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Ying K, Bai B, Gao X, Xu Y, Wang H, Xie B. Orally Administrable Therapeutic Nanoparticles for the Treatment of Colorectal Cancer. Front Bioeng Biotechnol 2021; 9:670124. [PMID: 34307319 PMCID: PMC8293278 DOI: 10.3389/fbioe.2021.670124] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 05/14/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common and lethal human malignancies worldwide; however, the therapeutic outcomes in the clinic still are unsatisfactory due to the lack of effective and safe therapeutic regimens. Orally administrable and CRC-targetable drug delivery is an attractive approach for CRC therapy as it improves the efficacy by local drug delivery and reduces systemic toxicity. Currently, chemotherapy remains the mainstay modality for CRC therapy; however, most of chemo drugs have low water solubility and are unstable in the gastrointestinal tract (GIT), poor intestinal permeability, and are susceptible to P-glycoprotein (P-gp) efflux, resulting in limited therapeutic outcomes. Orally administrable nanoformulations hold the great potential for improving the bioavailability of poorly permeable and poorly soluble therapeutics, but there are still limitations associated with these regimes. This review focuses on the barriers for oral drug delivery and various oral therapeutic nanoparticles for the management of CRC.
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Affiliation(s)
- Kangkang Ying
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC), Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, China
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bingjun Bai
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xing Gao
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuzi Xu
- Department of Oral Implantology and Prosthodontics, The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, China
| | - Hangxiang Wang
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC), Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, China
| | - Binbin Xie
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC), Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Hangzhou, China
- Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Kim CD, Kim SH, Jung SH, Kim JH. Clinical value of an adenosine triphosphate-based chemotherapy response assay in resectable stage III colorectal cancer. Ann Surg Treat Res 2019; 97:93-102. [PMID: 31384612 PMCID: PMC6669130 DOI: 10.4174/astr.2019.97.2.93] [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: 03/22/2019] [Revised: 06/23/2019] [Accepted: 07/02/2019] [Indexed: 12/02/2022] Open
Abstract
Purpose ATP-based chemotherapy response assay (ATP-CRA) is a well-documented and validated technology that can individualize chemotherapy. This study was undertaken to assess the usefulness of ATP-CRA in advanced colorectal cancer (CRC) patients receiving adjuvant chemotherapy. Methods A total of 136 patients with curative resection between January 2006 and April 2014 were evaluated using ATP-CRA. Patients received either the FOLFOX or Mayo clinic regimen chemotherapy following assay results. The sensitive-group (S-group) was defined as a drug-producing ≥ 40% reduction in ATP, and the resistant-group (R-group) as an ATP reduction of < 40%. These 2 groups were further subdivided to produce 4 subgroups: the FOLFOX sensitive subgroup (the FS subgroup [n = 65]), the Mayo sensitive subgroup (the MS subgroup [n = 40]), the FOLFOX resistant subgroup (the FR subgroup [n = 10]), and the Mayo resistant subgroup (the MR subgroup [n = 21]). Clinical responses and survival results were compared for both treatment regimens. Results The FS and MS subgroups showed a better disease-free survival rate (29% vs. 40%, 35% vs. 47.6%) and overall survival rate (92.3% vs. 80.0%, 87.5% vs. 76.2%) than FR and MR subgroups. The FS and MS subgroups showed a longer time to relapse (20.2 months vs. 9.5 months, 17.6 months vs. 16.4 months) than the FR and MR subgroups. Conclusion ATP-CRA tailored-chemotherapy has the potential to provide a survival benefit in resectable advanced CRC.
