“Prevention of CPT-11 Induced Toxicity by a Chinese Medicinal Formulation, PHY-906”

 

Shwu-Huey Liu*, Z. Jiang , J Liddil, K. Hu, E. A. Gullen and Yung-Chi Cheng.

Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510

 

Irinotecan hydrochloride (CPT-11, Camptosar®) is a clinically used anti-cancer agent, whose active metabolite is SN-38. The dose limiting toxicity is severe, delayed-onset diarrhea. This side effect is related to the biliary excretion of SN-38 glucuronide, which can be reactivated by b-Glucuronidase of bacteria in intestine to SN-38. A treatment that can decrease the formation of SN-38 in intestine should reduce the toxicity of CPT-11. PHY-906, a traditional Chinese herbal formulation used for thousands of years to treat various gastrointestinal ailments, shows potent inhibitory activity on E.coli b-Glucuronidase. This formulation, when giving orally, was compared with loperamide and other anti-diarrhea Chinese formulations (TJ-14ST, TJ-15, PHY-915) in female BDF-1 mice, bearing colon 38 carcinoma, that were treated with high dose of CPT-11. Only PHY-906 and PHY-915 decreased the toxicity of CPT-11, as measured by the weight lost of mice. However, PHY-915 antagonized the anti-tumor effect of CPT-11 while PHY-906 was shown to enhance the anti-cancer activity. The potent inhibition of b-Glucuronidase, decrease of toxicity and enhanced anti-tumor activity of CPT-11 are factors that suggest the PHY-906 should be developed to prevent CPT-11 toxicity.

 

National Meeting of the American Association of Cancer Research

San Francisco, CA, April 1-5, 2000.