Mechanism of the anti-tumour effect of biochemotherapy in melanoma: preliminary results.
During the conduct of a biochemotherapy trial in which cisplatin, vinblastine and dacarbazine (CVD) were administered concurrently with interleukin-2 (IL-2) plus interferon-alpha 2a (IFN-alpha 2a) (biochemotherapy) in advanced melanoma, we performed a series of laboratory studies in an attempt to understand better the mechanism of anti-tumour effect of the regimen. We initially hypothesized that CVD enhanced the anti-tumour effect of the biotherapy. However, in the first 10 patients studied, of whom eight were responders, we observed no lymphokine-associated killer cell (LAK) and minimal natural killer (NK) cell activities. This prompted us to change our initial hypothesis. Based on the work of others which showed a marked synergism between IL-1 alpha and cisplatin, apparently mediated by H2O2 derived from tumour-infiltrating macrophages, we reasoned that the biotherapy could enhance the cytotoxicity of the CVD regimen. To evaluate macrophage function, we measured serum neopterin levels in eight responders and seven non-responders. An increase of six or more times above baseline levels was observed in seven out of eight responders but in only two of seven non-responders (P = 0.041). We also examined the level of DNA inter-strand cross-link in peripheral blood mononuclear cells in four responders and four responders, as a means to evaluate the DNA repair process. A DNA cross-link index > or = 0.75 was observed in all four responders but only in one non-responder (P = 0.14). Our preliminary results suggest that concurrent biochemotherapy may exert its predominant anti-tumour effect by direct cytotoxicity and that macrophages may be involved in this process.
Buzaid, AC; Grimm, EA; Ali-Osman, F; Ring, S; Eton, O; Papadopoulos, NE; Bedikian, A; Plager, C; Legha, SS; Benjamin, R
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