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Affiliation(s)
- Chan Dong Kim
- Division of Colorectal Surgery, Department of Surgery, Yeungnam University Medical Center, Daegu, Korea
| | - So Hyun Kim
- Division of Colorectal Surgery, Department of Surgery, Yeungnam University Medical Center, Daegu, Korea
| | - Sang Hoon Jung
- Division of Colorectal Surgery, Department of Surgery, Yeungnam University Medical Center, Daegu, Korea
| | - Jae Hwang Kim
- Division of Colorectal Surgery, Department of Surgery, Yeungnam University Medical Center, Daegu, Korea
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Li LY, Kim SW, Nam EJ, Lee J, Kim S, Kim YT. Adenosine triphosphate-based chemotherapy response assay predicts long-term survival of primary epithelial ovarian cancer. Int J Gynecol Cancer 2019; 29:334-340. [PMID: 30718314 DOI: 10.1136/ijgc-2018-000058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 10/19/2018] [Accepted: 10/22/2018] [Indexed: 12/09/2022] Open
Abstract
OBJECTIVE The aim of this study is to analyze the long-term relapse-free survival and overall survival outcomes of primary ovarian cancer patients using adenosine triphosphate-based chemotherapy response analysis. METHODS In total, 162 primary epithelial ovarian cancer patients who underwent chemotherapy response assay for carboplatin, cisplatin, and paclitaxel by adenosine triphosphate-based chemotherapy response analysis prior to chemotherapy between December 2006 and November 2016 were retrospectively reviewed. Chemosensitivity with single or combined three agents and clinical characteristics of patients were studied to understand their correlation with long-term relapse-free survival and overall survival. RESULTS Median follow-up time was 61.4 (range 1 - 130) months. Univariate analysis showed the paclitaxel-sensitive group (HR = 0.625, 95%CI = 0.393 to 0.994), combined carboplatin and paclitaxel-sensitive group (HR = 0.574, 95%CI = 0.352 to 0.937), and combined carboplatin, cisplatin, and paclitaxel-sensitive group (HR = 0.489, 95%CI = 0.295 to 0.810) were highly associated with better relapse-free survival than their corresponding non-sensitive groups. The carboplatin-sensitive group (HR = 0.533, 95%CI = 0.303 to 0.939), cisplatin-sensitive group (HR = 0.433. 95%CI = 0.251 to 0.748), and combined carboplatin- and cisplatin-sensitive group (HR = 0.286, 95%CI = 0.142 to 0.576) were highly associated with better overall survival than their corresponding non-sensitive groups. Combined carboplatin, cisplatin, and paclitaxel chemosensitivity, together with International Federation of Gynecology and Obstetrics (FIGO) stage were independent predictors for relapse-free survival. Single or combined chemosensitivity of cisplatin and/or carboplatin, together with residual tumor size and FIGO stage, were significant independent predictors for overall survival on a multivariate hazard model. CONCLUSION Paclitaxel sensitivity is a prognostic factor of long-term relapse-free survival in patients with epithelial ovarian cancer, but platinum sensitivity is a more important prognostic factor for long-term overall survival.
