Chapter 14. Antineoplastic Agents

Publisher Summary Comparison of structure–activity relationships of nitrosoureas active against L1210 leukemia with their toxicities indicated that the neutral agents with octanol/water partition coefficients of -1.5 to -2.5 might have better therapeutic indices than those currently in use. Clinical demonstration that cross-resistance between mustard-type alkylating agents does not exist in some tumors was found when cyclophosphamide-resistant, advanced breast cancer responded to the treatment with peptichemio. Direct chemical evidence that DNA cross-linking is a product of alkylation with busulfan is presented int his chapter. Methotrexate polyglutamates, which are readily formed in human tumor cells and bind to dihydrofolate reductase, may be selectively retained in cells and may be important determinants of duration of action and cytotoxicity of methotrexate in human solid tumors. A study of the interaction between adriamycin and phospholipids indicate similar association constants for such complexes and for DNA complexes; the data suggest competitive behavior between a membrane site and target DNA and consequently, lipid components of cell membranes may be an important determinant in the behavior of this agents. Some amino acid and dipeptide derivatives of daunorubicin were more active than the parent against subcutaneously-inoculated LL. Chemical reduction to semiquinones and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent microsomal activation of adriamycin and daunorubicin resulted in covalent binding to DNA. A mitomycin C-dextran conjugate demonstrated increased antitumor activity in comparison with the free drug and cellular uptake of methotrexate-poly (L-lysine) conjugates far exceeded the uptake of free drug in drug sensitive and resistant lines.