Chemotherapy-induced toxicity is highly heritable in Drosophila melanogaster

Pharmacogenet Genomics. 2012 Apr;22(4):285-9. doi: 10.1097/FPC.0b013e3283514395.

Abstract

Objectives: Identification of the genes responsible for chemotherapy toxicity in Drosophila melanogaster may allow for the identification of human orthologs that similarly mediate toxicity in humans. To develop D. melanogaster as a model of dissecting chemotoxicity, we first need to develop standardized high-throughput toxicity assays and prove that the interindividual variation in toxicity as measured by such assays is highly heritable.

Methods: We developed a method for the oral delivery of commonly used chemotherapy drugs to Drosophila. Post-treatment female fecundity displayed a dose-dependent response to varying levels of the chemotherapy drug delivered. We fixed the dose for each drug at a level that resulted in a 50% reduction in fecundity and used a paternal half-sibling heritability design to calculate the heritability attributable to chemotherapy toxicity assayed by a decrease in female fecundity. The chemotherapy agents tested were carboplatin, floxuridine, gemcitabine hydrochloride, methotrexate, mitomycin C, and topotecan hydrochloride.

Results: We found that six currently widely prescribed chemotherapeutic agents lowered fecundity in D. melanogaster in both a dose-dependent and a highly heritable manner. The following heritability estimates were found: carboplatin, 0.72; floxuridine, 0.52; gemcitabine hydrochloride, 0.72; methotrexate, 0.99; mitomycin C, 0.64; and topotecan hydrochloride, 0.63.

Conclusion: The high heritability estimates observed in this study, irrespective of the particular class of drug examined, suggest that human toxicity may also have a sizable genetic component.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carboplatin / administration & dosage
  • Carboplatin / adverse effects
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives
  • Dose-Response Relationship, Drug
  • Drosophila melanogaster / genetics*
  • Drug Therapy / methods
  • Drug-Related Side Effects and Adverse Reactions
  • Female
  • Fertility / drug effects*
  • Floxuridine / administration & dosage
  • Floxuridine / adverse effects
  • High-Throughput Screening Assays*
  • Humans
  • Methotrexate / administration & dosage
  • Methotrexate / adverse effects
  • Mitomycin / administration & dosage
  • Mitomycin / adverse effects
  • Models, Animal*
  • Neoplasms / drug therapy*
  • Topotecan / administration & dosage
  • Topotecan / adverse effects

Substances

  • Floxuridine
  • Deoxycytidine
  • Mitomycin
  • Topotecan
  • gemcitabine
  • Carboplatin
  • Methotrexate