Analogs of tea polyphenols for breast cancer chemoprevention

Institution: SRI International
Investigator(s): Nurulain Zaveri, Ph.D. -
Award Cycle: 1996 (Cycle II) Grant #: 2KB-0083 Award: $429,092
Award Type: New Investigator Awards
Research Priorities
Etiology and Prevention>Prevention and Risk Reduction: ending the danger of breast cancer

Initial Award Abstract (1996)
Preventing breast cancer is a major priority issue of the Breast Cancer Research Program. Cancer preventative agents from natural sources are of special interest. The proposed research aims to develop a new, safe breast cancer preventative drug based on a natural product found in green tea extracts. The natural product, EGCG (epigallocatechin - 3 - gallate), has shown cancer preventative activity in laboratory models of breast cancer. Systematic changes will be made in the structure of EGCG to find a compound with the best cancer preventative activity and fewest side effects.

At present, very few drugs are being developed as cancer chemopreventatives. Several naturally occurring substances have cancer chemopreventative properties, but very little research has been done to try to develop these compounds to get the best preventative effect combined with the lowest toxicity. This is the case with the green tea compounds. Green tea extract was shown to have cancer preventative effects in several experimental models of breast, lung, stomach and prostate cancer. EGCG, but not the other compounds of green tea extract, caused significant shrinkage of breast tumors in experimental models. This information suggests a link between a specific chemical structure and antitumor activity and gives a good starting point for research to develop an even more effective drug to prevent breast cancer. Because humans have used green tea as a common beverage for centuries, it is also likely that the new compound based on EGCG will be very safe - an important advantage. However, there are two reasons why drinking several cups of green tea a day as a breast cancer prevention strategy is impractical: many people do not like tea, and green tea does contain several components besides EGCG, some of which may be detrimental. Therefore, this research will use the structure of EGCG, the main chemopreventative ingredient of green tea, as a model to develop more powerful chemopreventatives.

This research will combine computer-aided drug design and laboratory synthesis of compounds to determine which structural features of EGCG are important for chemopreventative activity. New compounds will be designed and synthesized to allow systematic exploration of which changes give the strongest cancer preventative effect and the fewest unwanted effects. The advantages of the approach are that the drug development effort is based on a compound known to have cancer preventative effects, and computer modeling is an economical way to design similar compounds and predict their success without going to the expense of making all of them. All compounds synthesized will be tested in cell culture experiments to provide feedback for designing improved versions. This is an efficient way to find the few best compounds which are worth more extensive testing.

Final Report (2001)
Notes: This abstract was submitted for the 2001 BCRP Symposium and updates the results of this grant and links the results with a newly funded BCRP grant on this topic. The grant was extended 1-yr, until June 2000, to complete the aims and expenditures.

Current initial human studies to evaluate dose and efficacy (called Phase I trials) of green tea and its most abundant active compound (a catechin, (-) epigallocatechin-3-gallate, or EGCG) recommend a daily intake of 7-8 cups of green tea daily for a beneficial effect. The neurological and gastrointestinal side effects of this dose however, are caffeine-related. A significant problem with the use of green tea as a chemopreventive is the extremely low oral bioavailability of EGCG (<1%) and its extensive metabolic conjugation (deactivation this compound by the digestive system). Such poor absorption requires one to drink at least 7-8 cups of green tea a day to gain its chemopreventive benefit. Green tea consumption has been associated with decreased risk of breast, pancreatic, colon, esophageal, and lung cancers in humans.

A recent study showed that the principal site of the (antioxidant) activity of EGCG thought responsible for its anti-cancer properties, is the trihydroxyphenyl B ring and not the 3-galloyl D-ring. Given the low bioavailability of EGCG, we believe that it is possible to modify parts of the EGCG molecule, particularly the A-ring and possibly the D-ring, to modulate and improve oral absorption, without affecting chemopreventive potency.

With our previous grant (2KB-0083), we successfully developed the first versatile chemical synthesis of EGCG (and other catechins in green tea) which allows us to modify the various portions of the EGCG molecule. We synthesized several analogs (i.e., similar compounds) using our synthesis approach, one of which was found to be nearly as potent as EGCG itself in in vitro (‘test tube’) growth inhibition assays in breast cancer cell lines irrespective of estrogen receptor (ER) status.

Our current grant (2000/6JB-0068) proposes to use our devised synthesis approach in a preclinical drug discovery effort with the overall goal of rapidly identifying a potent, orally active potential breast cancer chemopreventive drug candidate. We will test these analogs for their in vitro growth inhibition and chemopreventive properties, but more importantly, the active analogs will concurrently be evaluated in in vitro models of intestinal permeability and oral bioavailability, the Caco-2 human intestinal cell line monolayer model, as well as in metabolism models, to provide immediate feedback on our design of the appropriate, orally bioavailable analogs and the validity of our approach. Completion of these studies will enable us to identify a potential preclinical drug candidate for further development as a safe breast cancer chemopreventive drug based on a natural product.

Synthetic analogs of green tea catechins and their in vitro cell growth inhibition activity. Proceedings 199 AACR-NCI-EORTC international Conference, Clin. Cancer Res. 5(S), 3844 (1999).
Periodical:Clinical Cancer Research
Index Medicus: Clin Cancer Res
Authors: Zaveri, Nurulain T. and Chao Wa-Ru
Yr: 1999 Vol: 5 Nbr: 568 Abs: Pg:3844