TY - JOUR T1 - Sensitization of 1,3-bis(2-Chloroethyl)-1-nitrosourea and Cisplatin Cytotoxicity by 5-Bromo-2′-deoxyuridine in Human Glioma JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1404 LP - 1409 VL - 289 IS - 3 AU - William R. Mancini AU - Elizabeth R. Glaze AU - Philip L. Stetson AU - Harry S. Greenberg Y1 - 1999/06/01 UR - http://jpet.aspetjournals.org/content/289/3/1404.abstract N2 - 5-Bromo-2′-deoxyuridine (BrdUrd) was found to increase the cytotoxicity induced 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 cell loss was observed in exponentially growing cells. As cells approached plateau growth, cytotoxicity was reduced as indicated by greater cell viability. 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 indicate BrdUrd must be incorporated into DNA for the enhanced effect to be observed. In exponentially growing cells, sensitization was dependent upon both the concentration of BrdUrd and alkylating agent. Using regression analysis (at 95% CL), a relationship between the level of bromouracil in DNA and the extent of enhanced cytotoxicity was observed at two concentrations of BCNU (r2 = 0.99, 0.96). Although it is known that bifunctional alkylating agents exert cytotoxicity by forming cross-links between cDNA strands, increased cross-link formation was not observed in BrdUrd substituted DNA as determined by alkaline elution. The data suggest that DNA damage induced by halogenated pyrimidines may not involve interstrand cross-links and that these agents may be useful in the treatment of glioma in combination with alkylating agents. The American Society for Pharmacology and Experimental Therapeutics ER -