Lu Chunhua, Kamat Aparna A, Lin Yvonne G, Merritt William M, Landen Charles N, Kim Tae Jin, Spannuth Whitney, Arumugam Thiru, Han Liz Y, Jennings Nicholas B, Logsdon Craig, Jaffe Robert B, Coleman Robert L, Sood Anil K
Department of Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2007 Jul 15;13(14):4209-17. doi: 10.1158/1078-0432.CCR-07-0197.
Pericytes are known to provide a survival advantage for endothelial cells. We hypothesize that strategies aimed at dual targeting of tumor-associated endothelial cells and pericytes will be highly efficacious.
Paclitaxel-sensitive (HeyA8 and SKOV3ip1) or paclitaxel-resistant (HeyA8-MDR) orthotopic tumors in mice were examined for therapeutic efficacy by targeting the endothelial cells (using a vascular endothelial growth factor receptor inhibitor, AEE788) and pericytes (using STI571) alone or in combination. Additional therapy and survival studies in combination with paclitaxel were also done. Following therapy, tumors were examined for endothelial cell apoptosis, pericyte coverage, microvessel density, and proliferation.
AEE788 inhibited tumor growth by 45% and 59% in the HeyA8 and SKOV3ip1 models, respectively, whereas STI571 alone was not effective. AEE788 plus STI571 resulted in 69% to 84% inhibition of tumor growth in both models. Moreover, combination of these agents with paclitaxel was even more effective, resulting in up to 98% inhibition of tumor growth. The triple combination was even effective in the HeyA8-MDR model. Remarkably, this triple combination also resulted in improved survival compared with all other groups (P<0.001) and caused regression of formed tumors. Pericyte coverage was significantly decreased in the STI571 treatment groups, and microvessel density was significantly reduced in the AEE788 treatment groups. AEE788 induced endothelial cell apoptosis, which was further enhanced by the addition of STI571.
Strategies targeting both endothelial cells and pericytes are highly effective for in vivo treatment of ovarian carcinoma. This antiangiogenic effect may be partially due to decreased pericyte coverage, thus increasing the sensitivity of tumor vasculature to therapy. These encouraging data support the development of clinical trials based on this strategy.
已知周细胞可为内皮细胞提供生存优势。我们推测，针对肿瘤相关内皮细胞和周细胞的双重靶向策略将具有高效性。
通过单独或联合靶向内皮细胞（使用血管内皮生长因子受体抑制剂AEE788）和周细胞（使用STI571），检测小鼠体内对紫杉醇敏感（HeyA8和SKOV3ip1）或耐药（HeyA8-MDR）的原位肿瘤的治疗效果。还进行了与紫杉醇联合的额外治疗和生存研究。治疗后，检测肿瘤的内皮细胞凋亡、周细胞覆盖率、微血管密度和增殖情况。
在HeyA8和SKOV3ip1模型中，AEE788分别使肿瘤生长抑制了45%和59%，而单独使用STI571无效。AEE788加STI571在两个模型中均导致肿瘤生长抑制69%至84%。此外，这些药物与紫杉醇联合使用更有效，导致肿瘤生长抑制率高达98%。三联组合在HeyA8-MDR模型中也有效。值得注意的是，与所有其他组相比，这种三联组合还提高了生存率（P<0.001），并使已形成的肿瘤消退。STI571治疗组的周细胞覆盖率显著降低，AEE788治疗组的微血管密度显著降低。AEE788诱导内皮细胞凋亡，添加STI571后进一步增强。
针对内皮细胞和周细胞的策略对卵巢癌的体内治疗非常有效。这种抗血管生成作用可能部分归因于周细胞覆盖率降低，从而增加了肿瘤血管对治疗的敏感性。这些令人鼓舞的数据支持基于该策略开展临床试验。
