Buzaid A C, Grimm E A, Ali-Osman F, Ring S, Eton O, Papadopoulos N E, Bedikian A, Plager C, Legha S S, Benjamin R
Department of Melanoma/Sarcoma, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Melanoma Res. 1994 Oct;4(5):327-30. doi: 10.1097/00008390-199410000-00010.
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.
在一项生物化疗试验中，对于晚期黑色素瘤患者，顺铂、长春碱和达卡巴嗪（CVD）与白细胞介素-2（IL-2）加干扰素-α2a（IFN-α2a）同时给药（生物化疗），在此试验过程中，我们进行了一系列实验室研究，试图更好地理解该治疗方案的抗肿瘤作用机制。我们最初假设CVD可增强生物治疗的抗肿瘤作用。然而，在最初研究的10例患者中，其中8例有反应，我们未观察到淋巴因子激活的杀伤细胞（LAK）活性，自然杀伤（NK）细胞活性也极低。这促使我们改变最初的假设。基于其他人的研究工作，其显示IL-1α与顺铂之间存在明显协同作用，显然是由肿瘤浸润巨噬细胞产生的H2O2介导的，我们推断生物治疗可增强CVD方案的细胞毒性。为评估巨噬细胞功能，我们测量了8例有反应者和7例无反应者的血清新蝶呤水平。8例有反应者中有7例血清新蝶呤水平比基线水平升高6倍或更多，而7例无反应者中只有2例升高（P = 0.041）。我们还检测了4例有反应者和4例无反应者外周血单个核细胞中的DNA链间交联水平，作为评估DNA修复过程的一种方法。所有4例有反应者均观察到DNA交联指数≥0.75，而无反应者中只有1例（P = 0.14）。我们的初步结果表明，同时进行生物化疗可能通过直接细胞毒性发挥其主要抗肿瘤作用，并且巨噬细胞可能参与了这一过程。