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MESH Headings
- Adenocarcinoma, Clear Cell/drug therapy
- Adenocarcinoma, Clear Cell/metabolism
- Adenocarcinoma, Clear Cell/mortality
- Adenocarcinoma, Clear Cell/pathology
- Adenocarcinoma, Mucinous/drug therapy
- Adenocarcinoma, Mucinous/metabolism
- Adenocarcinoma, Mucinous/mortality
- Adenocarcinoma, Mucinous/pathology
- Adenosine Triphosphate/metabolism
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Carboplatin/administration & dosage
- Cystadenocarcinoma, Serous/drug therapy
- Cystadenocarcinoma, Serous/metabolism
- Cystadenocarcinoma, Serous/mortality
- Cystadenocarcinoma, Serous/pathology
- Docetaxel/administration & dosage
- Endometrial Neoplasms/drug therapy
- Endometrial Neoplasms/metabolism
- Endometrial Neoplasms/mortality
- Endometrial Neoplasms/pathology
- Female
- Follow-Up Studies
- Humans
- Middle Aged
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/metabolism
- Neoplasm Recurrence, Local/mortality
- Neoplasm Recurrence, Local/pathology
- Ovarian Neoplasms/drug therapy
- Ovarian Neoplasms/metabolism
- Ovarian Neoplasms/mortality
- Ovarian Neoplasms/pathology
- Paclitaxel/administration & dosage
- Prognosis
- Retrospective Studies
- Survival Rate
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Affiliation(s)
- Lan Ying Li
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Wun Kim
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Ji Nam
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - JungYun Lee
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sunghoon Kim
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young Tae Kim
- Department of Obstetrics and Gynecology, Women's Cancer Center, Yonsei cancer Center, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
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Kwon HY, Kim IK, Kang J, Sohn SK, Lee KY. In Vitro Adenosine Triphosphate-Based Chemotherapy Response Assay as a Predictor of Clinical Response to Fluorouracil-Based Adjuvant Chemotherapy in Stage II Colorectal Cancer. Cancer Res Treat 2016; 48:970-977. [PMID: 26511802 PMCID: PMC4946364 DOI: 10.4143/crt.2015.140] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Accepted: 09/30/2015] [Indexed: 12/20/2022] Open
Abstract
PURPOSE We evaluated the usefulness of the in vitro adenosine triphosphate-based chemotherapy response assay (ATP-CRA) for prediction of clinical response to fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer. MATERIALS AND METHODS Tumor specimens of 86 patients with pathologically confirmed stage II colorectal adenocarcinoma were tested for chemosensitivity to fluorouracil. Chemosensitivity was determined by cell death rate (CDR) of drug-exposed cells, calculated by comparing the intracellular ATP level with that of untreated controls. RESULTS Among the 86 enrolled patients who underwent radical surgery followed by fluorouracil-based adjuvant chemotherapy, recurrence was found in 11 patients (12.7%). The CDR ≥ 20% group was associated with better disease-free survival than the CDR < 20% group (89.4% vs. 70.1%, p=0.027). Multivariate analysis showed that CDR < 20% and T4 stage were poor prognostic factors for disease-free survival after fluorouracil-based adjuvant chemotherapy. CONCLUSION In stage II colorectal cancer, the in vitro ATP-CRA may be useful in identifying patients likely to benefit from fluorouracil-based adjuvant chemotherapy.
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Affiliation(s)
- Hye Youn Kwon
- Department of Surgery, Sahmyook Medical Center, Seoul, Korea
| | - Im-kyung Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jeonghyun Kang
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Seung-Kook Sohn
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kang Young Lee
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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Park JS, Kim JK, Yoon DS. Correlation of Early Recurrence With In Vitro Adenosine Triphosphate Based Chemotherapy Response Assay in Pancreas Cancer With Postoperative Gemcitabine Chemotherapy. J Clin Lab Anal 2016; 30:804-810. [PMID: 26991127 DOI: 10.1002/jcla.21940] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Revised: 12/13/2015] [Accepted: 12/28/2015] [Indexed: 11/05/2022] Open
Abstract
INTRODUCTION Gemcitabine-based regimens represent the standard systemic first line treatment in patients after pancreatic resection. However, the clinical impact of gemcitabine varies significantly in individuals because of chemoresistance. An in vitro adenosine triphosphate based chemotherapy response assay (ATP-CRA) was designed to evaluate the sensitivity of cancer cells to various chemotherapeutic agents. This study investigated the correlation between in vitro gemcitabine sensitivity of tumor cells and early recurrence after curative resection. METHOD From January 2007 to December 2010, the ATP-CRA for gemcitabine was tested in 64 patients surgically treated for pancreas cancer at Gangnam Severance Hospital, Seoul, Korea. We analyzed the relationship between chemosensitivity and early systemic recurrence in patients with pancreas cancer to predict disease-free survival (DFS) after curative resection in pancreas cancer. RESULT The mean cell death rate (CDR) was 20.0 (±14.5) and divided into two groups according to the mean values of the CDR. Lymphovascular invasion was more frequently shown in gemcitabine resistance group without statistical significance. In univariate and multivariate analysis, advanced tumor stage and gemcitabine sensitive group (CDR ≥ 20) were identified as independent prognostic factors for DFS. CONCLUSIONS Gemcitabine sensitivity measured by ATP-CRA was well correlated with in vivo drug responsibility to predict early recurrence following gemcitabine-based adjuvant chemotherapy in patients with pancreas cancer.
