Investigations with Nitroimidazoles in Clinical Oncology
Clinical investigations on the usefulness of nitroimidazole compounds in cancer therapy were initiated more than six years ago. The first drug to be used was metronidazole. The feasibility of using this compound at doses ten times higher than what was currently used as an anti-trichomonal and anti-amebic agent was assessed by performing Phase I toxicological and pharmacokinetic studies in blood and tumor tissues. At the completion of this initial study it was established that at doses of 6 g/m2 of surface area, peak plasma levels were obtained in the order of one millimolar with a distribution within tumor tissues of approximately 80–90% of the blood levels. Pilot clinical Phase II trials were initiated in order to assess the efficacy of this agent as a radiosensitizer of hypoxic tumor cells. Shortly thereafter and while these Phase II studies were conducted a new nitroimidazole, misonidazole, was available for toxicity and pharmacokinetic studies. It was soon discovered that misonidazole when given in multiple dose schedules reaching total dose of 11–12 g/m2, in addition to acute G.I. toxicity, peripheral neuropathies, ototoxicity and CNS symptomatology were the limitations for any further dose escalation. Within that dose limitation this new compound was tested for effectiveness as an enhancer of tumor response when combined with radiotherapy in the hope of improving the therapeutic ratio between normal and tumor tissues. In the interval of four years the studies with misonidazole have gone from initial toxicity and pharmacokinetic studies to Phase II and Phase III clinical studies. Presently there are five multiple institutions, cooperative groups in North America and two in Europe conducting clinical trials in order to assess its value as a radiosensitizer. This, in addition to at least 15 large medical centers in both North America and Europe that are conducting specific studies. Close to 1,000 cancer patients have already been treated with metronidazole or misonidazole used in high doses. Early results have shown an encouraging trend and it is expected that within the next one to two years definitive results on the Phase II and III clinical trials will become available. In the meantime, new drugs with the same or more effectiveness and likely less toxic are becoming available for initial clinical investigations. One of these drugs, the metabolite of misonidazole, desmethyl misonidazole, is presently available for clinical toxicity and pharmacokinetic studies.
In addition to their use as radiosensitizers of hypoxic tumor cells the nitroimidazoles are being tested as enhancers of cancer chemotherapeutic agents in man. Their pharmacological interaction and possible improvement of the therapeutic ratio in tumors when used with agents such as Cyclophosphamide and 5-FU are currently being assessed.
KeywordsHigh Performance Liquid Chromatographic Peripheral Neuropathy Hypoxic Cell Peak Plasma Level Therapeutic Ratio
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