van Laarhoven H W M, Gambarota G, Heerschap A, Lok J, Verhagen I, Corti A, Toma S, Gallo Stampino C, van der Kogel A, Punt C J A
Department of Medical Oncology, University Medical Centre Nijmegen, Nijmegen, The Netherlands.
Invest New Drugs. 2006 Jan;24(1):27-36. doi: 10.1007/s10637-005-4540-2.
TNF-alpha may improve drug delivery to tumors by alteration of vascular permeability. However, toxicity precludes its systemic administration in patients. NGR-TNF comprises TNF coupled to the peptide CNGRC, which is a ligand for CD13. CD13 is expressed on tumor vasculature. Therefore, to assess the efficacy of NGR-TNF its biological effect on tumor vasculature should be measured rather than its effect on tumor growth. The aim of this study was to assess the effects of a low dose of NGR-TNF (5 ng/kg) on vascular permeability, tumor hypoxia, perfusion and proliferation in lymphoma bearing mice. MRI measurements with blood pool contrast agent showed an increased leakage of the contrast agent from the vasculature in NGR-TNF treated tumors compared with controls (p < 0.05), suggesting NGR-TNF-induced vascular permeability. Immunohistochemical analysis two hours after NGR-TNF treatment showed a decrease in tumor hypoxia (p < 0.1) and an increase in labeling index of the S-phase marker bromodeoxyuridine (p < 0.1), possibly due to an increase in tumor blood flow after NGR-TNF treatment. Although a decrease in tumor hypoxia and an increase in labeling index could have lead to increased tumor growth, in this experiment after one day a decrease in tumor volume was measured. Possibly, the effects on tumor hypoxia and proliferation two hours after treatment are transient and overruled by other, more longlasting effects. For example, the observed increase in vascular permeability may lead to haemoconcentration and increased interstitial pressure, ultimately resulting in an reduction of tumor blood flow and thus a decrease in tumor growth. A beneficial effect of NGR-TNF in combination with other therapeutical agents may therefore critically depend on the sequence and timing of the regimens. Currently, NGR-TNF is being tested in clinical studies.
肿瘤坏死因子-α（TNF-α）可能通过改变血管通透性来改善药物向肿瘤的递送。然而，其毒性使其无法在患者中进行全身给药。NGR-TNF由与肽CNGRC偶联的TNF组成，CNGRC是CD13的配体。CD13在肿瘤血管系统上表达。因此，为了评估NGR-TNF的疗效，应该测量其对肿瘤血管系统的生物学效应，而不是其对肿瘤生长的效应。本研究的目的是评估低剂量NGR-TNF（5 ng/kg）对荷淋巴瘤小鼠血管通透性、肿瘤缺氧、灌注和增殖的影响。使用血池造影剂的磁共振成像测量显示，与对照组相比，NGR-TNF治疗的肿瘤中造影剂从血管系统的渗漏增加（p < 0.05），提示NGR-TNF诱导的血管通透性。NGR-TNF治疗两小时后的免疫组织化学分析显示肿瘤缺氧减少（p < 0.1），S期标志物溴脱氧尿苷的标记指数增加（p < 0.1），这可能是由于NGR-TNF治疗后肿瘤血流增加所致。尽管肿瘤缺氧减少和标记指数增加可能导致肿瘤生长增加，但在本实验中，一天后测量到肿瘤体积减小。可能治疗后两小时对肿瘤缺氧和增殖的影响是短暂的，并被其他更持久的效应所抵消。例如，观察到的血管通透性增加可能导致血液浓缩和间质压力增加，最终导致肿瘤血流减少，从而肿瘤生长降低。因此，NGR-TNF与其他治疗药物联合使用的有益效果可能严重取决于治疗方案的顺序和时间。目前，NGR-TNF正在临床研究中进行测试。