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Affiliation(s)
- Joon Seong Park
- Pancreatobiliary Cancer Clinic, Department of Surgery, Gangnam Severance Hospital, Yonsei University Health System, Seoul, Korea
| | - Jae Keun Kim
- Pancreatobiliary Cancer Clinic, Department of Surgery, Gangnam Severance Hospital, Yonsei University Health System, Seoul, Korea
| | - Dong Sup Yoon
- Pancreatobiliary Cancer Clinic, Department of Surgery, Gangnam Severance Hospital, Yonsei University Health System, Seoul, Korea.
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Bounaix Morand du Puch C, Nouaille M, Giraud S, Labrunie A, Luce S, Preux PM, Labrousse F, Gainant A, Tubiana-Mathieu N, Le Brun-Ly V, Valleix D, Guillaudeau A, Mesturoux L, Coulibaly B, Lautrette C, Mathonnet M. Chemotherapy outcome predictive effectiveness by the Oncogramme: pilot trial on stage-IV colorectal cancer. J Transl Med 2016; 14:10. [PMID: 26791256 PMCID: PMC4721000 DOI: 10.1186/s12967-016-0765-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 12/28/2015] [Indexed: 12/25/2022] Open
Abstract
Background Colorectal cancer (CRC) remains a major public concern. While conventional chemotherapeutic regimens have proved useful against advanced/metastatic diseases, progresses are to be made to effectively cure the large portion of patients not benefiting from these treatments. One direction to improve response rates is to develop chemosensitivity and resistance assays (CSRAs) efficiently assisting clinicians in treatment selection process, an already long preoccupation of oncologists and researchers. Several methods have been described to this day, none achieving yet sufficient reliability for recommended use in the clinical routine. Methods
We led a pilot study on 19 metastatic CRC patients evaluating capacity of the Oncogramme, a standardized process using tumor ex vivo models, to provide chemosensitivity profiles and predict clinical outcome of patients receiving standard CRC chemotherapeutics. Oncogramme responses were categorized according to the method of percentiles to assess sensitivity, specificity and concordance. Results We report from a primary analysis a success rate of 97.4 %, a very good sensitivity (84.6 %), a below-average specificity (33.3 %), along with a global agreement of 63.6 % and a concordance between Oncogramme results and patients’ responses (Kappa coefficient) of 0.193. A supplementary analysis, focusing on CRC patients with no treatment switch over a longer time course, demonstrated improvement in specificity and concordance. Conclusions Results establish feasibility and usefulness of the Oncogramme, prelude to a larger-scale trial. Advantages and drawbacks of the procedure are discussed, as well as the place of CSRAs within the future arsenal of methods available to clinicians to individualize treatments and improve patient prognosis. Trial registration: ClinicalTrials.gov database, registration number: NCT02305368 Electronic supplementary material The online version of this article (doi:10.1186/s12967-016-0765-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | - Michelle Nouaille
- Centre d'Investigation Clinique, INSERM 1435, Centre hospitalier régional universitaire de Limoges Dupuytren, 2 avenue Martin Luther King, 87042, Limoges Cedex, France.
| | - Stéphanie Giraud
- Oncomedics SAS, ESTER technopole, 1 avenue d'Ester, 87069, Limoges, France.
| | - Anaïs Labrunie
- Centre d'Épidémiologie, de Biostatistique et de Méthodologie de la Recherche, Centre hospitalier régional universitaire de Limoges Dupuytren, 2 rue du Dr Marcland, 87025, Limoges Cedex, France.
