Open AccessBiochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells.
Author(s) -
Kevin J. Scanlon,
Edward M. Newman,
Ying Lu,
David G. Priest
Publication year - 1986
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.83.23.8923
Subject(s) - cisplatin , thymidylate synthase , cytotoxicity , cell culture , ovarian carcinoma , biology , biochemistry , ovarian cancer , pharmacology , chemistry , in vitro , cancer research , fluorouracil , chemotherapy , cancer , genetics
The human ovarian cell line A2780 was exposed to either cisplatin (10 microM) or 5-fluorouracil (5FUra) (5 microM) for 1 hr. Cytotoxicity was less than 14% with either agent alone. Cisplatin (10 microM) and 5FUra (5 microM) in combination for 1 hr caused a 76% reduction in cell growth. Thymidine (dThd, 10 microM), if given concomitantly with the combination of cisplatin and 5FUra, completely protected the tumor cells. A 30-min exposure to cisplatin increased the intracellular pools of 5,10-methylenetetrahydrofolate and tetrahydrofolate 2.5-fold. The capacity of intact cells to form 5-fluorodeoxyuridylate (FdUMP)-thymidylate (dTMP) synthase complex when incubated with fluorodeoxyuridine (FdUrd) was enhanced 2.5-fold when the cells were pretreated with cisplatin. These experiments demonstrate that cisplatin can increase the availability of the reduced folate necessary for tight binding of FdUMP to dTMP synthase, thus enhancing the cytotoxicity of the cisplatin and 5FUra combination.