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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
. 1988 Feb;85(3):650–653. doi: 10.1073/pnas.85.3.650

Elevated expression of thymidylate synthase cycle genes in cisplatin-resistant human ovarian carcinoma A2780 cells.

K J Scanlon 1, M Kashani-Sabet 1
PMCID: PMC279612  PMID: 3422447

Abstract

Activity of the thymidylate synthase cycle was compared in the human ovarian carcinoma cell line A2780 and a subline that is resistant to cisplatin by a factor of 3. Resistant cells exhibited a 3-fold increase in mRNA for both dihydrofolate reductase (5,6,7,8-tetrahydrofolate:NADP+-oxidoreductase, EC 1.5.1.3) and thymidylate synthase (5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45) when compared with the parent line. Resistance to cisplatin also resulted in a 2.5-fold increase in enzyme activity for dihydrofolate reductase and thymidylate synthase; however, this increase did not result from amplification of the genes for these two enzymes. These data suggest that the initial step of cisplatin resistance in A2780 cells is a consequence of enhanced expression of the thymidylate synthase cycle.

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Selected References

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  1. Andrews P. A., Murphy M. P., Howell S. B. Differential sensitization of human ovarian carcinoma and mouse L1210 cells to cisplatin and melphalan by glutathione depletion. Mol Pharmacol. 1986 Dec;30(6):643–650. [PubMed] [Google Scholar]
  2. Ayusawa D., Shimizu K., Koyama H., Kaneda S., Takeishi K., Seno T. Cell-cycle-directed regulation of thymidylate synthase messenger RNA in human diploid fibroblasts stimulated to proliferate. J Mol Biol. 1986 Aug 20;190(4):559–567. doi: 10.1016/0022-2836(86)90241-x. [DOI] [PubMed] [Google Scholar]
  3. Gasser C. S., Schimke R. T. Cell cycle regulation of transfected murine dihydrofolate reductase genes. J Biol Chem. 1986 May 25;261(15):6938–6946. [PubMed] [Google Scholar]
  4. 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]
  5. Hayman R., McGready R., Van der Weyden M. B. A rapid radiometric assay for dihydrofolate reductase. Anal Biochem. 1978 Jul 1;87(2):460–465. doi: 10.1016/0003-2697(78)90696-6. [DOI] [PubMed] [Google Scholar]
  6. Kamen B. A., Takach P. L., Vatev R., Caston J. D. A rapid, radiochemical-ligand binding assay for methotrexate. Anal Biochem. 1976 Jan;70(1):54–63. doi: 10.1016/s0003-2697(76)80047-4. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Morandi C., Masters J. N., Mottes M., Attardi G. Multiple forms of human dihydrofolate reductase messenger RNA. Cloning and expression in Escherichia coli of their DNA coding sequence. J Mol Biol. 1982 Apr 15;156(3):583–607. doi: 10.1016/0022-2836(82)90268-6. [DOI] [PubMed] [Google Scholar]
  9. Ozols R. F., Young R. C. Chemotherapy of ovarian cancer. Semin Oncol. 1984 Sep;11(3):251–263. [PubMed] [Google Scholar]
  10. Rode W., Scanlon K. J., Moroson B. A., Bertino J. R. Regulation of thymidylate synthetase in mouse leukemia cells (L1210). J Biol Chem. 1980 Feb 25;255(4):1305–1311. [PubMed] [Google Scholar]
  11. 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]
  12. Scanlon K. J., Berkowitz K., Pallai M. E., Waxman S. Inhibition of methionine transport by methotrexate in mitogen-stimulated human lymphocytes. Cancer Treat Rep. 1983 Jul-Aug;67(7-8):631–639. [PubMed] [Google Scholar]
  13. Scanlon K. J., Cashmore A. R., Kashani-Sabet M., Pallai M., Dreyer R. N., Moroson B. A., Saketos M. Inhibition of methionine uptake by methotrexate in mouse leukemia L1210 cells. Cancer Chemother Pharmacol. 1987;19(1):21–24. doi: 10.1007/BF00296249. [DOI] [PubMed] [Google Scholar]
  14. Scanlon K. J., Cashmore A. R., Kashani-Sabet M., Pallai M., Dreyer R. N., Moroson B. A., Saketos M. Inhibition of methionine uptake by methotrexate in mouse leukemia L1210 cells. Cancer Chemother Pharmacol. 1987;19(1):21–24. doi: 10.1007/BF00296249. [DOI] [PubMed] [Google Scholar]
  15. Scanlon K. J., Newman E. M., Lu Y., Priest D. G. Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. Proc Natl Acad Sci U S A. 1986 Dec;83(23):8923–8925. doi: 10.1073/pnas.83.23.8923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Schabel F. M., Jr, Skipper H. E., Trader M. W., Laster W. R., Jr, Griswold D. P., Jr, Corbett T. H. Establishment of cross-resistance profiles for new agents. Cancer Treat Rep. 1983 Oct;67(10):905–922. [PubMed] [Google Scholar]
  18. 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]
  19. Singer-Sam J., Simmer R. L., Keith D. H., Shively L., Teplitz M., Itakura K., Gartler S. M., Riggs A. D. Isolation of a cDNA clone for human X-linked 3-phosphoglycerate kinase by use of a mixture of synthetic oligodeoxyribonucleotides as a detection probe. Proc Natl Acad Sci U S A. 1983 Feb;80(3):802–806. doi: 10.1073/pnas.80.3.802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Teicher B. A., Cucchi C. A., Lee J. B., Flatow J. L., Rosowsky A., Frei E., 3rd Alkylating agents: in vitro studies of cross-resistance patterns in human cell lines. Cancer Res. 1986 Sep;46(9):4379–4383. [PubMed] [Google Scholar]

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