The effectiveness of clinically useful antitumor agents as inhbitors of RNA polymerases

Many clinically useful antitumor agents effective inhibitors of both the exogenous Escherichia coli DNA-dependent RNA polymerases in vitro and the endogenous polymerase in mammalian cultured cells. The drug concentrations required for this inhibition are comparable to those achievable plasma levels in man for Actinomycin D, Adriamycin, 5-Fluorouracil, ICRF 159, Melphalan, Methotrexate and Vincristine. Therefore before the mechanisms of these drugs can be fully understood inhibition of RNA synthesis and its implications in the continued survival and replication of cells must be considered. Although chemotherapeutic agents have generally been considered to exert their cytotoxic affects by directly interfering with DNA metabolism or by inhibiting enzymatic pathways in purine and pyrimidine nucleotide metabolism, these data emphasize that this is an oversimplication. Most agents have multiple effective target sites within the cell and the primary cytotoxic events responsible for their clinical effectiveness remain to be elucidated.