Botanical Activity Relationship in Traditional Chinese Medicine: Studies of PHY906 as an Adjuvant Therapy with Cancer Chemotherapeutic Agents

 

Shwu-Huey Liu¹, Zaoli Jiang¹ and Yung-Chi Cheng².

¹PhytoCeutica, Inc., New Haven, CT;  ²Yale University School of Medicine, New Haven, CT 

 

PHY906, a Chinese medicinal formulation consisting of four different botanicals, has been shown in mouse models to enhance the therapeutic index of several anticancer agents such as irinotecan (CPT-11), 5-fluorouracil (5-FU), irinotecan/5-fluorouracil/leucovorin (LV), etoposide and L-OddC by both potentiating the antitumor effects of the therapeutic agents as well as reducing various host toxicities.   To investigate whether there is a need of all four botanicals to achieve the full observed biological activity, five formulations were studied: the complete formulation with all four botanicals and each of four formulations missing one of the botanical ingredients (A, B, C, D).  In the BDF-1 mice bearing Colon 38 tumor model, the potentiation of the antitumor effect of CPT-11 was impaired when either botanical A or botanical B was removed from the PHY906 formulation.  In contrast, botanicals C and D were not found to contribute to the potentiation of the antitumor effect of CPT-11.  However, when examining weight loss as an undesired toxic side effect of CPT-11, all of the botanicals except for B, contributed in protecting against body weight loss. Thus, the biological activity of PHY906 observed require all four botanicals.  Studies of the effects of botanicals on cytochrome P450 isozymes (CYP1A2, 2C9, 2C19, 2D6 and 3A4) in vitro have also been conducted to examine potential action of botanicals on isolated enzyme targets. One of these enzymes, CYP3A4, is known to be the major metaboling enzyme for CPT-11.  While studies in the BDF-1 mice bearing Colon 38 tumor model indicate that PHY906 has no effect on the pharmacokinetics or pharmacodynamics of CPT-11, it was observed that PHY906 was found to act as inhibitor of individual cytochrome P450 isozymes with different potency.  Individual P450 inhibition studies of both the single botanicals as well as the four separate formulations of three botanicals, indicate that there are interactions between specific botanicals that modulate the individual enzyme inhibitory effects.  These studies indicate the complex, compensatory and multi-factorial nature of botanical drug actions in both in vivo and in vitro studies in keeping with the philosophy of original Traditional Chinese Medicine. Currently, PHY906 is in Phase I//IIa clinical trials as a modulator of CPT-11/5-FU/LV in colorectal cancer patients.

 

 

National Meeting of the American Association of Cancer Research

San Francisco, CA, April 6-10, 2002.