DECREASED DRUG ACCUMULATION AND INCREASED TOLERANCE TO DNA-DAMAGE IN TUMOR-CELLS WITH A LOW-LEVEL OF CISPLATIN RESISTANCE

In an attempt to examine the cellular changes associated with cisplati n resistance, we selected a cisplatin-resistant (A431/Pt) human cervix squamous cell carcinoma cell line following continuous in vitro drug exposure. The resistant subline was characterized by a 2.5-fold degree of resistance. In particular, we investigated the expression of cellu lar defence systems and other cellular factors probably involved in de aling with cisplatin induced DNA damage. Resistant cells exhibited dec reased platinum accumulation and reduced levels of DNA-bound platinum and interstrand cross-link frequency after short-term drug exposure. A nalysis of the effect of cisplatin on cell cycle progression revealed a cisplatin-induced G(2)M arrest in sensitive and resistant cells. Int erestingly, a slowdown in S-phase transit was found in A431/Pt cells. a comparison of the ability of sensitive and resistant cells to repair drug-induced DNA damage suggested that resistant cells were able to t olerate higher levels of cisplatin-induced DNA damage than their paren tal counterparts. Analysis of the expression of proteins involved in D NA mismatch repair showed a decreased level of MSH2 in resistant cells . Since MSH2 seems to be involved in recognition of drug-induced DNA d amage, this change may account for the increased tolerance to DNA dama ge observed in the resistant subline. In conclusion, the involvement o f accumulation defects and the increased tolerance to cisplatin-induce d DNA damage in these cisplatin-resistant cells support the notion tha t multiple changes contribute to confer a low level of cisplatin resis tance. (C) 1998 Elsevier Science Inc.