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Unexpected Cytokines in Serum of Malignant Melanoma Patients during Sequential Biochemotherapy¹

Departments of Cancer Biology [E. A. G., C. M. S.], Melanoma and Sarcoma Medical Oncology [O. E.], and Biostatistics [C-H. T., J. J. L.], University of Texas, M. D. Anderson Cancer Center, Houston Texas 77030, and Centro de Oncologia, Hospital Sirio-Libanes, Sao Paulo 01308-050, Brazil [A. C. B.]

Biochemotherapy, which combines traditional chemotherapy with immune modulating biologicals, produces an unexpectedly high response rate (>50%) in advanced melanoma patients. We hypothesize that immunological mechanism(s) are responsible for the increased response rate, and particularly that macrophage activation is involved in tumor reduction. Patients were randomized to receive chemotherapy, composed of cisplatin, vinblastine, and dacarbazine (CVD), or biochemotherapy, which is CVD followed by interleukin (IL)-2 and IFN-2b (CVD-BIO). Laboratory analysis was performed on sera from 41 patients from each arm. Measurements of macrophage activation (neopterin), nitric oxide production (nitrite), and tumor necrosis factor- (TNF-), IL-1, IL-1ß, IFN-, IL-6, IL-10, and soluble IL-2 receptor (sIL-2R) were performed. Six of the nine biological responses (nitrite, neopterin, IFN-, IL-6, soluble IL-2R, and IL-10) significantly (P < 0.0002) increased in the CVD-BIO patients but not in the CVD patients. The increased IL-6 (P = 0.04) and IL-10 (P = 0.05) correlated with patient response, but only when the minor responders were included in the analysis. Evidence of macrophage activation was found in CVD-BIO patients and not in those receiving CVD alone. In addition, an unusual cytokine elaboration composed of IL-6, IFN-, IL-10, nitrite, neopterin, and sIL-2R, but not the expected TNF- and IL-1, was detected. A trend of higher increase in IL-6 and IL-10 in patients having clinical response was found, suggesting an incomplete Th2 pattern of cytokine elaboration. These data show that macrophage activation does not appear to be critical in the response to CVD-BIO, but that IL-10 and IL-6 induced by the BIO component of the CVD-BIO were associated with tumor regression, and that their biology should be pursued further in the analysis of mechanism(s) of response.

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