RADIATION SURVIVAL PARAMETERS OF ANTINEOPLASTIC DRUG-SENSITIVE AND DRUG-RESISTANT HUMAN OVARIAN-CANCER CELL-LINES AND THEIR MODIFICATION BY BUTHIONINE SULFOXIMINE

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  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (5) , 2110-2115
Abstract
The optimum integration of chemotherapy and irradiation is of potential clinical significance in the treatment of ovarian cancer. A series of human ovarian cancer cell lines was developed in which dose-response relationships to standard anticancer drugs were determined and the patterns of cross-resistance between these drugs and irradiation were established. By stepwise incubation with drugs, sublines of A2780, a drug-sensitive cell line, were made 100-fold, 10-fold and 10-fold more resistant to Adriamycin (2780AD), melphalan (2780ME) and cisplatin (2780CP). Two additional cell lines, NIH:OVCAR-3nu(Ag+) and NIH:OVCAR-4(Ag+), were established from drug refractory patients. 2780ME, 2780CP, OVCAR-3nu(Ag+) and OVCAR-4(Ag+) were all cross-resistant to irradiation, with Do of 146, 187, 143 and 203, respectively. 2780AD remained sensitive to radiation, with a Do of 111, which was similar to that of A2780 (101). Glutathione (GSH) levels were elevated in 2780ME, 2780CP, OVCAR-3nu(Ag+) and OVCAR-4(Ag+) to 4.58, 6.13, 12.10 and 15.14 nmol/106 cells as compared to A2780, with 1.89 nmol/106 cells. The GSH level in 2780AD is only minimally higher than that in A2780 (2.94 nmol/106 cells). Buthionine sulfoximine, a specific inhibitor of GSH synthesis, significantly increases the radiation sensitivy of 2780ME (changing the Do from 143 to 95) and 2780CP to a lesser extent, suggesting that intracellular GSH levels may play an important role in the radiation response of certain neoplastic cells. The sequential use of irradiation following chemotherapy with melphalan and cisplatin may be less effective than a combined modality approach, which integrates radiation and chemotherapy prior to the development of drug resistance and cross-resistance to irradiation.