| In practice, anti-cancer treatments are selected on the basis of producing the best response in patients grouped by a common tissue in which the cancer originated. The problem with this approach is that, although a given cancer within an individual is clonal, malignancies arising from the same tissue in different individuals do not necessarily share the same genetic basis and are likely to be physiologically very different. The next generation of chemotherapies will be based on the specific mutations associated with a given cancer rather than tissue of origin. Currently, a number of cell lines and organisms are being used to identify specific synthetic lethal interactions between mutations associated with cancer cells and anti-cancer drugs. We developed an assay in which the consequences of anti-cancer agents and cell cycle inhibitors on the frequency and size of genetically compromised Drosophila wing and eye clones as well as the whole organisms were examined. Specifically we assayed for synthetic lethal interactions between the DNA damage/S-phase checkpoint mei-41/ATR and the following inhibitors: X-irradiation, cisplatin, doxorubicin, ICRF-193, camptothecin, aphidicolin, hydroxyurea and paclitaxel. In general, we found mei-41 mutant Drosophila were much more sensitive to inhibitor treatment than mei-41 eye and wing clones. X-irradiation, cisplatin, and hydroxyurea all produced significant synthetic lethal interactions at the level of the organism with mei-41 but failed to produce synthetic lethal interactions with mei-41 eye or wing clones. Among the inhibitors tested, camptothecin produced the most pronounced synthetic lethal interactions with the mei-41 somatic clones. Camptothecin treatment resulted in an approximately 8-fold reduction in the size of mei-41 wing clones and a greater than 15-fold reduction in the frequency of eye clones. |
