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 ovarian and breast tumors. The purpose of this study was to test whether the antitumor efficacy of PG-TXL depends on tumor type, as is the case for paclitaxel, and to test whether paclitaxel-resistant tumors could be responsive to PG-TXL. We evaluated the therapeutic activity of PG-TXL against four syngeneic 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 nude 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 its 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 tumors, 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 mice 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 difference 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 equivalent 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 not result in tumor regression, and the rate of lung metastases was 42%. These results clearly demonstrate that PG-TXL has significant therapeutic activity 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 applications are warranted.
Li
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Division of Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. cli@di.mdacc.tmc.edu
Price
J E
JE
Milas
L
L
Hunter
N R
NR
Ke
S
S
Yu
D F
DF
Charnsangavej
C
C
Wallace
S
S
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011099:Polyglutamic Acid / Q000627:therapeutic use / Q000031:analogs & derivatives; D012513:Sarcoma, Experimental / Q000188:drug therapy; D043823:Taxoids; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured
D043823:Taxoids; D011099:Polyglutamic Acid; D017239:Paclitaxel; C509139:paclitaxel poliglumex