MICROSATELLITE INSTABILITY, APOPTOSIS, AND LOSS OF P53 FUNCTION IN DRUG-RESISTANT TUMOR-CELLS

We have examined microsatellite instability and loss of p53 function i n human tumor cell line models of acquired anticancer drug resistance. We observe acquisition of an RER(+) phenotype in cell lines selected for resistance to cisplatin or doxorubicin. The majority of independen t cisplatin-resistant sublines are RER(+), whereas the parental line s hows no evidence of microsatellite instability. Microsatellite mutatio ns in random, nonselected subclones of a cisplatin-resistant line are observed in the absence of further drug exposure, suggesting that the RER(+) phenotype is a stable phenotype rather than being transiently i nduced by DNA damage. Furthermore, a cisplatin-resistant derivative sh ows reduction in a G:T mismatch recognition activity compared to the p arental line, Independent lines selected by multiple exposure to cispl atin show resistance factors of up to 5-fold by clonogenic assay and h ave reduced cisplatin-induced apoptosis. The resistant lines that are RER(+) show evidence of loss of p53-dependent functions, as measured b y loss of radiation-induced G(1) arrest and reduced C1P1 mRNA. Induced loss of p53 function by transfection of mutant TP53 does not cause a detectable RER(+) phenotype. We speculate that tolerance of DNA damage and expansion of cells with an RER(+) phenotype may select for reduce d ability to engage apoptosis and loss of p53 function.