Combination Therapy Of Interferon-α And Chemotherapy Normalize Tumor Vasculature

Objectives There are clinical data showing encouraging results in combination with DTIC (dacarbazine) with interferon (IFN)-αfor the treatment of melanoma. However, the mechanism underlying this combination therapy remains to be elucidated. Here, we identify pericyte as a target cell of this combination therapy responsible for the abnormal tumour vascular morphology in mice.Methods B16 cells were inoculated subcutaneously in mice. After 7 days, the animals were randomized into 3different group of 7 animals,control group and groups treated with DTIC±IFN-α. Tumor growth, immunohistochemical examinations of microvessel density(MVD)by CD31 and microvessel mature pericyte coverage index byα-SMA and hypoxic tumour area by HIF-α, real-time reverse transcription-polymerase chain reaction of mRNA coding for RGS5, a novel pericyte marker and western blot of RGS5 and HIF-αand digital radiography were analyzed.Results The addition of IFN-αto DTIC-treatment decreased tumor volume, redude the number of enlarged vessels, decreased microvessel density (MVD), up-regulated microvessel pericyte coverage index, reduce the expression of HIF-αand down-regulated the expression of RGS5 significantly.Conclusions This study revealed a new fuction of IFN-αthat not only targets endothelia cell but also pericyte, nomalizes tomor vasculature rather than destroys vessels directly and regulates RGS5, as a master gene Loss of which results in pericyte maturation, vascular normalization and consequent marked reductions in tumour hypoxia and vessel Leakiness. These experimental data establishes a previously unrecognized role of pericyte in tumour vascular normalization in the combination chemotherapy of malignant tumours like melanoma.