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Docetaxel Followed by Castration Improves Outcomes in LNCaP Prostate Cancer–Bearing Severe Combined Immunodeficient Mice

Authors' Affiliations: ¹ Department of Medicine, ² Division of Biostatistics, ³ Greenebaum Cancer Center, and ⁴ Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine and ⁵ Baltimore Veterans Affairs Medical Center, Baltimore, Maryland

Requests for reprints: Arif Hussain, Department of Medicine, University of Maryland School of Medicine, BRB 9-041, 655 West Baltimore Street, Baltimore, MD 21201. Phone: 410-328-3911; Fax: 410-328-6559; E-mail: ytang{at}som.umaryland.edu.

Purpose: Androgen ablation is the standard initial treatment for advanced prostate cancer; however, tumors eventually develop androgen independence and become incurable. Chemotherapy is commonly used after hormone treatment fails but has not shown significant survival benefit. Studies suggest that androgen ablation can select for a population of hormone-independent cells that are also relatively chemotherapy resistant. Thus, it may be therapeutically advantageous to target prostate cancer with chemotherapy before hormone ablation. This study was undertaken to determine the relative efficacy of such an approach in a preclinical model of prostate cancer.

Experimental Design: Severe combined immunodeficient mice bearing human LNCaP prostate tumors were treated with docetaxel and/or surgical castration applied singly, concurrently, or in different sequences. Treatment efficacy was determined by tumor volume and growth delay measurements. The extent of apoptosis in tumors in response to treatments was assessed via terminal deoxynucleotidyl transferase–mediated nick-end labeling (TUNEL) assays. In addition, Western blots were done to study the relative expression of Bcl-2 and Bax in the tumors.

Results: Docetaxel followed by castration showed the most potent antitumor effects. In contrast, with the exception of castration alone, castration followed by docetaxel produced the least antitumor activity. TUNEL assays confirmed that the density of apoptotic tumor cells was significantly greater for docetaxel followed by castration than for any other treatment. In tumors of mice treated with single modality therapies, Bax to Bcl-2 ratios decreased significantly after castration, whereas this ratio remained high after docetaxel treatment.

Conclusion: A treatment sequence of docetaxel followed by hormone ablation may be more effective in treating prostate cancer than concurrent docetaxel/hormone therapy or hormone ablation followed by docetaxel.

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