N-(2-CHLOROETHYL)-N'-CYCLOHEXYL-N-NITROSOUREA SENSITIVITY IN MISMATCHREPAIR-DEFECTIVE HUMAN-CELLS

To determine whether loss of mismatch repair (MMR) confers sensitivity to N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (CCNU), the sensitiv ity of MMR-defective (MMR-) variants was compared to that of their par ental cells, Loss of MMR confers between 2- and 5-fold hypersensitivit y to CCNU on HeLa, Raji, or Chinese hamster ovary cells, We also exami ned whether the sensitivity to CCNU is a general feature of MMR- human tumor cells, The majority expressed O-6-methylguanine-DNA-methyltrans ferase (MGMT; Mex(+) phenotype) that confers resistance to CCNU indepe ndent of their MMR status, The single Mex(-) MMR- SW48 cells were 4-fo ld more sensitive to CCNU than the Mex(-) MMR+ SW620 cells, CCNU sensi tivity of the Mex(+) cells was analyzed after treatment with the MGMT inhibitor O-6-benzylguanine. The MMR- AN3CA, LS174T, LoVo, and DU145 c ells were 1.4-4.3-fold more sensitive to CCNU than the MMR+ HeLaS3, HT 29, and A2780 cells. Hypersensitivity to CCNU was not seen in the MMR- cell lines DLD1, HEC1A, and HCT116, suggesting that other parameters, besides the MGMT and MMR defects, affect the cell's response to this drug, In contrast, loss of MMR was always associated with tolerance to the methylating agent N-methyl-N-nitrosourea. The sensitivity to CCNU in MMR- cells suggests a possible involvement of this repair pathway in repairing interstrand cross-links and may have implications for cli nical treatment of MMR- tumors.