Lichtenstein A
Department of Medicine, VA Wadsworth Hospital-UCLA Medical Center.
Clin Immunol Immunopathol. 1988 Jun;47(3):296-309. doi: 10.1016/s0090-1229(88)80008-4.
The mechanism of neutrophil-mediated lysis of tumor targets was investigated. Tumor lysis was directly related to the concentration of phorbol myristate acetate (PMA) used to stimulate PMNs. Lysis increased as the PMA concentration increased between 10(-7) and 10(-4) M. In contrast, the production of H2O2 plateaued between concentrations of 10(-5) and 10(-4) M. The K562 erythroleukemia cell, the target used in this study, was found to be relatively resistant to preformed H2O2, with an LD50 of 8.3 X 10(-3) M. Myeloperoxidase was not capable of enhancing K562 lysis. Although resistant to preformed H2O2, K562 lysis mediated by PMNs stimulated with 10(-7) M PMA was oxidative in nature. It was sensitive to inhibition by catalase and was not significant when PMNs from patients with chronic granulomatous disease were used. In contrast, PMN lysis stimulated by 10(-4) M PMA was nonoxidative in nature. The inhibitors catalase and superoxide dismutase had no effect on lysis, lysis was significant when the assay was performed in an anaerobic atmosphere, and PMNs from patients with chronic granulomatous disease were comparable to control PMNs in tumor lysis. A single-cell conjugate and cytotoxicity assay demonstrated that PMA was both able to increase the ability of PMNs to bind to tumor targets and to enhance their lysis of bound targets. These data indicate that PMNs are capable of achieving tumor lysis by nonoxidative pathways under certain conditions. The high-dose PMA model may be valuable as a tool for investigating these alternative mechanisms of tumor lysis.
研究了中性粒细胞介导的肿瘤靶细胞裂解机制。肿瘤裂解与用于刺激中性粒细胞的佛波酯肉豆蔻酸酯（PMA）浓度直接相关。当PMA浓度在10^(-7)至10^(-4) M之间增加时，裂解增加。相比之下，H2O2的产生在10^(-5)至10^(-4) M浓度之间达到平台期。本研究中使用的靶细胞K562红白血病细胞被发现对预先形成的H2O2相对耐药，其半数致死剂量（LD50）为8.3×10^(-3) M。髓过氧化物酶不能增强K562的裂解。尽管对预先形成的H2O2耐药，但由10^(-7) M PMA刺激的中性粒细胞介导的K562裂解本质上是氧化性的。它对过氧化氢酶抑制敏感，当使用慢性肉芽肿病患者的中性粒细胞时裂解不明显。相比之下，由10^(-4) M PMA刺激的中性粒细胞裂解本质上是非氧化性的。抑制剂过氧化氢酶和超氧化物歧化酶对裂解没有影响，在厌氧气氛中进行测定时裂解明显，慢性肉芽肿病患者的中性粒细胞在肿瘤裂解方面与对照中性粒细胞相当。单细胞结合和细胞毒性测定表明，PMA既能增加中性粒细胞与肿瘤靶细胞结合的能力，又能增强它们对结合靶细胞的裂解。这些数据表明，中性粒细胞在某些条件下能够通过非氧化途径实现肿瘤裂解。高剂量PMA模型作为研究肿瘤裂解这些替代机制的工具可能具有价值。