| | - Sandrine Luce
- Centre d'Épidémiologie, de Biostatistique et de Méthodologie de la Recherche, Centre hospitalier régional universitaire de Limoges Dupuytren, 2 rue du Dr Marcland, 87025, Limoges Cedex, France.
| | - Pierre-Marie Preux
- Centre d'Épidémiologie, de Biostatistique et de Méthodologie de la Recherche, Centre hospitalier régional universitaire de Limoges Dupuytren, 2 rue du Dr Marcland, 87025, Limoges Cedex, France.
| | - François Labrousse
- Centre hospitalier régional universitaire de Limoges Dupuytren, service d'anatomopathologie, 2 avenue Martin Luther King, 87042, Limoges Cedex, France.
| | - Alain Gainant
- Centre hospitalier régional universitaire de Limoges Dupuytren, service de chirurgie digestive, 2 rue du Dr Marcland, 87025, Limoges, France.
| | - Nicole Tubiana-Mathieu
- Centre hospitalier régional universitaire de Limoges Dupuytren, service d'oncologie médicale, 2 avenue Martin Luther King, 87042, Limoges Cedex, France.
| | - Valérie Le Brun-Ly
- Centre hospitalier régional universitaire de Limoges Dupuytren, service d'oncologie médicale, 2 avenue Martin Luther King, 87042, Limoges Cedex, France.
| | - Denis Valleix
- Centre hospitalier régional universitaire de Limoges Dupuytren, service de chirurgie viscérale, 2 avenue Martin Luther King, 87042, Limoges Cedex, France.
| | - Angélique Guillaudeau
- Centre hospitalier régional universitaire de Limoges Dupuytren, service d'anatomopathologie, 2 avenue Martin Luther King, 87042, Limoges Cedex, France.
| | - Laura Mesturoux
- Centre hospitalier régional universitaire de Limoges Dupuytren, service d'anatomopathologie, 2 avenue Martin Luther King, 87042, Limoges Cedex, France.
| | - Béma Coulibaly
- Centre hospitalier régional universitaire de Limoges Dupuytren, service d'anatomopathologie, 2 avenue Martin Luther King, 87042, Limoges Cedex, France.
| | | | - Muriel Mathonnet
- Centre hospitalier régional universitaire de Limoges Dupuytren, service de chirurgie digestive générale et endocrinienne, 2 avenue Martin Luther King, 87042, Limoges Cedex, France. .,Université de Limoges, Institut 145 GEIST, EA 3842 "Homéostasie cellulaire et pathologies", Facultés de médecine et de pharmacie, 2 rue du Dr Marcland, 87025, Limoges Cedex, France.
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Yoon YS, Kim JC. Recent applications of chemosensitivity tests for colorectal cancer treatment. World J Gastroenterol 2014; 20:16398-16408. [PMID: 25469008 PMCID: PMC4248183 DOI: 10.3748/wjg.v20.i44.16398] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 07/08/2014] [Accepted: 08/13/2014] [Indexed: 02/06/2023] Open
Abstract
The evaluation of therapeutic efficacy is necessary to predict the outcome of patients with metastatic colorectal cancer (CRC). In these patients, there is a critical need for predictive chemosensitivity assays and biomarkers to optimize efficacy and minimize toxicity. The introduction of targeted agents has improved the progression-free survival and overall survival of patients with metastatic disease. However, approximately 50% of patients do not show a positive response to chemotherapy and the selection of patients likely to respond to a specific regimen remains challenging. Cell culture-based chemosensitivity tests use autologous viable tumor cells to evaluate susceptibility to specific agents in vitro and predict their direct effects. Adenosine triphosphate-based assays and methyl thiazolyl-diphenyl-tetrazolium bromide-based assays are used widely as sensitivity tests because of their short assay period, technical simplicity, and the requirement of small amount of specimen. Among protein- and gene-based chemosensitivity assays, assessment of KRAS mutation status predicts the response to epidermal growth factor receptor-targeted therapy in CRC patients. The validation of predictive and prognostic markers enables the selection of therapeutic regimens with optimal efficacy and minimal toxicity for each patient, which has been termed personalized treatment. This review summarizes currently available predictive and prognostic chemosensitivity tests for metastatic CRC.
