Sensitization of 1,3-bis(2-chloroethyl)-1-nituosourea and cisplatin cytotoxicity by 5-bromo-2 '-deoxyuridine in human glioma

5-Bromo-2'-deoxyuridine (BrdUrd) was found to increase the cytotoxicity ind uced by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cisplatin in human glioma cells. At a fixed concentration of BrdUrd and BCNU, the greatest cel l loss was observed in exponentially growing cells. As cells approached pla teau growth, cytotoxicity was reduced as indicated by greater cell viabilit y. Under varying growth conditions the percentage of thymine replacement by bromouracil in DNA, as determined by gas chromatography/mass spectrometry analysis, declined as cultures approached maximum density. These data indic ate BrdUrd must be incorporated into DNA for the enhanced effect to be obse rved. In exponentially growing cells, sensitization was dependent upon both the concentration of BrdUrd and alkylating agent. Using regression analysi s (at 95% CL), a relationship between the level of bromouracil in DNA and t he extent of enhanced cytotoxicity was observed at two concentrations of BC NU (r(2) = 0.99, 0.96). Although it is known that bifunctional alkylating a gents exert cytotoxicity by forming cross-links between cDNA strands, incre ased cross-link formation was not observed in BrdUrd substituted DNA as det ermined by alkaline elution. The data suggest that DNA damage induced by ha logenated pyrimidines may not involve interstrand cross-links and that thes e agents may be useful in the treatment of glioma in combination with alkyl ating agents.