title: Chemotherapy-induced toxicity is highly heritable in Drosophila melanogaster.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Ecology and Evolution, University of California, Irvine, California, USA. gdvorkin@uci.edu
authors.forename: Galina
authors.initials: G
authors.lastname: Kislukhin
authors.forename: Maura L
authors.initials: ML
authors.lastname: Murphy
authors.forename: Mahtab
authors.initials: M
authors.lastname: Jafari
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Long
mesh_terms: D000818:Animals; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000235:genetics*; D004358:Drug Therapy / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005298:Fertility / Q000187:drug effects*; D005467:Floxuridine / Q000008:administration & dosage / Q000009:adverse effects; D057166:High-Throughput Screening Assays; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D016685:Mitomycin / Q000008:administration & dosage / Q000009:adverse effects; D023421:Models, Animal; D009369:Neoplasms / Q000188:drug therapy*; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects; D000093542:Gemcitabine
chemical_list: D005467:Floxuridine; D003841:Deoxycytidine; D016685:Mitomycin; D019772:Topotecan; D016190:Carboplatin; D008727:Methotrexate; D000093542:Gemcitabine