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 itself. We now report a water-soluble poly(L-glutamic acid)-paclitaxel conjugate (PG-TXL) that produces striking antitumor effects with diminished toxicity. A single i.v. injection of PG-TXL at its maximum tolerated dose (defined as that dose that produces a maximum 12-15% body weight 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 paclitaxel/kg resulted in the disappearance of an established implanted 13762F mammary adenocarcinoma (mean size, 2000 mm3) in rats. (An equivalent dose of PG-TXL is the amount of conjugate that contains the stated amount of paclitaxel.) Similarly, mice bearing syngeneic OCA-1 ovarian carcinoma (mean size, 500 mm3) were tumor-free within 2 weeks after a single i.v. injection of the conjugate at a dose equivalent to 160 mg of paclitaxel/kg. The conjugate has little if any intrinsic tubulin polymerization activity in vitro and is >20 times less potent in supporting the growth of a paclitaxel-dependent CHO mutant cell line. PG-TXL has a prolonged half-life in plasma and greater uptake in tumor as compared with paclitaxel. Furthermore, only a small amount of total radioactivity from PG-[3H]TXL was recovered as free [3H]paclitaxel in either the plasma or the tumor tissue within 144 h after drug injection. Histological studies of tumor tissues obtained from mice treated with PG-TXL show fewer apoptotic cells but more extensive tumor necrosis as compared with paclitaxel treatment. These data suggest that in addition to its role as a carrier for selective delivery of paclitaxel to the tumor, PG-TXL exerts distinct pharmacological actions of its own that may contribute to its remarkable antitumor efficacy.
Li
C
C
Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Yu
D F
DF
Newman
R A
RA
Cabral
F
F
Stephens
L C
LC
Hunter
N
N
Milas
L
L
Wallace
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D051379:Mice; D008870:Microtubules / Q000187:drug effects; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011099:Polyglutamic Acid / Q000627:therapeutic use / Q000031:analogs & derivatives; D051381:Rats; D012074:Remission Induction; D012995:Solubility; D043823:Taxoids; D014867:Water
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D014867:Water; D011099:Polyglutamic Acid; D017239:Paclitaxel; C509139:paclitaxel poliglumex