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Burnstock G, Di Virgilio F. Purinergic signalling and cancer. Purinergic Signal 2014; 9:491-540. [PMID: 23797685 DOI: 10.1007/s11302-013-9372-5] [Citation(s) in RCA: 257] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2013] [Accepted: 06/06/2013] [Indexed: 01/24/2023] Open
Abstract
Receptors for extracellular nucleotides are widely expressed by mammalian cells. They mediate a large array of responses ranging from growth stimulation to apoptosis, from chemotaxis to cell differentiation and from nociception to cytokine release, as well as neurotransmission. Pharma industry is involved in the development and clinical testing of drugs selectively targeting the different P1 nucleoside and P2 nucleotide receptor subtypes. As described in detail in the present review, P2 receptors are expressed by all tumours, in some cases to a very high level. Activation or inhibition of selected P2 receptor subtypes brings about cancer cell death or growth inhibition. The field has been largely neglected by current research in oncology, yet the evidence presented in this review, most of which is based on in vitro studies, although with a limited amount from in vivo experiments and human studies, warrants further efforts to explore the therapeutic potential of purinoceptor targeting in cancer.
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Burnstock G. Purinergic signalling in the gastrointestinal tract and related organs in health and disease. Purinergic Signal 2014; 10:3-50. [PMID: 24307520 PMCID: PMC3944042 DOI: 10.1007/s11302-013-9397-9] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 10/24/2013] [Indexed: 01/04/2023] Open
Abstract
Purinergic signalling plays major roles in the physiology and pathophysiology of digestive organs. Adenosine 5'-triphosphate (ATP), together with nitric oxide and vasoactive intestinal peptide, is a cotransmitter in non-adrenergic, non-cholinergic inhibitory neuromuscular transmission. P2X and P2Y receptors are widely expressed in myenteric and submucous enteric plexuses and participate in sympathetic transmission and neuromodulation involved in enteric reflex activities, as well as influencing gastric and intestinal epithelial secretion and vascular activities. Involvement of purinergic signalling has been identified in a variety of diseases, including inflammatory bowel disease, ischaemia, diabetes and cancer. Purinergic mechanosensory transduction forms the basis of enteric nociception, where ATP released from mucosal epithelial cells by distension activates nociceptive subepithelial primary afferent sensory fibres expressing P2X3 receptors to send messages to the pain centres in the central nervous system via interneurons in the spinal cord. Purinergic signalling is also involved in salivary gland and bile duct secretion.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street, London, NW3 2PF, UK,
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Ge WQ, Pu JX, Zheng SY. Clinical application of the adenosine triphosphate-based response assay in intravesical chemotherapy for superficial bladder cancer. Asian Pac J Cancer Prev 2012; 13:689-92. [PMID: 22524797 DOI: 10.7314/apjcp.2012.13.2.689] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE To investigate correlations between adenosine triphosphate chemotherapy response assay (ATP-CRA) and clinical outcomes after ATP-CRA-based chemotherapy for drug selection in patients receiving intravesical chemotherapy to prevent recurrence of superficial bladder cancer after surgery. METHODS The chemosensitivities of 12 anticancer drugs were evaluated, including 5-Fu ADM, and EPI, using ATP-CRA and primary tumor cell culture in 54 patients. In addition, a further 58 patients were treated according to clinical experience. Differences in post-chemotherapeutical effects between drug sensitivity assay and experience groups were compared. RESULTS The evaluable rate of the test was 96.3%, the clinical effective rate was 80.8%, the sensitivity rate was 97.6% (41/42), the specificity was 20%, the total predicting accuracy was 74.3%, the positive predictive value was 83.7% (41/49), the negative predictive value was 66.7% (2/3); in the drug sensitivity test group, the clinical effective rate was 80.8%, the experience group response rate was 63.8%, with a significant difference in clinical effects between the ATP-based sensitivity and experience groups (χ2 =7.0153, P<0.01). CONCLUSION ATP-CRA is a stable, accurate and potentially practical chemosensitivity test providing a predictor of chemotherapeutic response in patients with superficial bladder cancer.
