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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
3R29CA074819-04S1
Application #
6415109
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Rosenfeld, Bobby
Project Start
1997-07-15
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
4
Fiscal Year
2001
Total Cost
$27,237
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Radiation-Diagnostic/Oncology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Li, Chun; Wallace, Sidney (2008) Polymer-drug conjugates: recent development in clinical oncology. Adv Drug Deliv Rev 60:886-98
Milas, Luka; Mason, Kathryn A; Hunter, Nancy et al. (2003) Poly(L-glutamic acid)-paclitaxel conjugate is a potent enhancer of tumor radiocurability. Int J Radiat Oncol Biol Phys 55:707-12
Vega, Javier; Ke, Shi; Fan, Zhen et al. (2003) Targeting doxorubicin to epidermal growth factor receptors by site-specific conjugation of C225 to poly(L-glutamic acid) through a polyethylene glycol spacer. Pharm Res 20:826-32
Auzenne, Edmond; Donato, Nicholas J; Li, Chun et al. (2002) Superior therapeutic profile of poly-L-glutamic acid-paclitaxel copolymer compared with taxol in xenogeneic compartmental models of human ovarian carcinoma. Clin Cancer Res 8:573-81
Ke, S; Milas, L; Charnsangavej, C et al. (2001) Potentiation of radioresponse by polymer-drug conjugates. J Control Release 74:237-42
Zou, Y; Wu, Q P; Tansey, W et al. (2001) Effectiveness of water soluble poly(L-glutamic acid)-camptothecin conjugate against resistant human lung cancer xenografted in nude mice. Int J Oncol 18:331-6
Li, C; Ke, S; Wu, Q P et al. (2000) Tumor irradiation enhances the tumor-specific distribution of poly(L-glutamic acid)-conjugated paclitaxel and its antitumor efficacy. Clin Cancer Res 6:2829-34
Li, C; Ke, S; Wu, Q P et al. (2000) Potentiation of ovarian OCa-1 tumor radioresponse by poly (L-glutamic acid)-paclitaxel conjugate. Int J Radiat Oncol Biol Phys 48:1119-26
Oldham, E A; Li, C; Ke, S et al. (2000) Comparison of action of paclitaxel and poly(L-glutamic acid)-paclitaxel conjugate in human breast cancer cells. Int J Oncol 16:125-32
Li, C; Newman, R A; Wu, Q P et al. (2000) Biodistribution of paclitaxel and poly(L-glutamic acid)-paclitaxel conjugate in mice with ovarian OCa-1 tumor. Cancer Chemother Pharmacol 46:416-22

Showing the most recent 10 out of 13 publications