Phase I Clinical Trial of Oral Curcumin: Biomarkers of Systemic Activity and Compliance

 

Clin Cancer Res. 2004; 10(20):6847-54

 

During preclinical studies in rodents and clinical pilot studies Curcumin has shown anti-cancer activities. Its cancer prevention mechanism is thought to be by regulation of carcinogen-detoxifying enzymes such as glutathione S-transferase (GST), anti-oxidation and suppression of expression of the isoenzyme cyclooxygenase-2 (COX-2).

 

Objective:

The aim of the study was divided into three main categories.

  • To analyze toxicity of high doses of Curcumin administered orally to patients with advanced cancer.
  • To investigate the systemic effects of Curcumin consumption. 
  • To test the hypothesis that metabolism of Curcumin can be detected in blood or excreta of humans using LCMS.

 

Study Design:

Fifteen patients with adenocarcinoma of colon or rectum were chosen with no use of chemotherapeutic drugs within 28 days before enrolment. The patients were asked to abstain from NSAIDs. Patients were given 1, 2, 4 or 8 capsules each containing 500 mg of Curcumin C3 Complex® to provide dose escalation from 450 mg to 3.6 g daily until disease progression or withdrawal of consent. Blood, urine and feces were collected on 1, 2, 8 and 29th day of the study, while blood collection was predose, 0.5, 1, 2, 3, 6 and 8 h after Curcumin administration to measure the Curcumin and its metabolites.

The parameters evaluated during the trial (i.e. at baseline and at the end of the study) included fasting glucose level and lipid profile (total cholesterol, LDL-C, HDL-C and Triglycerides) along with liver and kidney function tests.

 

Results:

  • Curcumin was found to be well tolerated at all the dose levels and dose-limiting toxicity was not observed. 
  • Only two subjects showed gastrointestinal adverse events arising from Curcumin consumption at 0.45 and 3.6 g Curcumin after 1 and 4 months into treatment respectively, another patient consuming 0.9 g Curcumin daily experienced nausea.
  • Oral Curcumin administration at 3.6 g of Curcumin daily affected the LPS induced PGE2 levels. There was significant lowering of PGE2, difference reached significance on day 1 and day 29 of treatment. This suggested that consumption of 3.6 g of Curcumin daily is linked with inhibition of PGE2 induction in blood taken post dose compared to predose levels.
  • Curcumin was detected in plasma samples taken 0.5 and 1 h post dose from 3 patients consuming 3.6 g of Curcumin daily. Presence of Curcumin conjugates such as glucuronides and sulphates were confirmed by MS semi quantitation in blood, while analysis of urine suggested presence of Curcumin and conjugates in all samples from subjects consuming 3.6 g Curcumin daily.
  • Two patients exhibited stable disease after 2 months of treatment against progressive disease before treatment and remained on treatment for total 4 months.

 

Conclusion:

Administration of 0.5 to 3.6 g of Curcumin daily for 4 months was associated with only mild diarrhea as discernable toxicity. Consumption of 3.6 g of Curcumin generates detectable levels of Curcumin and its metabolites and 3.6 g of Curcumin causes inhibition of PGE2 production measured ex vivo

These conclusions lead the authors to propose oral dose of 3.6 g daily as suitable for evaluation in Phase II trials. 

 

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