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Affiliation(s)
- Wen-Qing Ge
- Department of Urinary Surgery, The First Affiliated hospital of Soochow University, Suzhou, China
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Hwang HY. A practical approach for assessing chemosensitivity in colorectal cancer cell lines by comparative analysis of cell viability and thymidylate synthase mRNA expression. JOURNAL OF THE KOREAN SURGICAL SOCIETY 2012; 82:28-34. [PMID: 22324043 PMCID: PMC3268140 DOI: 10.4174/jkss.2012.82.1.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 09/23/2011] [Accepted: 09/30/2011] [Indexed: 11/30/2022]
Abstract
Purpose The purpose of this study is to suggest a probable problem in chemosensitivity tests performed in practice and to speculate on practicable measures for more accurate chemosensitivity evaluation. Methods Three colorectal cancer cells (RSC, RRC1, and RRC2) were treated with 5-fluorouracil (5-FU). Inhibition percentage (%inhibition) of cancer cells and relative quantitation of thymidylate synthase (TS) mRNA were measured on day 2, day 5 after replacement of 70% media on day 2, day 7, and day 3 after replacement of all media on day 7. Doses that produced 50% inhibition (Dm) were calculated to evaluate drug effect. Relative quantitation of TS mRNA and correlations between TS mRNA levels and 5-FU concentrations were analyzed. Results RRC1 was more resistant than RRC2 on day 7, but Dm value of RRC2 increased three days after replacement of media from 12.3 to 18.1. Mean TS mRNA levels of RSC on D2 and D7 were significantly lower than those of RRC1 and RRC2, respectively (P = 0.004, P = 0.004 on D2; P = 0.010, P = 0.006 on D7). TS mRNA levels in RRC1 were significantly reversely correlated with 5-FU concentrations on day 2 (correlation coefficient = -0.867, P = 0.015). On the other hand, correlations were not significant in RRC2 (r = 0.067). Conclusion Evaluating %inhibition of cancer cells at one point in chemosensitivity tests seems to be inadequate in determining chemotherapeutic regimens. Multilateral approaches, such as trials evaluating cancer cell survival before and after media replacement and correlations between TS mRNA levels and 5-FU concentrations, needs to be implemented for the practical application of chemosensitivity tests.
