Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1986 Dec;83(23):8923–8925. doi: 10.1073/pnas.83.23.8923

Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells.

K J Scanlon, E M Newman, Y Lu, D G Priest
PMCID: PMC387045  PMID: 3466165

Abstract

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.

Full text

PDF
8923

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aull J. L., Rice A. C., Tebbetts L. A. Interactions of platinum complexes with the essential and nonessential sulfhydryl groups of thymidylate synthetate. Biochemistry. 1977 Feb 22;16(4):672–677. doi: 10.1021/bi00623a018. [DOI] [PubMed] [Google Scholar]
  2. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  3. Gross R. B., Scanlon K. J. Amino acid membrane transport properties of L1210 cells resistant to cisplatin. Chemioterapia. 1986 Feb;5(1):37–43. [PubMed] [Google Scholar]
  4. Heidelberger C., Danenberg P. V., Moran R. G. Fluorinated pyrimidines and their nucleosides. Adv Enzymol Relat Areas Mol Biol. 1983;54:58–119. [PubMed] [Google Scholar]
  5. Houghton J. A., Maroda S. J., Jr, Phillips J. O., Houghton P. J. Biochemical determinants of responsiveness to 5-fluorouracil and its derivatives in xenografts of human colorectal adenocarcinomas in mice. Cancer Res. 1981 Jan;41(1):144–149. [PubMed] [Google Scholar]
  6. Juckett D. A., Rosenberg B. Actions of cis-diamminedichloroplatinum on cell surface nucleic acids in cancer cells as determined by cell electrophoresis techniques. Cancer Res. 1982 Sep;42(9):3565–3573. [PubMed] [Google Scholar]
  7. Kesavan V., Sur P., Doig M. T., Scanlon K. J., Priest D. G. Effects of methotrexate on folates in Krebs ascites and L1210 murine leukemia cells. Cancer Lett. 1986 Jan;30(1):55–59. doi: 10.1016/0304-3835(86)90132-1. [DOI] [PubMed] [Google Scholar]
  8. Krebs H. A., Hems R., Tyler B. The regulation of folate and methionine metabolism. Biochem J. 1976 Aug 15;158(2):341–353. doi: 10.1042/bj1580341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Moran R. G., Spears C. P., Heidelberger C. Biochemical determinants of tumor sensitivity to 5-fluorouracil: ultrasensitive methods for the determination of 5-fluoro-2'-deoxyuridylate, 2'-deoxyuridylate, and thymidylate synthetase. Proc Natl Acad Sci U S A. 1979 Mar;76(3):1456–1460. doi: 10.1073/pnas.76.3.1456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ozols R. F., Young R. C. Chemotherapy of ovarian cancer. Semin Oncol. 1984 Sep;11(3):251–263. [PubMed] [Google Scholar]
  11. Poirier M. C., Lippard S. J., Zwelling L. A., Ushay H. M., Kerrigan D., Thill C. C., Santella R. M., Grunberger D., Yuspa S. H. Antibodies elicited against cis-diamminedichloroplatinum(II)-modified DNA are specific for cis-diamminedichloroplatinum(II)-DNA adducts formed in vivo and in vitro. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6443–6447. doi: 10.1073/pnas.79.21.6443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Priest D. G., Veronee C. D., Mangum M., Bednarek J. M., Doig M. T. Comparison of folylpolyglutamate hydrolases of mouse liver, kidney, muscle and brain. Mol Cell Biochem. 1982 Mar 19;43(2):81–87. doi: 10.1007/BF00423095. [DOI] [PubMed] [Google Scholar]
  13. Rogan A. M., Hamilton T. C., Young R. C., Klecker R. W., Jr, Ozols R. F. Reversal of adriamycin resistance by verapamil in human ovarian cancer. Science. 1984 Jun 1;224(4652):994–996. doi: 10.1126/science.6372095. [DOI] [PubMed] [Google Scholar]
  14. Rooney M., Kish J., Jacobs J., Kinzie J., Weaver A., Crissman J., Al-Sarraf M. Improved complete response rate and survival in advanced head and neck cancer after three-course induction therapy with 120-hour 5-FU infusion and cisplatin. Cancer. 1985 Mar 1;55(5):1123–1128. doi: 10.1002/1097-0142(19850301)55:5<1123::aid-cncr2820550530>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  15. Rosenberg B. Fundamental studies with cisplatin. Cancer. 1985 May 15;55(10):2303–23l6. doi: 10.1002/1097-0142(19850515)55:10<2303::aid-cncr2820551002>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  16. Scanlon K. J., Cashmore A. R., Moroson B. A., Dreyer R. N., Bertino J. R. Inhibition of serine metabolism by tetrahydrohomofolate in L1210 mouse leukemia cells. Mol Pharmacol. 1981 May;19(3):481–490. [PubMed] [Google Scholar]
  17. Scanlon K. J., Safirstein R. L., Thies H., Gross R. B., Waxman S., Guttenplan J. B. Inhibition of amino acid transport by cis-diamminedichloroplatinum(II) derivatives in L1210 murine leukemia cells. Cancer Res. 1983 Sep;43(9):4211–4215. [PubMed] [Google Scholar]
  18. Schabel F. M., Jr, Trader M. W., Laster W. R., Jr, Corbett T. H., Griswold D. P., Jr cis-Dichlorodiammineplatinum(II): combination chemotherapy and cross-resistance studies with tumors of mice. Cancer Treat Rep. 1979 Sep-Oct;63(9-10):1459–1473. [PubMed] [Google Scholar]
  19. Shionoya S., Lu Y., Scanlon K. J. Properties of amino acid transport systems in K562 cells sensitive and resistant to cis-diamminedichloroplatinum(II). Cancer Res. 1986 Jul;46(7):3445–3448. [PubMed] [Google Scholar]
  20. Washtien W. L., Santi D. V. Assay of intracellular free and macromolecular-bound metabolites of 5-fluorodeoxyuridine and 5-fluorouracil. Cancer Res. 1979 Sep;39(9):3397–3404. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES