Irinotecan, alone or in combination with the tyrosine kinase inhibitor CEP-751, may be useful for the treatment of medullary thyroid cancer (MTC), say investigators from Johns Hopkins University School of Medicine in Baltimore, Maryland, USA.
The team, led by Barry Nelkin, explain in the Journal of Clinical Endocrinology & Metabolism that there is currently no effective systemic treatment for MTC, a cancer of the follicular C-cells, which commonly occurs in people with an inherited or acquired mutation in the RET receptor tyrosine kinase gene.
Nelkin et al therefore tested the sensitivity of a human MTC cell line, called TT, in response to irinotecan alone or in combination with the tyrosine kinase inhibitor CEP-751.
Analyses showed that in the TT cells treated with irinotecan, growth was inhibited even at the lowest concentrations of the drug – 200 nM – and significant cytotoxicity at doses greater than 500 nM.
The activity of irinotecan was augmented by the addition of the RET inhibitor CEP-751. Specifically, the combination of 1 µM of irinotecan and 100 nM of CEP-751 resulted in levels of cell death comparable to those seen among cells that had been treated with 5 µM of irinotecan.
Furthermore, in mice bearing subcutaneous TT xenograft tumors, dramatic responses to irinotecan treatment were seen, with complete remission induced in 100% of the mice after 70 days.
The addition of CEP-751 appeared to extend the duration of complete remission to more than 130 days. In contrast, in untreated mice, tumors developed during this time.
"These results suggest that irinotecan, alone or in combination, may be useful for treatment of MTC," the scientists comment.
"The implications of the results of the combination treatment also suggest the potential for possible future clinical utility of a combination of a tyrosine kinase inhibitor and irinotecan for MTC," they add.