DNA: Still A Target Worth Aiming At?

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.

Chemical and Enzymatic Reductive Activation of Acylfulvene to Isomeric Cytotoxic Reactive Intermediates

“…In the presence of PTGR1 and NADPH or rat liver cytosol, AF has been shown to preferentially alkylate purine bases as single nucleosides and in ctDNA, and the corresponding adducts have been detected in cells. The major DNA adducts, 3-AF-deoxyadenosine (3-AF-dAdo) and 7-AF-deoxyguanosine (7-AF-dGuo), formed by AF in the presence of PTGR1 and NADPH, are thermally unstable and depurinate during neutral thermal hydrolysis 29 (Scheme 4). These adducts have been previously identified and characterized.…”

“…5 was reacted with dAdo, dGuo, or ctDNA in aqueous solution (pH 7) at 37 °C for 24 hours. Samples were heated to 90 °C to induce hydrolysis 29 of modified bases. After removal of water by rotary evaporation, the dried mixture was reconstituted in methanol and assayed by LC-MS to determine whether 3-AF-Ade and 7-AF-Gua were formed.…”

Mechanism Targeted Discovery of Antitumor Marine Natural Products

“…Ecteinascidin 743 (ET-743) inhibits DNA synthesis (therefore cell proliferation) and is in clinical trials for cancer [138,139]. Phase II clinical trials have demonstrated efficacy with ET-743 as a first or second-line treatment of advanced soft-tissue sarcoma [140,141]. ET-743 is an example of potential chemotherapeutic agents targeting DNA synthesis discovered through serendipitous screening.…”