Docetaxel (Taxotere) is a hemisynthetic, anti-cancer compound with good preclinical and clinical activity in a variety of systemic neoplasms. We tested its activity against malignant gliomas using local delivery methods. Antitumor activity was assessed in vitro against human (U87 and U80 glioma) and rat brain-tumor (9L gliosarcoma and F98 glioma) cell lines. For in vivo evaluation, we incorporated docetaxel into a biodegradable polymer matrix, determined associated toxicity in the rat brain, and measured efficacy at extending survival in a rat model of malignant glioma. Also, we examined the combined local delivery of docetaxel with carmustine (BCNU) against the experimental intracranial glioma. Rats bearing intracranial 9L gliosarcomas were treated 5 days after tumor implantation with various polymers (placebo, 5% docetaxel, 3.8% BCNU, or 5% docetaxel and 3.8% BCNU combination). Animals receiving docetaxel polymers (n = 15, median survival 39.1 days) had significantly improved survival over control animals (n = 12, median survival 22.5 days, P = 0.01). Similarly, animals receiving BCNU polymers (n = 15, median survival 39.3 days, 13.3% long-term survivors) demonstrated an increase in survival compared to the controls (P = 0.04). Animals receiving the combination polymers demonstrated a modest increase in survival compared to either chemotherapeutic agent alone (n = 14, median survival 54.9 days, 28.6% long-term survivors) with markedly improved survival over controls (P = 0.003). We conclude that locally delivered docetaxel shows promise as a novel anti-glioma therapy and that the combination of drug regimens via biodegradable polymers may be a great therapeutic benefit to patients with malignant glioma.
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Acknowledgments The authors thank Rhoda Croft and Dr. Ritu Goel for assistance in the preparation of this manuscript.The research reviewed in this paper was partially funded by the National Cooperative Drug Discovery Group (UO1-CA52857) of the National Cancer Institutes of Health, Bethesda, MD, and by Guilford Pharmaceutical Corp., Baltimore, MD. Generous support for this research was received from the Norton Foundation in memory of Robin Norton. Dr. Sampath is the recipient of the NIH National Research Service Award CA-09574 and is a speaker for Rhone-Poulenc Rorer.Under a licensing agreement between Guilford Pharmaceuticals and the Johns Hopkins University, Dr. Brem is entitled to a share of royalty received by the University on sales of products described in this work. Dr. Brem and the University own Guilford Pharmaceuticals stock, which is subject to certain restrictions under the University policy. Dr. Brem also is a paid consultant to Guilford Pharmaceuticals. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest polices.
- Biodegradable polymers
- Combinedinterstitial chemotherapy