title: Combinatorial effect of maytansinol and radiation in Drosophila and human cancer cells.
abstract: Combination therapy, in which two or more agents are applied, is more effective than single therapies for combating cancer. For this reason, combinations of chemotherapy with radiation are being explored in clinical trials, albeit with an empirical approach. We developed a screen to identify, from the onset, molecules that act in vivo in conjunction with radiation, using Drosophila as a model. Screens through two small molecule libraries from the NCI Developmental Therapeutics Program yielded microtubule poisons; this class of agents is known to enhance the effect of radiation in mammalian cancer models. Here we report an analysis of one microtubule depolymerizing agent, maytansinol isobutyrate (NSC292222; maytansinol), in Drosophila and in human cancer cells. We find that the effect of maytansinol is p53 dependent in Drosophila cells and human cancer cells, that maytansinol enhances the effect of radiation in both systems, and that the combinatorial effect of drug and radiation is additive. We also uncover a differential sensitivity to maytansinol between Drosophila cells and Drosophila larvae, which illustrates the value of studying cell behavior in the context of a whole organism. On the basis of these results, we propose that Drosophila might be a useful model for unbiased screens through new molecule libraries to find cancer drugs for combination therapy.
authors.affiliation: Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309-0347, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Edwards
authors.forename: Mara
authors.initials: M
authors.lastname: Gladstone
authors.forename: Petros
authors.initials: P
authors.lastname: Yoon
authors.forename: David
authors.initials: D
authors.lastname: Raben
authors.forename: Barbara
authors.initials: B
authors.lastname: Frederick
authors.forename: Tin Tin
authors.initials: TT
authors.lastname: Su
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003131:Combined Modality Therapy; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000528:radiation effects*; D045325:HCT116 Cells; D006801:Humans; D007814:Larva / Q000187:drug effects / Q000528:radiation effects; D008453:Maytansine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011839:Radiation, Ionizing; D008941:Spindle Apparatus / Q000187:drug effects / Q000528:radiation effects; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; C562224:maytansinol; D008453:Maytansine