We have developed a series of human colon carcinoma cell lines with different biological properties which include responsive to mitomycin C (MMC) and """"""""naturally"""""""" refractory (NR) to MMC. We have also selected sublines of MMC-resistant cells (SR) from the sensitive parental subpopulations. Naturally refractory and MMC selected cell lines will be compared to define the spectrum of mechanisms of MMC resistance that are encountered and to determine whether particular mechanisms of resistance are associated with either selected resistance or """"""""natural resistance"""""""". Cell lines will be identified as responsive or refractory by challenge of cells with MMC as cell cultures and as xenografts in athymic mice. Possible mechanisms of MMC resistance include MMC influx and efflux alterations, lack of MMC activation by microsomal enzymes, enhanced repair of MMC-DNA adducts, and MMC inactivation reactions. Differences in these properties between sensitive and resistant cells will be explored. MMC influx, efflux, and deactivation reactions will be studied using radioactive MMC, MMC activation will be compared using spectrophotometric methods, and DNA interstrand crosslink formation and repair will be followed by alkaline elution methods. MMC analogs that have superior activity to MMC in murine test systems will be evaluated for their efficacy against MMC refractory colon cancer cell lines. Finally, we will characterize the mechanisms of MMC resistance and the efficacy of MMC analogs to circumvent this resistance among human colon cancer cells cloned from early passage cultures of clinical colon cancer specimens. The identification of specific mechanisms of resistance and development of model systems reflecting these mechanisms will have impact on the clinical utilization of MMC, the future clinical development of new MMC analogs, and the development of in vitro and in vivo models for the evaluation of new anticancer drugs and analogs of existing drugs.
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