hMSH3 overexpression and cellular response to cytotoxic anticancer agents

Mutations or transcriptional silencing of mismatch repair genes have been l inked with tumour cell resistance to O-6-guanine methylating agents, 6-thio guanine, cisplatin, doxorubicin and etoposide. Recently, it has been demons trated that overexpression of the MSH3 protein is associated with depletion of the mismatch binding factor MutS alpha, and then with a marked reductio n in the efficiency of base/base mismatch repair. In the present study we e valuated sensitivity of the HL-60 cell line and its methotrexate-resistant subline HL-60R, which overexpresses the hMSH3 gene, to a panel of chemother apeutic agents. Cell growth inhibition induced by temozolomide, 6-thioguani ne and N-methyl-N ' -nitro-N-nitrosoguanidine was significantly lower in th e hMSH3-overexpressing HL-60R cell line as compared with the HL-60 parental line. Moreover, HL-60R cells were more resistant than HL-60 cells to chrom osome aberrations induced by either N-methyl-N ' -nitro-N-nitrosoguanidine or temozolomide, and to apoptosis triggered by the latter drug. Both cell l ines were equally susceptible to growth inhibition induced by cisplatin, et oposide or doxorubicin. In addition, HL-60 and HL-60R cells showed comparab le sensitivity to the clastogenic and apoptotic effects of cisplatin and et oposide. These results further confirm that loss of base/base mismatch repa ir is the most important molecular mechanism involved in cell resistance to O-6-guanine methylating agents and 6-thioguanine. However, the status of t he mismatch repair system could still influence tumour cell sensitivity to cisplatin, etoposide and doxorubicin, depending on the specific component o f the system that is lost, and on the genetic background of the cell.