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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
09:19

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Published on: February 6, 2015

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Sunita J Shukla1, Shiwei Duan, Judith A Badner

  • 1Department of Human Genetics, University of Chicago, Chicago Illinois 60637, USA.

Pharmacogenetics and Genomics
|February 28, 2008
PubMed
Abstract

Insights

Genetic factors influence cisplatin toxicity. This study identified specific gene variants associated with cisplatin-induced cell death, offering new avenues for personalized cancer treatment strategies.

Area of Science:

  • Pharmacogenomics
  • Cancer Biology
  • Genetics

Background:

  • Cisplatin is a vital chemotherapy drug, but its use is limited by nephrotoxicity and neuropathy.
  • Genetic factors influencing patient response and toxicity to cisplatin remain largely uncharacterized.

Purpose of the Study:

  • To identify novel genes and genetic variants contributing to cellular susceptibility to cisplatin.
  • To characterize the genetic basis of cisplatin-induced cytotoxicity using a cell-based model.

Main Methods:

  • Utilized lymphoblastoid cell lines from 27 Centre d'Etude du Polymorphisme Humain pedigrees.
  • Defined phenotype by cell growth inhibition after cisplatin exposure.
  • Performed linkage analysis and quantitative transmission disequilibrium tests on single nucleotide polymorphisms (SNPs).

Main Results:

  • Significant heritability for cisplatin cytotoxicity was observed (0.32–0.43).
  • Identified 11 genomic regions associated with cytotoxic phenotypes, with a notable region on chromosome 4q21.3-q35.2.
  • Discovered 20 significant SNPs, including 10 within five genes, linked to cisplatin-induced cytotoxicity; four SNPs explained over 10% of apoptosis variation.

Conclusions:

  • Genetic factors play a crucial role in cisplatin-induced cytotoxicity and apoptosis.
  • The identified cell lines serve as a model for discovering novel pharmacogenetic variants related to drug toxicity.

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