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Research Articles: Therapeutics, Targets, and Development

Effect of population and gender on chemotherapeutic agent–induced cytotoxicity

¹ Section of Hematology-Oncology, Department of Medicine, ² Biostatistics Consulting Laboratory, Department of Health Studies, and ³ Department of Human Genetics, University of Chicago, Chicago, Illinois

Requests for reprints: M. Eileen Dolan, Section of Hematology-Oncology, Department of Medicine, University of Chicago, Box MC2115, 5841 S Maryland Avenue, Chicago, IL 60637. Phone: 773-702-4441; Fax: 773-702-0963. E-mail: edolan{at}medicine.bsd.uchicago.edu

Abstract

Large interindividual variance is observed in both response and toxicity associated with chemotherapy. Our goal is to identify factors that contribute to chemotherapy-induced toxicity. To this end, we used EBV-transformed B-lymphoblastoid HapMap cell lines derived from 30 Yoruban trios (African descent) and 30 Centre d' Etude du Polymorphisme Humain (CEPH) trios (European descent) to evaluate population- and gender-specific differences in cytotoxicity of carboplatin, cisplatin, daunorubicin, and etoposide using a high-throughput, short-term cytotoxicity assay. The IC₅₀ was compared for population- and gender-specific differences for the four drugs. We observed large interindividual variance in IC₅₀ values for carboplatin, cisplatin, daunorubicin, and etoposide for both Yoruban and CEPH populations (range from 8- to 433-fold). Statistically significant differences in carboplatin and daunorubicin IC₅₀ were shown when comparing Yoruban cell lines (n = 89) to CEPH cell lines (n = 87; P = 0.002 and P = 0.029, respectively). This population difference in treatment induced cytotoxicity was not seen for either cisplatin or etoposide. In the Yoruban population, cell lines derived from females were less sensitive to platinating agents than males [median carboplatin IC₅₀, 29.1 versus 24.6 µmol/L (P = 0.012); median cisplatin IC₅₀, 7.0 versus 6.0 µmol/L (P = 0.020) in female and male, respectively]. This difference was not observed in the CEPH population. These results show that population and gender may affect risk for toxicities associated with certain chemotherapeutic agents. [Mol Cancer Ther 2007;6(1):31–6]

Grant support: This Pharmacogenetics of Anticancer Agents Research Group (http://pharmacogenetics.org) study was supported by NIH/National Institute of General Medical Sciences grant GM61393 and by NIH/National Institute of General Medical Sciences Pharmacogenetics Research Network and Database (U01GM61374, http://pharmgkb.org/; Russ Altman, Principal Investigator).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ http://www.hapmap.org/.

⁵ See http://locus.umdnj.edu/.

⁶ http://www.biotek.com/products/.

⁷ http://www.hapmap.org.

⁸ http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE2552.

⁹ http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE2552.

Received 9/22/06; revised 10/23/06; accepted 11/20/06.

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