Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions

Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit carcinogenesis of mu rine skin, stomach, intestine and liver. However, the toxicology, pharmacok inetics and biologically effective dose of curcumin in humans have not been reported. This prospective phase-I study evaluated these issues of curcumi n inpatients with one of the following five highrisk conditions: 1) recentl y resected urinary bladder cancer; 2) arsenic Bowen's disease of the skin; 3) uterine cervical intraepithelial neoplasm (CIN); 4) oral leucoplakia; an d 5) intestinal metaplasia of the stomach. Curcumin was taken orally for 3 months. Biopsy of the lesion sites was done immediately before and 3 months after starting curcumin treament. The starting dose was 500 mg/day. If no toxicity greater than or equal to grade II was noted in at least 3 successi ve patients, the dose was then escalated to another level in the order of 1 000, 2000, 4000, 8000, and 12000 mg/day. The concentration of curcumin in s erum and urine was determined by high pressure liquid chromatography (HPLC) . A total of 25 patients were enrolled in this study. There was no treatmen t-related toxicity up to 8000 mg/day. Beyond 8000 mg/day, the bulky, volume of the drug was unacceptable to the patients. The serum concentration of c urcumin usually peaked at 1 to 2 hours after oral intake of crucumin and gr adually declined within 12 hours. The average peak serum concentrations aft er taking 4000 mg, 6000 mg and 8000 mg of curcumin were 0.51 +/- 0.11 muM, 0.63 +/- 0.06 muM, and 1.77 +/- 1.87 muM, respectively. Urinary excretion o f curcumin was undetectable. One of 4 patients with CIN and 1 of 7 patients with oral leucoplakia proceeded to develop frank malignancies in spite of curcumin treatment. In contrast, histologic improvement of precancerous les ions was seen in 1 out of 2 patients with recently resected bladder cancer, 2 out of 7 patients of oral leucoplakia, 1 out of 6 patients of intestinal metaplasia of the stomach, 1 out of 4 patients with CIN and 2 out of 6 pat ients with Bowen's disease. In conclusion, this study demonstrated that cur cumin is not toxic to humans up to 8000 mg/day when taken by mouth for 3 mo nths. Our results also suggest a biologic effect of curcumin in the chemopr evention of cancer.