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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Associations between ABCC2 polymorphisms and cisplatin disposition and efficacy
J A Sprowl1, V Gregorc, C Lazzari
1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.
Clinical Pharmacology and Therapeutics
|April 27, 2012
Summary
ABCC2 transporter does not significantly impact cisplatin resistance or efficacy in cancer patients. In vitro findings on drug-transporter interactions require verification in human studies.
Area of Science:
- Pharmacogenomics
- Cancer Biology
- Drug Metabolism
Background:
- The ATP-binding cassette subfamily 2 (ABCC2), also known as multidrug resistance-associated protein 2 (MRP2) or canalicular multispecific organic anion transporter (cMOAT), is a transporter protein.
- In vitro studies suggest a role for ABCC2 in conferring resistance to platinum-based chemotherapy agents like cisplatin.
- Understanding the in vivo relevance of ABCC2 in cisplatin response is crucial for optimizing cancer therapy.
Purpose of the Study:
- To investigate the association between ABCC2 genetic variations and cisplatin pharmacokinetics and efficacy in cancer patients.
- To evaluate the impact of Abcc2 knockout on cisplatin disposition and toxicity in a murine model.
- To determine if ABCC2 single-nucleotide polymorphisms (SNPs) correlate with ABCC2 expression and cisplatin-induced cytotoxicity.
Main Methods:
- Analysis of cisplatin pharmacokinetics and efficacy in 237 cancer patients, correlating with seven common ABCC2 SNPs.
- Assessment of cisplatin disposition and toxicity in Abcc2 knockout (Abcc2−/−) mice.
- Correlation analysis of ABCC2 SNPs with ABCC2 expression in the NCI60 cell line panel and with cisplatin-induced cytotoxicity.
Main Results:
- Abcc2 knockout did not alter cisplatin disposition or toxicity in mice.
- No significant association was found between the studied ABCC2 SNPs and cisplatin pharmacokinetics (P > 0.12) or efficacy (P > 0.41) in cancer patients.
- The investigated ABCC2 SNPs did not correlate with ABCC2 expression in the NCI60 panel (P > 0.26) or with cisplatin-induced cytotoxicity (P = 0.21).
Conclusions:
- ABCC2 genetic variations do not appear to be significant determinants of cisplatin pharmacokinetics or clinical efficacy in the studied patient cohort.
- In vivo and human clinical data suggest that the role of ABCC2 in cisplatin resistance observed in vitro may not translate to clinical relevance.
- These findings underscore the necessity of validating in vitro drug-transporter interactions through human studies to accurately predict clinical outcomes.
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