Expression of collateral sensitivity to cisplatin, methotrexate, and fluorouracil in a human ovarian carcinoma cell line following exposure to fractionated x-irradiation in vitro.
Examples of collateral sensitivity, even in experimental tumor systems, remain few. Preliminary data from this laboratory indicated that certain tumor cells expressed increased sensitivity to cisplatin after exposure in vitro to x-irradiation. To further clarify whether the type of fractionated radiation procedure used clinically can induce hypersensitivities to certain antitumor drugs we have pre-exposed the human ovarian carcinoma cell line JA-T/P derived from a tumor from an untreated patient to fractionated x-irradiation (total dose 50 Gy) in vitro. The resultant subline JA-T/DXR-10 expressed collateral sensitivity to cisplatin (CDDP), methotrexate (MTX) and fluorouracil (5-FU), but not to acute x-irradiation. Hypersensitivity to CDDP was associated with decreased activity of DNA polymerase beta (3.5-fold, P less than .01), but unaltered glutathione metabolism. Pre-incubation with cyclosporin A or with 3-aminobenzamide significantly enhanced (twofold, P less than .01) CDDP-induced cytotoxicity in JA-T/P cells, but not in the DXR-10 subline. Consistent with MTX hypersensitivity dihydrofolate reductase activity was significantly decreased (2.9-fold, P less than .01). Despite collateral sensitivity to 5-FU, however, thymidylate synthase activity was increased (twofold, P less than .05) suggesting alternative mechanisms for 5-FU-induced cytotoxicity in these JA-T/DXR-10 cells. These data demonstrate that DNA repair and associated reduced folate metabolism can be modified not only by drugs but also by fractionated x-irradiation.
Dempke
W C
WC
Laboratory of Cellular Chemotherapy, Imperial Cancer Research Fund Laboratories, Lincoln's Inn Fields, London, UK.
Hosking
L K
LK
Hill
B T
BT
D002945:Cisplatin / Q000494:pharmacology*; D003131:Combined Modality Therapy; D003536:Cystadenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000532:radiotherapy; D004351:Drug Resistance / Q000528:radiation effects; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D005978:Glutathione / Q000032:analysis; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000532:radiotherapy; D013762:Tetrahydrofolate Dehydrogenase / Q000032:analysis; D013940:Thymidylate Synthase / Q000032:analysis; D014407:Tumor Cells, Cultured
D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D005978:Glutathione; D002945:Cisplatin; D005472:Fluorouracil; D008727:Methotrexate