BIOLOGY AND THERAPEUTIC TARGETING OF IL-8 AND MUC18/MCAM

人黑色素瘤细胞表达白细胞介素-8（IL-8）与其体内转移潜能相关。此外，原发性皮肤黑色素瘤的UV-B照射诱导IL-8 mRNA和蛋白质的产生，并增加裸鼠肿瘤的生长和转移。此外，异位表达的IL-8基因进入原发性皮肤黑色素瘤导致在体内肿瘤生长和转移的增加。IL-8通过上调MMP-2的表达和活性发挥其血管生成作用。这些观察结果表明，IL-8可能是黑色素瘤血管生成，肿瘤生长和转移的介质，此外，IL-8可能是针对恶性黑色素瘤的免疫治疗的靶点。实际上，作为单一模式施用的完全人源化的IL-8中和抗体（ABX-IL-8）抑制裸鼠模型中人黑素瘤的生长和转移。MCAM/MUC 18是一种粘附分子， 对晚期原发性和转移性黑色素瘤细胞，其通过MMP-2的上调和增加的外渗而有助于获得转移表型。完全人源化抗MUC 18抗体（ABX-MA 1）在裸鼠模型中抑制人黑素瘤细胞的生长、血管生成和转移。因为用化疗剂DTIC治疗黑素瘤细胞引起IL-8的上调;我们假设ABX-IL 8将增强DTIC的临床有益的细胞毒性作用。此外，我们假设抑制IL-8和MUC 18的治疗策略可能在临床上有益。为了解决这些假设，我们提出以下具体目标： . 在动物模型中评价ABX-IL 8与达卡巴嗪（DTIC）组合对人黑素瘤的生长、血管生成和转移的作用，并确定IL-8调节黑素瘤细胞中MMP-2表达的机制 . 在动物模型中确定MUC 18阻断剂+DTIC的组合在抑制黑素瘤生长和转移方面是否优于单独的MUC 18阻断剂上级 . 在动物模型中评估IL-8和MUC 18联合阻断对黑色素瘤生长和转移的影响 . 评价IL-8和/或MUC 18阻断联合或不联合DTIC化疗对III期黑色素瘤患者组织标本中血管生成和细胞凋亡以及临床结局的影响 这些研究将阐明IL-8和/或MUC 18调节作为治疗黑色素瘤患者的新模式的一部分的潜力，以及了解IL-8和/或MUC 18在进展中的作用。

Expression of interleukin-8 (IL-8) by human melanoma cells correlates with their metastatic potential in vivo. Moreover, UV-B irradiation of primary cutaneous melanoma induces IL-8 mRNA and protein production and increases both tumor growth and metastasis in nude mice. In addition, ectopic expression of the IL-8 gene into primary cutaneous melanoma resulted in an increase in tumor growth and metastasis in vivo. IL-8 exerts its angiogenic effect through up-regulation of MMP-2 expression and activity. These observations suggest that IL-8 could be a mediator of angiogenesis, tumor growth and metastasis in melanoma; furthermore, IL-8 may be a target for immunotherapy against malignant melanoma. Indeed, a fully-humanized neutralizing antibody to IL-8 (ABX-IL-8) administered as a single modality inhibits growth and metastasis of human melanoma in a nude mice model. MCAM/MUC18 is an adhesion molecule expressed on advanced primary and metastatic melanoma cells which contributes to acquisition of metastatic phenotype through up-regulation of MMP-2 and increased extravasation. A fully-humanized anti-MUC18 antibody (ABX-MA1) inhibits growth, angiogenesis and metastasis of human melanoma cells in a nude mouse model. Because treatment of melanoma cells with the chemotherapeutic agent DTIC causes upregulation of IL-8; we hypothesize that ABX-IL8 will potentiate the clinically beneficial cytotoxic effect of DTIC. In addition, we hypothesize that a treatment strategy inhibiting both IL-8 and MUC18 may be clinically beneficial. To address these hypotheses, we propose the following specific aims: . Evaluate the effect of ABX-IL8 in combination with dacarbazine (DTIC) on growth, angiogenesis and metastasis of human melanoma in an animal model and determine the mechanism by which IL-8 regulates MMP-2 expression in melanoma cells . Determine if the combination of MUC18 blockade plus DTIC is superior to MUC18 blockade alone in inhibition of melanoma growth and metastasis in an animal model . Evaluate the effect of combined IL-8 and MUC18 blockade on melanoma growth and metastasis in an animal model . Evaluate effects of IL-8 and/or MUC18 blockade with or without DTIC chemotherapy on angiogenesis and apoptosis in tissue specimens and clinical outcome in patients with stage III melanoma These studies will elucidate the potential of IL-8 and/or of MUC18 regulation as part of the new modalities to treat patients with melanoma, as well as to understand the role of IL-8 and/or MUC18 in progression.