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Synergistic effect of ketoconazole and antineoplastic agents on hormone-independent prostatic cancer cells
T Eichenberger1, J Trachtenberg, P Chronis
1Division of Urology, Toronto General Hospital, Ontario.
Abstract:
Ketoconazole has been recently used in the primary treatment of patients with metastatic cancer of the prostate and is identified as a potent inhibitor of cytochrome P450-dependent adrenal and testicular androgen production. The drug has also shown activity in patients failing conventional hormonal manipulation. We subsequently showed that ketoconazole in vitro has a direct cytotoxic effect on human androgen-independent prostatic cancer cell lines. In order to better define the possible role of ketoconazole on hormone-independent prostatic cancer, we incubated the cells from human androgen-independent prostatic cancer lines in a methylcellulose tumour colony assay with different doses of the drug and increasing doses of conventional cytotoxic agents (etoposide, bleomycin, vinblastine, methotrexate, and teniposide). We demonstrated synergistic suppression of prostate cancer clonogenic cell growth by ketoconazole in the presence of vinblastine or etoposide. This observation may assign a new and important role for ketoconazole as part of combination chemotherapy in the treatment of patients with advanced prostatic cancer.
Insights
Ketoconazole shows promise in treating advanced prostate cancer by directly killing cancer cells. It enhances chemotherapy by synergizing with vinblastine or etoposide, suggesting a new combination therapy role.
Area of Science:
- Oncology
- Pharmacology
Background:
- Ketoconazole inhibits androgen production and has shown activity in advanced prostate cancer.
- Ketoconazole exhibits in vitro cytotoxic effects on androgen-independent prostate cancer cell lines.
Purpose of the Study:
- To investigate the role of ketoconazole in hormone-independent prostate cancer.
- To evaluate ketoconazole's efficacy in combination with conventional cytotoxic agents.
Main Methods:
- Human androgen-independent prostate cancer cell lines were cultured in methylcellulose.
- Cells were treated with varying doses of ketoconazole and cytotoxic agents (etoposide, bleomycin, vinblastine, methotrexate, teniposide).
- Tumor colony assay was used to assess clonogenic cell growth suppression.
Main Results:
- Ketoconazole demonstrated synergistic suppression of prostate cancer cell growth when combined with vinblastine.
- Ketoconazole also showed synergistic effects with etoposide in inhibiting prostate cancer cell growth.
- These findings indicate a potential role for ketoconazole in combination chemotherapy.
Conclusions:
- Ketoconazole may play a significant role in combination chemotherapy for advanced prostate cancer.
- The synergistic effects observed suggest improved treatment strategies for hormone-independent prostate cancer.