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DNA: still a target worth aiming at? A review of new DNA-interactive agents
1Department of Medical Oncology, Glasgow University, Bearsden, Glasgow, Scotland. DAANTHONEY@Netscape.net
Abstract:
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.
Insights
New DNA-interactive cytotoxic agents show promise by targeting tumor cells through novel mechanisms, including protein interactions and gene expression inhibition. Clinical trials are ongoing for various cancers, with toxicity management strategies being developed.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Most cytotoxic agents target DNA, but lack of tumor cell selectivity limits their value.
- Novel DNA-interactive agents are being developed with mechanisms beyond direct DNA damage.
Purpose of the Study:
- To review three new classes of cytotoxic agents that interact with DNA.
- To explore their novel mechanisms of action and clinical potential.
Main Methods:
- Review of pre-clinical and clinical data for irofulven, cyclopropylpyrroloinole analogues, and ecteinascidins.
- Analysis of DNA damage, repair mechanisms, and protein interactions.
- Evaluation of clinical trial outcomes and toxicity profiles.
Main Results:
- Irofulven induces DNA damage repaired by helicases, showing synergy with topoisomerase inhibitors and activity in pancreatic, ovarian, and prostate cancers.
- Minor groove alkylating agents, like cyclopropylpyrroloinole analogues, may inhibit gene expression; myelosuppression is dose-limiting.
- Ecteinascidin-743 (ET-743) binds DNA and may inhibit gene transcription by sequestering transcription factors, showing activity in soft tissue sarcoma and breast cancer.
Conclusions:
- Novel DNA-interactive agents offer improved selectivity and efficacy through unique mechanisms.
- Further clinical development is warranted, with attention to schedule-dependent toxicity and administration methods.