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

Gastrointestinal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05494320
• Other study ID #: 279
• Status: Recruiting
• Start date: August 15, 2021
• Est. completion date: December 31, 2022

Study information

• Verified date: August 2022
• Source: Ain Shams University
• Contact: Sara Mohamed Abdel Aziz, Master Student
• Phone: 00201119215516
• Email: dr.sara.mohamed75[@]gmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: December 31, 2022
• Est. primary completion date: August 5, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. gastrointestinal cancer Patients ( = stages II ) who receive Oxaliplatin based chemotherapy ( FOLFOX6 ) for adjuvant and metastatic setting.

2. Eastern Cooperative Oncology Group ( ECOG ) performance = 2.

3. Adequate bone marrow functions ,liver functions and renal functions.

Exclusion Criteria:

1. Patients who have any clinical neuropathy.

2. Pateints with Diabetes mellitus.

3. Serious comorbid systemic disorder incompatible with study.

4. Pregnancy.

5. Other primary tumors.

Related Conditions & MeSH terms

• Gastrointestinal Cancer
• Gastrointestinal Neoplasms
• Neurotoxicity Syndromes

Intervention

Drug:
• Folfox Protocol
Folfox: It includes the drugs leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin.

Locations

Country	Name	City	State
Egypt	Ain shams university	Cairo	Abassia

Sponsors (1)

Lead Sponsor	Collaborator
Ain Shams University

Country where clinical trial is conducted

Egypt, 

References & Publications (10)

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André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009 Jul 1;27(19):3109-16. doi: 10.1200/JCO.2008.20.6771. Epub 2009 May 18. — View Citation

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Cappell MS. Pathophysiology, clinical presentation, and management of colon cancer. Gastroenterol Clin North Am. 2008 Mar;37(1):1-24, v. doi: 10.1016/j.gtc.2007.12.002. Review. — View Citation

Cecchin E, D'Andrea M, Lonardi S, Zanusso C, Pella N, Errante D, De Mattia E, Polesel J, Innocenti F, Toffoli G. A prospective validation pharmacogenomic study in the adjuvant setting of colorectal cancer patients treated with the 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimen. Pharmacogenomics J. 2013 Oct;13(5):403-9. doi: 10.1038/tpj.2012.31. Epub 2012 Aug 7. — View Citation

Ewertz M, Qvortrup C, Eckhoff L. Chemotherapy-induced peripheral neuropathy in patients treated with taxanes and platinum derivatives. Acta Oncol. 2015 May;54(5):587-91. doi: 10.3109/0284186X.2014.995775. Epub 2015 Mar 9. Review. — View Citation

Grady WM, Markowitz SD. The molecular pathogenesis of colorectal cancer and its potential application to colorectal cancer screening. Dig Dis Sci. 2015 Mar;60(3):762-72. doi: 10.1007/s10620-014-3444-4. Epub 2014 Dec 10. Review. — View Citation

Mirakhorli M, Rahman SA, Abdullah S, Vakili M, Rozafzon R, Khoshzaban A. Multidrug resistance protein 2 genetic polymorphism and colorectal cancer recurrence in patients receiving adjuvant FOLFOX-4 chemotherapy. Mol Med Rep. 2013 Feb;7(2):613-7. doi: 10.3892/mmr.2012.1226. Epub 2012 Dec 7. — View Citation

Nguyen TQ, Bui TO, Tran PT, Tran VT, Nguyen VH, Chu QH, Bui TAT, Le NQ, Le VQ, Dao VT. Modified Folfox6 as Adjuvant Chemotherapy in Vietnamese Patients With Colorectal Cancer. Cancer Control. 2019 Jan-Dec;26(1):1073274819864111. doi: 10.1177/1073274819864111. — View Citation

Nichetti F, Falvella FS, Miceli R, Cheli S, Gaetano R, Fucà G, Infante G, Martinetti A, Antoniotti C, Falcone A, Di Bartolomeo M, Cremolini C, de Braud F, Pietrantonio F. Is a pharmacogenomic panel useful to estimate the risk of oxaliplatin-related neurotoxicity in colorectal cancer patients? Pharmacogenomics J. 2019 Oct;19(5):465-472. doi: 10.1038/s41397-019-0078-0. Epub 2019 Feb 4. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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