BERKELEY, CA (UroToday.com) - Docetaxel (DOC) is one of the most promising anticancer drugs used for the treatment of various cancers, yet it still remains ineffective against some metastatic and hormone-refractory prostate cancers largely because the drug is too toxic to increase its dose without causing damage in normal organs.[1]
| "...the docetaxel/doxorubicin mixing ratios identified in this study would be useful to design combination drug cocktails or delivery systems to improve chemotherapy for prostate cancer patients." |
To improve antitumor activity and attenuate toxicity, DOC has been combined in the clinic with other anticancer agents, such as prednisolone, mitoxantrone, estramustine, or doxorubicin (DOX).[2, 3, 4] Among these options, the combination of DOC with DOX holds particular promise because pharmacokinetic and pharmacodynamic properties of both drugs have been extensively studied in vitro and in vivo for the past decades. However, the therapeutic effects of DOC/DOX combination are subject to change by subtle differences in drug mixing ratios and treatment schedule, suggesting that there would be an optimal combination setting, a ‘sweet point’ where the maximum synergy between DOC and DOX can be achieved to kill prostate cancer cells. Therefore, identification of such an optimal combination setting is critical to design an effective and safe prostate cancer therapy, potentially delivering both drugs at an optimal condition to tumor tissues in controlled and targeted manners using drug delivery technology.
In our recent study, we tested our hypothesis by investigating the combination effects of DOC and DOX at various combination settings in PC3 and DU145 prostate cancer cells, hormone-independent in vitro models. The unified theory, proposed by Chou et al., was used to estimate the combination indices (CIs), indicative of synergy (CI < 0.9), additivity (0.9 < CI < 1.1), and antagonism (CI > 1.1) for various concentrations and mixing ratios. DOC showed a biphasic cytotoxicity pattern with a half maximal inhibitory concentration (IC50) at the picomolar range for PC3 and DU145, following 72 h drug exposure. On the contrary, the IC50 of DOX was in the micromolar range, indicating that DOC is about 1000 times more potent than doxorubicin in vitro. Strong synergy was seen when PC3 was treated with DOC at concentrations lower than its IC50 values (0.125 ~ 0.5 nM) plus DOX (2 ~ 8 times IC50). Equipotent drug combination treatments (7 × 7 concentrations) revealed that the DOC/DOX combination led to high synergy and effective cell death only in a narrow concentration range in DU145, identifying the sweet spot for maximum drug synergy. The combination of DOC and DOX in multiple dose levels was also examined, underlining the importance of identifying an exact drug mixing ratio that would allow for the greatest therapeutic effect of the DOC/DOX combination. Therefore, the DOC/DOX mixing ratios identified in this study would be useful to design combination drug cocktails or delivery systems to improve chemotherapy for prostate cancer patients.
References:
- Galsky, M.D. and N.J. Vogelzang, Docetaxel-based combination therapy for castration-resistant prostate cancer. Ann Oncol, 2010. 21(11): p. 2135-44.
- Petrylak, D.P., et al., Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med, 2004. 351(15): p. 1513-20.
- Tannock, I.F., et al., Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med, 2004. 351(15): p. 1502-12.
- Budman, D.R., A. Calabro, and W. Kreis, Synergistic and antagonistic combinations of drugs in human prostate cancer cell lines in vitro. Anticancer Drugs, 2002. 13(10): p. 1011-6.
Written by:
Eleftheria Tsakalozou, Allison M. Eckman, and Younsoo Bae* as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
*Assistant Professor
Department of Pharmaceutical Sciences
College of Pharmacy
The University of Kentucky
789 South Limestone, Room 333
Lexington, KY 40536-0596
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Combination effects of docetaxel and doxorubicin in hormone-refractory prostate cancer cells - Abstract
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