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Oltipraz: clinical opportunities for cancer chemoprevention. p
1Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205, USA.
Abstract:
Oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione], originally developed as an antischistosomal agent, protects against chemical carcinogenesis in lung, trachea, forestomach, small intestine, colon, breast, skin, liver and urinary bladder in rodents. Oltipraz induces electrophile detoxication enzymes, resulting in diminished carcinogen-DNA adduct formation and reduced cytotoxicity, an important component of anticarcinogenic actions. Phase I trials of this drug have been recently conducted in the United States and indicate that the maximum tolerated dose is about 125 mg/day over a six-month period. Grade I/II dose-limiting toxicities included photosensitivity/heat intolerance, gastrointestinal, and neurologic toxicities. Ongoing studies are monitoring relationships between dose scheduling, drug plasma concentrations and pharmacodynamic action. Subsequent trials with this agent might most appropriately target individuals at high risk for occupational or environmental exposures to genotoxic carcinogens. Towards this end, a randomized, placebo-controlled Phase II study is planned for people at high risk for exposure to aflatoxins and development of hepatocellular carcinoma. Modulation of biomarkers reflecting the biologically effective dose of aflatoxin will serve as study endpoints.
Insights
Oltipraz, an antischistosomal drug, shows promise in preventing chemical carcinogenesis across multiple organs in rodents by boosting detoxifying enzymes. Phase I trials reveal a maximum tolerated dose of 125 mg/day, with side effects including photosensitivity and gastrointestinal issues.
Area of Science:
- Chemoprevention
- Drug Development
- Toxicology
Background:
- Oltipraz, initially an antischistosomal agent, demonstrates broad-spectrum protection against chemical carcinogenesis in preclinical rodent models.
- The drug functions by inducing electrophile detoxication enzymes, thereby reducing carcinogen-DNA adduct formation and cytotoxicity.
Purpose of the Study:
- To evaluate the safety and tolerability of Oltipraz in humans.
- To explore the potential of Oltipraz as a chemopreventive agent against genotoxic carcinogens, particularly aflatoxins.
Main Methods:
- Phase I clinical trials were conducted in the United States to determine the maximum tolerated dose (MTD) and dose-limiting toxicities.
- A randomized, placebo-controlled Phase II study is planned to assess Oltipraz efficacy in individuals at high risk for aflatoxin exposure and hepatocellular carcinoma.
Main Results:
- The maximum tolerated dose of Oltipraz was determined to be approximately 125 mg/day over a six-month period.
- Grade I/II dose-limiting toxicities included photosensitivity, heat intolerance, gastrointestinal disturbances, and neurological effects.
Conclusions:
- Oltipraz is a potential chemopreventive agent with a defined MTD and manageable toxicities in humans.
- Future research will focus on high-risk populations, such as those exposed to aflatoxins, utilizing biomarker modulation as study endpoints.