Unlike other nitrosourea antitumor agents in active clinical use, the glucose analogue chlorozotocin has reduced bone marrow suppression while retaining antitumor activity. The property has been correlated with increased alkylation of L1210 versus murine bone marrow DNA. The objectives of this research include: 1. Determination of the mechanism of transport of chlorozotocin in L1210 and murine bone marrow cells. The results will be compared with those obtained with CCNU, a myelosuppression cyclohexyl derivative. 2. Studies will be conducted to determine if the selectivity of toxicity for tissues can be explained by differences in intracellular drug distribution. The binding of chlorozotocin and CCNU in subfractions of chromatin, and in transcriptionally active versus inactive chromatin, will be studied and compared with CCNU. 3. Determination as to whether the glucose carrier of chlorozotocin alters the quantitative and qualitative alkylation of nucleic acids in bone marrow versus L1210 cells; alkylated base extracts from these tissues will be identified and quantitated after exposure to chlorozotocin and CCNU. 4. The identification of the mechanisms of chlorozotocin's bone marrow sparing property will provide essential information for the design and development of future nitrosourea antitumor agents.
