9月8日美国Pharmacyclics公司宣布他们已经开始了一项关于莫特沙芬钆(Xcytrin)注射液的Ⅱ其日临床试验,试验的目的是评价单一制剂Xcytrin用于治疗复发性、转移性非小细胞肺癌的安全性和有效性。试验招募了美国和加拿大的108名应用铂撮入疗法治疗癌症转移失败的患者.随机分成两组分别注射Xcytrin 10mg·kg^-1·w^-1和15mg·kg^-1·(3w)^-1,Xcytrin是一种具有独特作用机理的抗癌因子. Xcytrin是第一个处于研究中的texaphyrins类药物,是一种理性设计的小分子药物,通过一种独特的方式在细胞内发挥作用。Xcytrin具有新型的作用机制,它是一种肿瘤特异性的活性氧簇(ROS) 分子细胞内发生器。因为癌细胞代谢旺盛(包括厌氧糖酵解),因此给药后Xcytrin能选择性的聚集在癌细胞内,又因为Xcytrin是一种常磁性化合物,因此可以进行磁共振成象(MRI)。MRI试验已经证明了Xcytrin对原发和转移肿瘤具有靶向作用。在癌细胞内部,Xcytrin破坏细胞代谢,干扰能力流动,导致ROS的产生。通过这种机制,Xcytrin就有可能导致癌细胞对放疗和化疗产生的氧化应激(有氧化-还原作用参与的一种特殊的损伤)更加敏感。在癌细胞内产生ROS能促进细胞调亡,导致选择性的杀死癌细胞的效果。 Motexafin gadolinium (Xcytrin®) alters the cytotoxic effect of the transition metal cations zinc and cadmium on cancer cell lines Darren Magda, Philip Lecane and Richard A. Miller Pharmacyclics, Inc., Sunnyvale, CA Motexafin gadolinium (MGd, Xcytrin®) selectively localizes in tumors and promotes stress by oxidizing intracellular reducing species. It was recently shown by microarray analysis that treatment of A549 human lung carcinoma cells with MGd led to induction of metallothioneins (MT) and zinc transporter 1 (Hacia, Proc. AACR 43:3211, 2002). We have also reported that MGd catalytically oxidizes vicinal thiols such as those present in the active site of thioredoxin reductase and the cofactor dihydrolipoate (Biaglow, Proc. AACR 42:3589, 2001). In the present study, we describe the effect of MGd and other metallotexaphyrins on the response of cancer cell lines to treatment with the transition metal cations cadmium and zinc. The results indicate that MGd at low concentrations modulates the cytotoxicity of these ions in cancer cells. Human lymphoma (HF-1) or lung carcinoma (A549) cells were cultured in microplates containing RPMI 1640 medium supplemented with 10% fetal bovine serum. Zinc (0-100 µM) or cadmium (0-50 µM) and 0-25 µM MGd or metal congeners dysprosium texaphyrin (Dy-Tex), manganese texaphyrin (Mn-Tex), or lutetium texaphyrin (MLu) were added for 24 hr. Medium was exchanged and proliferation was assessed using a tetrazole (MTT) reduction assay at the end of 3 days. In other experiments, HF-1 cells grown in 10 cm dishes were treated with MGd and zinc for 3 days, Coulter counted, and analyzed by flow cytometry using propidium iodide and annexin V. Cadmium alone strongly suppressed cell proliferation under these conditions. Treatment with 6.25 µM or higher MGd lowered the IC50 of cadmium in HF-1 cells but raised the IC50 in A549 cells, presumably by MT induction. Treatment with 6.25 µM or higher MGd lowered the IC50 of zinc in both HF-1 and A549 cells. MGd alone had no effect on proliferation at the concentrations tested. Dy-Tex had a lesser effect on response of HF-1 to zinc, whereas MLu and Mn-Tex were inactive. A similar trend of sensitization to zinc and protection from cadmium was observed in A549 cells for these analogues. In HF-1, MGd (25 µM) and zinc (50 µM) decreased proliferation 2.5-fold after 3 days relative to treatment with MGd or zinc alone and increased late apoptotic cells from 15% to 30% as assessed by staining with PI and annexin V. In summary, our findings suggest that MGd sensitizes cancer cell lines to zinc and may either sensitize or antagonize response to cadmium, depending on the cell line. These observations support the characterization of MGd as a redox cycling agent that targets vicinal thiols and alters metal cation homeostasis by inducing metallothionein expression. |