the Effect of ABCC2 Genetic Polymorphism on Neurotoxicity in Gastrointestinal Cancer Patients Receiving Oxaliplatin

Study Overview
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Brief Summary
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Study the effect of genetic polymorphism (rs1885301, rs4148396 and rs3740066) in the membrane of Multidrug resistance protein 2 (MRP2) encoded by ATP-binding cassette C2 (ABCC2) gene and its genetic expression levels on neurotoxicity in gasrtointestinal cancer patients reciving Oxaliplatin-based chemotherapy.

Detailed Description
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Several solutes carriers and ATP-binding cassette transporters have been implicated in the influx or efflux of platinum-based chemotherapeutic agents such as cisplatin, carboplatin, and oxaliplatin. The ATP-binding cassette (ABC-) transporter superfamily contains several family members that may confer intrinsic or acquired multidrug resistance (MDR) by extruding anticancer agents or their metabolites from cells and suppression of such transporters may lead to sensitisation to cytostatic agents. Multidrug resistance protein 2 (MRP2), encoded by the ATP-binding cassette C2 (ABCC2) gene , is an efflux pump located on the apical membrane of many polarized cells, which transports conjugate compounds by an ATP-dependent mechanism like oxaliplatin. Single nucleotide polymorphisms (SNPs) in genes involved in drug transport like ABCC2 gene may lead to higher intracellular oxaliplatin accumulation in the dorsal root ganglia and thus increased risk of Oxaliplatin-induced peripheral neurotoxicity (OXPN). Enhanced ABCC2 expression can lead to decreased cellular glutathione content. Glutathione is needed for oxaliplatin detoxification via conjugation, and it was reported that low glutathione intra- cellular levels can cause increased oxaliplatin cytotoxicity. Moreover, ABCC2 mediates the export of the oxaliplatin-glutathione conjugated form, and ABCC2 overexpressing cells were resistant to platinum derivatives.

Official Title
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The Effect of ATP-Binding Cassette C2 (ABCC2) Transporter Genetic Polymorphism on Neurotoxicity in Gastrointestinal Cancer Patients Receiving Oxaliplatin -Based Chemotherapy

Conditions
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Gastrointestinal Cancer

Intervention / Treatment
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* Drug: Folfox Protocol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: gastrointestinal cancer Patients ( ≥ stages II ) who receive Oxaliplatin based chemotherapy ( FOLFOX6 ) for adjuvant and metastatic setting. Eastern Cooperative Oncology Group ( ECOG ) performance ≤ 2. Adequate bone marrow functions ,liver functions and renal functions. Exclusion Criteria: Patients who have any clinical neuropathy. Pateints with Diabetes mellitus. Serious comorbid systemic disorder incompatible with study. Pregnancy. Other primary tumors.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Folfox Protocol|Folfox: It includes the drugs leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| neurotoxicity | the effect of genetic polymorphism (rs1885301, rs4148396 and rs3740066) in the membrane of Multidrug resistance protein 2 (MRP2) encoded by ATP-binding cassette C2 (ABCC2) gene and its genetic expression levels on neurotoxicity in gastrointestinal cancer patients reciving Oxaliplatin-based chemotherapy. Grading of peripheral neuropathy using National Cancer Institute's Common Toxicity Criteria for Adverse Event ( NCI- CTCAE V5.0 ) will be assessed at baseline and before each cycle. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neurotoxicity, oxaliplatin, genetic polymorphism