COMPLETE REGRESSION OF WELL-ESTABLISHED TUMORS USING A NOVEL WATER-SOLUBLE POLY(L-GLUTAMIC ACID) PACLITAXEL CONJUGATE

Despite an intensive search, few water-soluble paclitaxel derivatives have been shown to have a therapeutic index superior to paclitaxel its elf, We non report a water-soluble poly(L-glutamic acid)-paclitaxel co njugate (PG-TXL) that produces striking antitumor effects with diminis hed toxicity. A single i.v. injection of PG-TXL at its maximum tolerat ed dose (defined as that dose that produces a maximum 12-15% body weig ht loss within 2 weeks after a single i.v. injection) equivalent to 60 mg of paclitaxel/kg and at even a lower dose equivalent to 40 mg of p aclitaxel/kg resulted in the disappearance of an established implanted 13762F mammary adenocarcinoma (mean size, 2000 mm(3)) in rats. (An eq uivalent dose of PG-TXL is the amount of conjugate that contains the s tated amount of paclitaxel.) Similarly, mice bearing syngeneic OCA-1 o varian carcinoma (mean size, 500 mm(3)) were tumor-free within 2 weeks after a single i.v. injection of the conjugate at a dose equivalent t o 160 mg of paclitaxel/kg. The conjugate has little if any intrinsic t ubulin polymerization activity ia vitro and is > 20 times less potent in supporting the growth of a paclitaxel-dependent CHO mutant cell lin e, PG-TXL has a prolonged half-life in plasma and greater uptake in tu mor as compared with paclitaxel. Furthermore, only a small amount of t otal radioactivity from PG-[H-3]TXL, was recovered as free [H-3]paclit axel in either the plasma or the tumor tissue within 144 h after drug injection, Histological studies of tumor tissues obtained from mice tr eated with PG-TXL show fewer apoptotic cells hut more extensive tumor necrosis as compared with paclitaxel treatment. These data suggest tha t in addition to its role as a carrier for selective delivery of pacli taxel to the tumor, PG-TXL exerts distinct pharmacological actions of its own that may contribute to its remarkable antitumor efficacy.