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Relationships between genetic polymorphisms and anticancer drug cytotoxicity vis-à-vis the NCI-60 panel

Valérie Le Morvan1, Ricardo Bellott, François Moisan

  • 1Laboratoire de Pharmacologie des Agents Anticancéreux, Institut Bergonié, 229 Cours de l'Argonne, 33076 Bordeaux-cedex, France.

Pharmacogenomics
|September 20, 2006
PubMed
Abstract

Insights

Genetic variations in drug metabolism and DNA repair genes influence anticancer drug effectiveness. The NCI-60 panel reveals genotype-cytotoxicity relationships, aiding personalized cancer treatment strategies.

Area of Science:

  • Pharmacogenomics
  • Cancer Cell Biology
  • Molecular Toxicology

Background:

  • The National Cancer Institute (NCI)-60 panel comprises 60 human tumor cell lines used for screening anticancer agents.
  • This panel is valuable for correlating anticancer drug cytotoxicity with cellular molecular characteristics.
  • Investigated potential for linking gene polymorphisms in drug metabolism, transport, and DNA repair to drug cytotoxicity.

Purpose of the Study:

  • To explore the utility of the NCI-60 panel for establishing genotype-cytotoxicity relationships.
  • To investigate the impact of specific gene polymorphisms on anticancer drug efficacy.

Main Methods:

  • Analyzed three common single nucleotide polymorphisms (SNPs) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
  • SNPs studied: Lys751Gln in Xeroderma pigmentosum complementation group D (XPD, ERCC2), Asp1104His in Xeroderma pigmentosum complementation group G (XPG, ERCC5), and Ile105Val in glutathione S-transferase P1 (GSTP1).
  • Utilized cytotoxicity data from NCI databases.

Main Results:

  • Allelic frequencies: ERCC2 (33%), ERCC5 (23%), GSTP1 (39%).
  • ERCC2 polymorphism significantly impacted cytotoxicity of most agents, with lower IC50 in variant homozygous lines, notably for taxanes (threefold lower mean IC50).
  • ERCC5 polymorphism affected taxane cytotoxicity (fourfold higher IC50 in variant homozygous lines).
  • GSTP1 polymorphism correlated with cytotoxicity of topoisomerase inhibitors, antimetabolites, and N7 alkylating agents.

Conclusions:

  • The NCI-60 panel can identify clinically relevant associations between specific genotypes and anticancer agent cytotoxicity.
  • Findings support the potential for genotype-guided selection of anticancer therapies.

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