title: Common variants of Drosophila melanogaster Cyp6d2 cause camptothecin sensitivity and synergize with loss of Brca2.
abstract: Many chemotherapeutic agents selectively target rapidly dividing cells, including cancer cells, by causing DNA damage that leads to genome instability and cell death. We used Drosophila melanogaster to study how mutations in key DNA repair genes affect an organism's response to chemotherapeutic drugs. In this study, we focused on camptothecin and its derivatives, topotecan and irinotecan, which are type I topoisomerase inhibitors that create DNA double-strand breaks in rapidly dividing cells. Here, we describe two polymorphisms in Drosophila Cyp6d2 that result in extreme sensitivity to camptothecin but not topotecan or irinotecan. We confirmed that the sensitivity was due to mutations in Cyp6d2 by rescuing the defect with a wild-type copy of Cyp6d2. In addition, we showed that combining a cyp6d2 mutation with mutations in Drosophila brca2 results in extreme sensitivity to camptothecin. Given the frequency of the Cyp6d2 polymorphisms in publcly available Drosophila stocks, our study demonstrates the need for caution when interpreting results from drug sensitivity screens in Drosophila and other model organisms. Furthermore, our findings illustrate how genetic background effects can be important when determining the efficacy of chemotherapeutic agents in various DNA repair mutants.
authors: Tufts University, Department of Biology, Medford, Massachusetts 02155, USA.
authors: Adam M
authors: AM
authors: Thomas
authors: Carrie
authors: C
authors: Hui
authors: Adam
authors: A
authors: South
authors: Mitch
authors: M
authors: McVey
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects*; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005816:Genetic Complementation Test; D019476:Insect Proteins / Q000235:genetics*; D000077146:Irinotecan; D011110:Polymorphism, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*; D019772:Topotecan / Q000494:pharmacology
chemical_list: D024682:BRCA2 Protein; D017931:DNA Primers; D029721:Drosophila Proteins; D019476:Insect Proteins; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D019772:Topotecan; D003577:Cytochrome P-450 Enzyme System; C581834:cytochrome P-450 CYP6D2; D002166:Camptothecin
keywords: chemotherapeutics; cytochrome p450; double-strand breaks; homologous recombination