Antitumor activity of poly(L-glutamic acid)-paclitaxel on syngeneic and xenografted tumors

Poly(L-glutamic acid)-paclitaxel (PG-TXL) is a new water-soluble paclitaxel derivative that has shown remarkable antitumor activity against both ovari an and breast tumors, The purpose of this study was to test whether the ant itumor efficacy of PG-TXL depends on tumor type, as is the case for paclita xel, and to test whether paclitaxel-resistant tumors could be responsive to PG-TXL, We evaluated the therapeutic activity of PG-TXL against four synge neic murine tumors (MCa-4, MCa-35, HCa-1, and FSa-II) inoculated i.m. into C3Hf/Kam mice, a human SKOV3ip1 ovarian tumor injected i,p, into nude mice, and a human MDA-MB-435Lung2 breast tumor grown in the mammary fat pad of n ude mice. Two paclitaxel-responsive murine tumors, MCa-4 and MCa-35, showed significant growth delay with PG-TXL given as a single i.v. injection at i ts maximum tolerated dose of 160 mg of equivalent paclitaxel/kg or even at a lower dose of 120 mg of equivalent paclitaxel/kg. The other two murine tu mors, HCa-1 and FSa-II, did not respond particularly well to either of the two agents, although significant growth delay was observed for both tumors with PG-TXL, In mice with SKOV3ip1 tumors, the median survival times for mi ce treated with PG alone and PG-TXL at doses of 60 or 120 mg of equivalent paclitaxel/kg were 43, 61, and 75 days, respectively; no survival differenc e was found between paclitaxel-treated and Cremophor vehicle-treated mice. In mice with MDA-MB-435Lung2 tumor, PG-TXL at a dose of 120 mg of equivalen t paclitaxel/kg produced regression of the tumor in 50% of the animals, and in the remaining mice, micrometastases in the lung were found only in 25% of the animals. In comparison, treatment with paclitaxel at 60 mg/kg did no t result in tumor regression, and the rate of lung metastases was 42%. Thes e results clearly demonstrate that PG-TXL has significant therapeutic activ ity against breast and ovarian tumors tested in this study. Future studies to elucidate the mechanism of action of PG-TXL and to assess its clinical a pplications are warranted.