Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma
Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma
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DOI：
10.1016/s0002-9440(10)64164-8
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发表时间：
2002-07-01
影响因子：
6
通讯作者：
Bar-Eli, M
中科院分区：
文献类型：
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作者：
Huang, SY;Mills, L;Bar-Eli, M
白细胞介素-8 （IL-8）最近被证明作为一种有丝分裂和血管生成因子，有助于人类黑色素瘤的进展。在本研究中，我们研究了一种全人源抗IL-8抗体（abx -IL-8）靶向IL-8是否可能成为一种潜在的治疗策略，以控制黑色素瘤的血管生成、生长和转移。将人黑色素瘤细胞A375SM（高IL-8产生细胞）和TXM-13（中IL-8产生细胞）皮下注射到裸鼠体内，然后用abx - IL-8（每周1 mg/3次，ig，连续3周）处理裸鼠。与对照组igg处理的小鼠相比，abx - il8处理的小鼠两种黑色素瘤的肿瘤生长均受到显著抑制。当静脉注射黑色素瘤细胞时，ABX-IL8治疗也抑制了实验性转移。ABX-IL8阻断IL-8可显著抑制人黑色素瘤细胞启动子活性和基质金属蛋白酶-2胶原酶活性，减少体外重建基底膜侵袭。在体内，ABX-IL8治疗导致基质金属蛋白酶-2的表达降低，肿瘤血管形成（血管生成）减少，肿瘤细胞凋亡增加。此外，在体外血管形成实验中，ABX-IL8直接干扰人脐静脉内皮细胞的小管形成。综上所述，这些结果表明ABX-IL8作为一种治疗黑色素瘤和其他实体肿瘤的潜在效用，无论是单独治疗还是与常规化疗或其他抗肿瘤药物联合使用。
Interleukin-8 (IL-8) has recently been shown to contribute to human melanoma progression by functioning as a mitogenic and angiogenic factor. In the present study, we investigated whether targeting IL-8 by a fully human anti-IL-8 antibody (ABX-IL8) could be a potential therapeutic strategy to control angiogenesis, growth, and metastasis of melanoma. The human melanoma cells A375SM (high IL-8 producer) and TXM-13 (intermediate IL-8 producer) were injected subcutaneously into nude mice, which were then treated with ABX-IL8 (I mg/3 times weekly, i.p., for 3 weeks). Tumor growth of both melanomas in ABX-IL8-treated mice was significantly inhibited when compared with control IgG-treated animals. ABX-IL8 treatment also suppressed experimental metastasis when the melanoma cells were injected intravenously. IL-8 blockade by ABX-IL8 significantly inhibited the promoter activity and the collagenase activity of matrix metalloproteinase-2 in human melanoma cells, resulting in decreased invasion through reconstituted basement membrane in vitro. In vivo, ABX-IL8 treatment resulted in decreased expression of matrix metalloproteinase-2, and decreased vascularization (angiogenesis) of tumors concomitant with increased apoptosis of tumor cells. Moreover, in an in vitro vessel formation assay, ABX-IL8 directly interfered with the tubule formation by human umbilical vein endothelial cells. Taken together, these results point to the potential utility of ABX-IL8 as a modality to treat melanoma and other solid tumors either alone or in combination with conventional chemotherapy or other anti-tumor agents.