of Cancer Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York, USA
| | - Youcef. M. Rustum
- Department of Cancer Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York, USA
| | - Mukund Seshadri
- Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York, USA
- Department of Dentistry and Maxillofacial Prosthetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York, USA
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