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N-(2-Chloroethyl)-N'-cyclohexyl-N-nitrosourea Sensitivity in Mismatch Repair-defective Human Cells¹

Istituto Superiore di Sanità, 00161 Rome, Italy [G. A., S. C., S. M., M. B.], and Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms EN6 3LD, United Kingdom [R. H.]

To determine whether loss of mismatch repair (MMR) confers sensitivity to N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (CCNU), the sensitivity of MMR-defective (MMR^-) variants was compared to that of their parental cells. Loss of MMR confers between 2- and 5-fold hypersensitivity to CCNU on HeLa, Raji, or Chinese hamster ovary cells. We also examined whether the sensitivity to CCNU is a general feature of MMR^- human tumor cells. The majority expressed O⁶-methylguanine-DNA-methyltransferase (MGMT; Mex⁺ phenotype) that confers resistance to CCNU independent of their MMR status. The single Mex^- MMR^- SW48 cells were 4-fold more sensitive to CCNU than the Mex^- MMR⁺ SW620 cells. CCNU sensitivity of the Mex⁺ cells was analyzed after treatment with the MGMT inhibitor O⁶-benzylguanine. The MMR^- AN3CA, LS174T, LoVo, and DU145 cells were 1.4–4.3-fold more sensitive to CCNU than the MMR⁺ HeLaS3, HT29, 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 clinical treatment of MMR^- tumors.

¹ Supported in part by the Consiglio Nazionale delle Ricerche (Consiglio Nazionale delle Ricerche-Applicazioni Cliniche della Ricerca Oncologica), by the Associazione Italiana Ricerca sul Cancro, and by the Human and Capital Mobility Programme of the European Union.

² To whom requests for reprints should be addressed, at Istituto Superiore di Sanità, Section of Chemical Carcinogenesis, Viale Regina Elena 299, 00161 Rome, Italy. Phone/Fax: 39-6-49902355; E-mail: bignami@net.iss.it.

Received 5/19/97. Accepted 10/29/97.

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