MECHANISMS OF ACTION OF HIGHLY EFFICACIOUS PGA-TAXOL

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Taxol (paclitaxel) has shown significant activity against several types of malignant diseases, including breast cancer. As with most chemotherapeutic agents, however, the maximal dose of taxol is limited by toxicity. In humans, drug-induced toxicity is manifest as granulocytopenia and peripheral neuropathy. Other major difficulties in the clinical use of taxol include poor aqueous solubility and drug resistance. A strategy of polymer-drug conjugation has been attempted to improve the utility and efficacy of taxol. Specifically, a highly water-soluble polymer-taxol conjugate (PGA-taxol) which has shown remarkable in vivo antitumor activity in two rodent tumor models has been developed. In rats bearing intramuscularly implanted 13762 mammary tumor (approx. 2400 mm3 at time of treatment), a single intravenous injection of PGA-taxol at a dose of 40 mg equiv. Taxol/kg body weight induced complete tumor regression. In comparison, the same dose of taxol delayed tumor growth only 9 days (vs. Cremophor vehicle-treated controls). Furthermore, the inhibition of tumor growth by PGA-taxol was achieved with less toxicity than that produced by the less effective taxol treatment. Additionally, PGA-taxol showed activity against taxol-resistant tumor cells, demonstrating that conjugation of chemotherapeutic drugs to polymeric carries may be an useful strategy to overcome drug resistance. To better understand the enhanced antitumor efficacy of PGA-taxol and aid in the future design and development of polymeric drug carriers for selective delivery of chemotherapeutic agents, it is important to investigate further the pharmacological and toxicological properties of PGA-taxol. These studies should also be crucial in planning future human trials of PGA-taxol as a potentially powerful anti-cancer agent. The specific aims of this proposal are (1) to synthesize and characterize monomeric glutamic acid-taxol conjugate and PGA- taxol conjugates of different molecular weights; (2) to study their in vitro cytotoxicity and cellular accumulation kinetics; (3) to examine whether PGA-taxol has a unique mechanism of action different from that of taxol; (4) to assess their toxicity and in vivo antitumor activity in appropriate tumor models; and (5) to study their pharmacokinetics, tissue distribution, and intratumoral distribution.