• New Agents for Taxol-Resistant Ovarian Carcinoma

New Agents for Taxol-Resistant Ovarian Carcinoma
Posted May 1, 2012
Jim Klostergaard, Ph.D., University of Texas M. D. Anderson Cancer Center, Houston, Texas

Primary diagnosis of ovarian cancer often occurs at late stages of the disease, when metastasis has already occurred. After surgical debulking (removal of a portion of the tumor), adjuvant chemotherapy treatment with platinum and/or taxane compounds often produces high initial response rates, followed by high relapse rates, with patients exhibiting a drug-resistant form of disease correlating with poor probability of 5-year survival. Previous clinical trials showed improved survival rates, in patients with low-volume disease, when these drugs were administered intraperitoneally rather than intravenously. Several types of tumors, including ovarian, express significant amounts of the CD44 family of cell surface proteins, and Dr. Jim Klostergaard, of the University of Texas M. D. Anderson Cancer Center, hypothesized that they would provide an effective target to allow for localization of therapies to tumors, thus lowering overall toxicity. Dr. Klostergaard received a New Investigator Award from the fiscal year 2000 Department of Defense Ovarian Cancer Research Program to test hyaluronic acid (HA), the natural ligand for CD44, as a backbone for paclitaxel (TXL) prodrugs.

Dr. Klostergaard prepared HA-TXL and analyzed its toxicity and antitumor activity in two CD44+ human ovarian carcinoma xenograft mouse models. He was able to establish that a small intraperitoneal dose of this HA-based prodrug, below the maximum tolerated dose, reduced or eliminated tumor burden and prolonged survival when compared to controls. His current work in several human ovarian cancer models, including those that are taxane-resistant, indicates that frequent low doses of targeted HA-TXL are more effective than a systemic treatment based on the maximum tolerated dose and is under revision for publication in Clinical Cancer Research. This validates the potential for CD44-HA interactions to be used in the targeted delivery of anticancer agents specifically to cancer cells.

Reference:

Auzenne E, Ghosh SC, Khodadadian M, Rivera B, Farquhar D, Price RE, Ravoori M, Kundra V, Freedman RS, and Klostergaard J. 2007. Hyaluronic acid-paclitaxel: Antitumor efficacy against CD44(+) human ovarian carcinoma xenografts. Neoplasia 9:479-486.

Link:

Public and Technical Abstracts: New Agents for Taxol-Resistant Ovarian Carcinoma

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