DNA acts as the final target for most clinically effective
cytotoxic agents, but the lack of selectivity for
tumor cells has raised questions about the value of developing new
DNA-interactive agents. Three new classes of
cytotoxic agents are reviewed; each interacts directly with
DNA but cytotoxicity appears to be mediated through novel mechanisms, including the interaction with specific
proteins by
DNA-bound
drug molecules.
Irofulven is the lead compound of the illudin family of molecules. It causes a novel type of DNA damage whose repair is dependent on functioning
DNA helicases. Pre-clinical and clinical synergy between
irofulven and agents which inhibit topoisomerases has been observed. Clinical trials with
irofulven have shown significant activity and phase II studies in pancreatic, ovarian and
prostatic cancer are ongoing. Toxicity in the form of myelosuppression and
fatigue have been shown to be schedule dependent, with intermittent administration appearing to significantly reduce toxicity.
DNA-interacting agents which alkylate bases exposed in the minor groove have been derived from a number of natural sources. The minor groove alkylation appears to be sequence specific; although the significance of this specificity for cytotoxicity is unclear, one proposed mechanism is through inhibition of expression of particular genes. Three cyclopropylpyrroloinole analogues which cause sequence specific minor groove alkylation are currently under clinical assessment. Myelosuppression is the dose limiting toxicity and is biphasic in its time course. Moderate activity in phase I trials has been observed. Ecteinascidins represent one of the increasing number of groups of drugs isolated from marine organisms. Ecteinascidin-743 (ET-743) is the most advanced in its clinical development. Binding to the minor groove of
DNA occurs, although with a different base specificity from other compounds. The cytotoxic effects of
ET-743 may occur by inhibition of the inducible transcription of a number of genes by sequestration of specific
transcription factors. Clinical trials of
ET-743 have shown significant activity, and phase II trials are underway in
soft tissue sarcoma and
breast cancer. Hepatic toxicity and myelosuppression are predictable and appear associated with peak plasma concentrations, whereas efficacy seems to be improved with prolonged infusion.