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Shahar Frenkel, Dudi Shneor, Alik Honigman, Jacob Pe'er; Novel combinatorial treatment option for metastatic uveal melanoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4337.
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© ARVO (1962-2015); The Authors (2016-present)
To date, chemotherapy for metastatic uveal melanoma (mUM) is limited to dacarbazine (DTIC) and fotemustine. We tested the effect of the common chemotherapeutic drug doxorubicin (DOX) on cell mortality in order to expand the chemotherapeutic arsenal for mUM.
We examined the effect of both DITC and DOX in five different uveal melanoma cell lines - originating from metastases (OMM1, OMM2.3 and OMM2.5) and from primary tumors (92.1 and MEL270) and performed dose response tests using both drugs. Based on our previous results, we hypothesized that combining DOX and knockdown of CREB will increase cellular death. To test our hypothesis, we infected cells with replicative competent retroviruses (RCR) expressing shRNA against CREB to create a continuous infective knockdown of CREB.
Both chemotherapeutic drugs induced cell death in a dose dependent manner. Knockdown of CREB in these cells increased the effect of DOX on cell mortality.
Treatment with DOX is at least as efficient and in some cases even more efficient than DTIC in inducing UM cell mortality in vitro. Moreover, the ability of combining CREB knockdown and DOX treatment to achieve the same amount of cell death in lower concentrations of DOX may result in fewer side effects from DOX. This combination is a possible new treatment for metastatic uveal melanoma.
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