Lev Dina Chelouche, Onn Amir, Melinkova Vladislava O, Miller Claudia, Stone Valerie, Ruiz Maribelis, McGary Eric C, Ananthaswamy Honnavara N, Price Janet E, Bar-Eli Menashe
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Unit 0173, 7777 Knight Rd, Houston, TX 77054, USA.
J Clin Oncol. 2004 Jun 1;22(11):2092-100. doi: 10.1200/JCO.2004.11.070. Epub 2004 May 3.
In recent years, the incidence of cutaneous melanoma has increased more than that of any other cancer. Dacarbazine is considered the gold standard for treatment, having a response rate of 15% to 20%, but most responses are not sustained. Previously, we have shown that short exposure of primary cutaneous melanoma cells to dacarbazine resulted in the upregulation of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF). The purpose of the present study was to determine how long-term exposure of melanoma cells to dacarbazine would affect their tumorigenic and metastatic potential in vivo.
The primary cutaneous melanoma cell lines SB2 and MeWo were repeatedly exposed in vitro to increasing concentrations of dacarbazine, and dacarbazine-resistant cell lines SB2-D and MeWo-D were selected and examined for their ability to grow and metastasize in nude mice.
The dacarbazine-resistant cell lines SB2-D and MeWo-D exhibited increased tumor growth and metastatic behavior in vivo. This increase could be explained by the activation of RAF, MEK, and ERK, which led to the upregulation of IL-8 and VEGF. More IL-8, VEGF, matrix metalloproteinase-2 (MMP-2), and microvessel density (CD-31) were found in tumors produced by SB2-D and MeWo-D in vivo than in those produced by their parental counterparts. No mutations were observed in BRAF.
Our results have significant clinical implications. Treatment of melanoma patients with dacarbazine could select for a more aggressive melanoma phenotype. We propose that combination treatment with anti-VEGF/IL-8 or MEK inhibitors may potentiate the therapeutic effects of dacarbazine.
近年来，皮肤黑色素瘤的发病率增长幅度超过了其他任何癌症。达卡巴嗪被认为是治疗的金标准，有效率为15%至20%，但大多数反应难以持续。此前，我们已表明，原发性皮肤黑色素瘤细胞短期暴露于达卡巴嗪会导致白细胞介素-8（IL-8）和血管内皮生长因子（VEGF）上调。本研究的目的是确定黑色素瘤细胞长期暴露于达卡巴嗪会如何影响其在体内的致瘤和转移潜能。
原发性皮肤黑色素瘤细胞系SB2和MeWo在体外反复暴露于浓度递增的达卡巴嗪，筛选出对达卡巴嗪耐药的细胞系SB2-D和MeWo-D，并检测它们在裸鼠体内生长和转移的能力。
对达卡巴嗪耐药的细胞系SB2-D和MeWo-D在体内表现出肿瘤生长和转移行为增加。这种增加可以通过RAF、MEK和ERK的激活来解释，这导致IL-8和VEGF上调。与亲代细胞系产生的肿瘤相比，SB2-D和MeWo-D在体内产生的肿瘤中发现更多的IL-8、VEGF、基质金属蛋白酶-2（MMP-2）和微血管密度（CD-31）。BRAF未观察到突变。
我们的结果具有重要的临床意义。用达卡巴嗪治疗黑色素瘤患者可能会选择出更具侵袭性的黑色素瘤表型。我们建议联合使用抗VEGF/IL-8或MEK抑制剂可能会增强达卡巴嗪的治疗效果。
