HMLH1 EXPRESSION AND CELLULAR-RESPONSES OF OVARIAN TUMOR-CELLS TO TREATMENT WITH CYTOTOXIC ANTICANCER AGENTS

Loss of expression of the hMLH1 and hPMS2 subunits of the MutL alpha-m ismatch repair complex is a frequent event (9/10) in independent cispl atin resistant derivatives of a human ovarian carcinoma cell line, How ever, only hMLH1 mRNA is decreased in these MutL alpha-deficient lines , No alterations in the levels of the hMSH2 and hMSH6 (GTBP) subunits of the MutS alpha-comples are observed, An increase in the proportion of ovarian tumours negative for the hMLH1 subunit is observed in sampl es taken at second look laporotomy after chemotherapy (36%: 4/11), com pared to untreated tumours (10%: 4/39), No significant difference is o bserved for hMSH2, hMSH6 or hPMS2. Furthermore, cisplatin and doxorubi cin-resistant ovarian lines deficient in hMLH1 expression are cross-re sistant to 6-thioguanine and the methylating agent N-methyl-N-nitrosou rea (MNU). Depletion of O-6-alkylguanine-DNA-alkyltransferase (ATase) activity confers only limited increased sensitivity to MNU. Thus the m ismatch repair deficient lines retain DNA damage tolerance even after ATase depletion, The hMLH1 deficient lines also lose ability to engage G1 and G2 cell cycle arrest after cisplatin damage, Together these da ta suggest that loss of hMLH1 expression may be a high frequency event following exposure of ovarian tumour cells to cisplatin and may be cr itically involved in the development of drug resistance, Thus, the hML H1 status of these cells appears to be highly correlated with the abil ity to engage cell death and cell cycle arrest after DNA damage induce d by cisplatin.