Elevated expression of thymidylate synthase cycle genes in cisplatin-resistant human ovarian carcinoma A2780 cells.
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.
Scanlon
K J
KJ
Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA 91010.
Kashani-Sabet
M
M
D000818:Animals; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002453:Cell Cycle; D002945:Cisplatin / Q000494:pharmacology*; D004351:Drug Resistance; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D007939:Leukemia L1210; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D013762:Tetrahydrofolate Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D013940:Thymidylate Synthase / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology
D009363:Neoplasm Proteins; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D002945:Cisplatin