A ROLE OF GLUTATHIONE IN RESISTANCE MECHANISMS TO CIS-DIAMMINEDICHLOROPLATINUM(II) IN HUMAN OVARIAN-CANCER CELL-LINES IN-VITRO

Abstract

The effects of D,L-buthionine-S, R-sulphoximine (BSO) on the cellular glutathione (GSH) levels and cis-diamminedichloroplatinum (II) (CDDP) sensitivity of human ovarian cancer cell lines (HRA, KK and MH) with different sensitivity to CDDP were examined. HRA cells were derived from ascites of a patient with serous cystadenocarcinoma of the ovary who responded well to CDDP-based combination chemotherapy. KK and MH cells were also established from ascites of a patient with clear cell carcinoma of the ovary and with serous cystadenocarcinoma of the ovary, respectively who did not respond to CDDP-based combination chemotherapy. The KK and MH cell lines showed 2.93- and 7.80-fold higher resistance to CDDP in vitro than HRA cells, respectively and had also cross-resistance to its analogues. Although GSH levels in the CDDP sensitive HRA cells were 33.4 nmol/10(7) cells, the CDDP resistant KK and MH cells showed 5.61-and 10.48-fold higher GSH levels, respectively. The higher the GSH levels the more rapid depletion of the cellular GSH by BSO occurred. Cystine, a component of GSH, resulted in an increase of the cellular GSH in these cell lines. When the cellular GSH levels were changed by BSO or cystine, changes of the IC50 to CDDP and its analogues of the CDDP resistant KK and MH cells correlated with those of the cellular GSH levels while the IC50 values of the CDDP sensitive HRA cells remained unchanged. In addition, when these resistant cell lines (but not HRA cells) were incubated with CDDP, the cellular GSH levels markedly increased. From these results, we conclude that GSH may have a role in the mechanisms of intrinsic resistance to CDDP and its analogues of the KK and MH cell lines.