The role of thymidylate synthetase inhibitors in bromodeoxyuridine-induced neoplasia in Drosophila.

When 5-bromodeoxyuridine (BUdR) or 5-iododeoxyuridine is administered to Drosophila larvae together with 5-fluorouracil, many of the adult flies show growth lesions in the form of extra bristles and other supernumerary wing structures. The hypothesis that the growth lesions are the result of thymidine analog incorporation in DNA and that the effects of this incorporation are increased by feeding 5-fluorouracil, which interferes with endogenous synthesis of thymidine monophosphate, was tested by using two other inhibitors of thymidylate synthetase in combination with BUdR. In the presence of methotrexate or trifluorothymidine (F3TdR), the incidence of neoplastic lesions was markedly increased over that obtained in control larvae given BUdR alone. 5-Fluorouracil and methotrexate do not induce extra bristles or growth of supernumeraries in Drosophila, but F3TdR offered alone induces lesions similar to those following treatment with a combination of BUdR and a thymidylate inhibitor. This exceptional case supports the above hypothesis since F3TdR is not only an inhibitor of thymidylate synthetase but can also be incorporated into DNA. Increased incorporation of BUdR in Drosophila DNA is demonstrated by giving methotrexate or F3TdR to actively feeding larvae, and DNA samples from larvae given BUdR3H with these inhibitors were examined by CsCl density-