In Vivo Induction of the Interferon-Stimulated Protein 2′5′Oligoadenylate Synthetase in Tumor and Peripheral Blood Cells During IFN-α Treatment of Metastatic Melanoma

Interferon-α (IFN-α) therapy induces a response in a proportion of patients with metastatic melanoma. However, the mechanism of the antitumor action and reason(s) for resistance to IFN therapy are not known. To investigate whether lack of clinical response may be due to resistance of the melanoma cells to IFN-α or to an inability of IFN-α to reach the tumor cells during treatment, we investigated the in vivo and in vitro susceptibility of primary tumor cells obtained through fine needle aspiration biopsies and peripheral blood mononuclear cells (PBMC) to the induction of the IFN-induced enzyme 2′5′-oligoadenylate synthetase (2′5′OAS) during initiation of IFN-α therapy in 10 patients with metastatic melanoma. None of the patients showed an objective response to IFN-α treatment. The melanoma cells from 2 of the 10 patients were resistant to IFN-induced enhancement of 2′5′OAS in vitro. This correlated well with the in vivo induction of 2′5′OAS in the malignant cells, as no in vivo induction was seen in the 2 patients whose malignant cells were resistant in vitro, whereas tumor cells from 7 of 8 of the remaining patients showed enhancement also in vivo. This study shows that it is possible to monitor the cellular susceptibility of tumor cells to IFN-α in vivo and that melanoma cells from a small percentage of patients are resistant to the cellular effects of IFN-α. Furthermore, the absence of a clinical response to IFN-α therapy in the majority of melanoma patients can be explained neither by impaired cellular susceptibility to IFN nor by an inability of IFN-α to reach the tumor.