Water-Soluble Prodrugs of Taxol Against Colon Cancer

The objective is the development of taxol prodrugs targeted for the treatment of colon cancer. Mortality due to colorectal cancer is second only to lung cancer and is estimated to cause 58,300 deaths a year. New case estimates are higher and are more than double for 1992. Site specific drug delivery is a desirable form of administering drugs. The benefits are increased efficiency and reduced toxic side effects. The anticancer natural diterpenoid, taxol, was found to have significant anti-tumor activity against a variety of cancers. It differs from other naturally occurring drugs because it has a unique mechanism of action which promotes the assembly of microtubules and inhibits their disassembly inhibiting cell proliferation. Taxol therapy suffers due to water solubility problems of the drug resulting in formulation problems. There are several approaches to attain this goal through the prepara- tion of salts. These acid-base salts have problems of stability, toxicity, physiological pH disturbance and non-specific hydrolysis by esterases. Although there are more than 60 derivatives known, taxol beta-glucosides and beta-galactosides are not known. Such derivatives are attractive because they are likely to have increased water solubility and reduced absorption in the upper G.I. tract. More importantly both types of glycosides might be expected in analogy with other plant glycosides, to be cleaved by bacterial glycosidases, and to regenerate as a site-specific chemotherapeutic agent for the treatment of colorectal cancer. The specific aims are 1. the synthesis of taxol glucoside and galactoside, 2. determination of the partition coefficients, 3. enzymatic hydrolysis of the prodrug by glycosidases, and 4. in vitro and in vivo hydrolysis of the glycosides by contents of rat gastrointestinal tract.