Cancer Biology, Kimmel Cancer Center/Thomas Jefferson University, Philadelphia, United States.
Ionizing radiation is used frequently in the management of multiple tumor types, including both organ confined and locally advanced prostate cancer. Enhancing tumor radiosensitivity could both reduce the amount of radiation required for definitive treatment and improve clinical outcome. Androgen suppression therapy improves clinical outcomes when combined with radiation therapy, but is associated with significant acute and chronic toxicities; hence, there is a clear need for alternative means to increase the therapeutic window of radiotherapy. Herein, it is demonstrated that the mTOR inhibitors rapamycin (sirolimus) and temsirolimus limit both hormone therapy-sensitive and castration-resistant prostate cancer cell proliferation as single agents, and have a profound radiosensitization effect when used in combination with ionizing radiation. Importantly, the observed radiosensitization was influenced by the treatment schedule, wherein adjuvant administration of mTOR inhibitors was most effective at limiting prostate cancer cell population doubling. This schedule-dependent influence on in vitro treatment outcome was determined to be the result of relative effects on the cell cycle kinetics. Lastly, adjuvant administration of either mTOR inhibitor tested after ionizing radiation significantly decreased clonogenic cell survival of both hormone therapy-sensitive and castration-resistant prostate cancer cells compared to ionizing radiation alone. Taken together, these data demonstrate that inhibition of mTOR confers a radiosensitization phenotype that is dependent on relative cell cycle kinetics and provide a foundation for clinical assessment.
Written by:
Schiewer MJ, Den R, Hoang DT, Augello MA, Lawrence YR, Dicker AP, Knudsen KE. Are you the author?
Reference: Endocr Relat Cancer. 2011 Sep 8. Epub ahead of print.
doi: 10.1530/ERC-11-0072
PubMed Abstract
PMID: 21903859
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