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Submitted on August 22, 2005
Accepted on October 20, 2005
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231. Cephalon Inc., West Chester, Pennsylvania 19380
* To whom correspondence should be addressed. E-mail: bnelkin{at}jhmi.edu.
Context: Medullary thyroid cancer is a cancer of the parafollicular C-cells which commonly presents with an inherited or acquired RET gene mutation. There is currently no effective systemic treatment for MTC.
Objective: To investigate a systemic therapeutic approach to treat MTC. We studied the sensitivity of an MTC cell line and xenograft to Irinotecan, alone and in combination with the tyrosine kinase inhibitor, CEP-751.
Results: In TT cell culture and xenografts, irinotecan treatment was highly effective. This effect was augmented by treatment with CEP-751. Treatment of TT cell xenografts resulted in durable complete remission in 100% of the mice, with median time to recurrence of 70 days for irinotecan alone and > 130 days for irinotecan plus CEP-751. While irinotecan induced an S-phase checkpoint arrest in TT cells, CEP-751 in combination with irinotecan resulted in a loss of this arrest. CEP-751 induced a loss in the induction of the DNA repair program marked by phospho-H2AX and the checkpoint pathway marked by the activated Chk1 pathway.
Conclusions: Irinotecan treatment was highly effective in a preclinical model of human medullary thyroid carcinoma resulting in complete remission in 100% of xenografts treated. The duration of remission was further enhanced by combination with the kinase inhibitor, CEP-751. These results suggest that irinotecan, alone or in combination, may be useful for treatment of medullary thyroid carcinoma.
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