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Affiliation(s)
- Hyun Yong Hwang
- Department of Laboratory Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
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Zhang XL, Shi HJ, Cui SZ, Tang YQ, Ba MC. Prospective, randomized trial comparing 5-FU/LV with or without oxaliplatin as adjuvant treatment following curative resection of gastric adenocarcinoma. Eur J Surg Oncol 2011; 37:466-72. [PMID: 21414740 DOI: 10.1016/j.ejso.2011.01.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Revised: 01/07/2011] [Accepted: 01/25/2011] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND To investigate the efficacy and toxicity of FOLFOX4 regimen and LV5Fu2 regimen in patients with advanced gastric adenocarcinoma after curative gastrectomy. METHODS Eighty patients with gastric adenocarcinoma after curative gastrectomy were randomized to receive a 2-h infusion of leucovorin (LV; 200mg/m(2)/d) followed by a 5-fluorouracil (5-FU) bolus (400mg/m(2)/d) and 22-h infusion (600 mg/m(2)/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m(2) as a 2-h infusion on day 1 (FOLFOX4 regimen or LV5Fu2 regimen). The observation points were recurrence free survival, overall survival and toxicity of the two groups. RESULTS All patients had received curative gastrectomy (R0 resection) before received either of the two regimens. The 3-year recurrence free survival rate and the 3-year overall survival rate in FOLFOX4 group were all significantly better than those in the control group (median, 30.0 months vs. 16.0 months, P<0.05; 36.0 months vs. 28.0 months, P<0.05). COX multivariant analysis was used to evaluate the prognostic factors and oxaliplatin was found to be the independent prognostic factor and could improve the survival rate in FOLFOX4 group. Grade 3/4 peripheral neuropathy occurred in 19% in FOLFOX4 group. There was no significant difference between the two groups in neutropenia, leukopenia, anemia, gastrointestinal reaction and so on. Three patients in each group were lost to follow up during treatment. CONCLUSION FOLFOX4 regimen showed good efficacy and an acceptable safety profile for patients with advanced gastric adenocarcinoma after curative gastrectomy compared with the control group. It may prove to be a suitable alterative regimen in this indication.
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Affiliation(s)
- X-L Zhang
- Department of Abdominal Surgery (Section 2), Cancer Hospital of Guangzhou Medical College, No. 78 Hengzhigang Road, Guangzhou, Guangdong Province, China
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Park S, Woo Y, Kim H, Lee YC, Choi S, Hyung WJ, Noh SH. In vitro adenosine triphosphate based chemotherapy response assay in gastric cancer. J Gastric Cancer 2010; 10:155-61. [PMID: 22076180 PMCID: PMC3204504 DOI: 10.5230/jgc.2010.10.4.155] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2010] [Accepted: 10/14/2010] [Indexed: 12/24/2022] Open
Abstract
Purpose The purpose of this study was to investigate the reliability and the clinical applicability of the adenosine-triphosphate-based chemotherapy response assay (ATP-CRA) as a method of determining in vitro chemosensitivity in patients with gastric cancer. Materials and Methods A total of 243 gastric cancer tissue samples were obtained from gastrectomies performed between February 2007 and January 2010. We evaluated the effectiveness of the ATP-CRA assay in determining the chemosensitivity of gastric cancer specimens using eleven chemotherapeutic agents - etoposide, doxorubicin, epirubicin, mytomicin, 5-fluorouracil, oxaliplatin, irinotecan, docetaxel, paclitaxel, methotraxate, and cisplatin - for chemosensitivity studies using ATP-CRA. We assessed the failure rate, the cell death rate, and the chemosensitivity index. Results The failure rate of ATP-CRA was 1.6% (4/243). The mean coefficient of variation for triplicate ATP measurements was 6.5%. Etoposide showed the highest cell death rate (35.9%) while methotrexate showed the lowest (16.6%). The most active chemotherapeutic agent was etoposide, which most frequently ranked highest in the chemosensitivity test: 31.9% (51/160). Oxaliplatin was more active against early gastric cancers than advanced gastric cancers, whereas docetaxel was more active against advanced cancers. The lymph node negative group showed a significantly higher cell death rate than the lymph node positive group when treated with doxorubicin, epirubicin, and mitomycin. Conclusions ATP-CRA is a stable and clinically applicable in vitro chemosensitivity test with a low failure rate. The clinical usefulness of ATP-CRA should be evaluated by prospective studies comparing the regimen guided by ATP-CRA with an empirical regimen.
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Affiliation(s)
- Seulkee Park
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
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Wang C, Ho PC, Lim LY. Wheat germ agglutinin-conjugated PLGA nanoparticles for enhanced intracellular delivery of paclitaxel to colon cancer cells. Int J Pharm 2010; 400:201-10. [DOI: 10.1016/j.ijpharm.2010.08.023] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Revised: 08/05/2010] [Accepted: 08/22/2010] [Indexed: 10/19/2022]
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