LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice
LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice
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DOI：
10.1007/s00280-003-0713-x
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发表时间：
2004-02-01
影响因子：
3
通讯作者：
Teicher, BA
中科院分区：
文献类型：
--
作者：
Keyes, KA;Mann, L;Teicher, BA
血管生成在肿瘤生长中起着重要作用。血管生成生长因子可用作抗血管生成活性的生物标志物，因为它们的血浆浓度与针对血管生成靶标的治疗功效相关。 SW2 小细胞肺癌 (SCLC)、Caki-1 肾细胞癌和 HCT-116 结肠癌肿瘤在裸鼠中产生可测量的血浆 VEGF、bFGF 和 TGFbeta。携带这些人类肿瘤异种移植物的小鼠每天两次口服 PKCbeta 抑制剂 LY317615（SW2 和 HCT116 第 14-30 天，Caki-1 第 21-39 天）。每三天从对照小鼠和治疗小鼠收集血浆。与对照血浆浓度相比，LY317615 在开始治疗后 5-7 天开始显着降低患有 SW2 SCLC 和 Caki-1 肾细胞癌的小鼠的血浆 VEGF 水平。 LY317615 治疗终止后和研究期间（另外 2 至 3 周），VEGF 血浆水平仍然受到抑制。携带 HCT116 异种移植物的小鼠的血浆 VEGF 水平未因 LY317615 治疗而改变，并且在任何动物中，血浆 bFGF 和 TGF-β 均未因 LY317615 改变。 CD31免疫组织化学染色显示，LY317615使所有三种肿瘤的瘤内血管密度降低了近40%。只有 Caki-1 肿瘤对单药 LY317615 治疗有反应，并具有可测量的肿瘤生长延迟。因此，体内 PKCbeta 的意外抑制导致 VEGF 产生减少，并在治疗后持续存在，并导致瘤内血管减少。血浆 VEGF 是 LY317615 反应的弱标志物，血浆 bFGF 和 TGFbeta 不是 LY317615 活性的标志物。
Angiogenesis plays an important role in tumor growth. Angiogenic growth factors may be useful as biomarkers of antiangiogenic activity since their plasma concentrations correlate with the efficacy of treatments directed toward angiogenic targets. SW2 small-cell lung carcinoma (SCLC), Caki-1 renal cell carcinoma and HCT-116 colon carcinoma tumors produce measurable plasma VEGF, bFGF and TGFbeta in nude mice. Mice bearing these human tumor xenografts were treated orally twice daily with the PKCbeta inhibitor, LY317615 (days 14-30 for SW2 and HCT116, and days 21-39 for Caki-1). Plasma was collected every 3 days from control and treated mice. LY317615 significantly decreased plasma VEGF levels in mice bearing SW2 SCLC and Caki-1 renal cell carcinoma compared to control plasma concentrations beginning 5-7 days after initiating therapy. VEGF plasma levels remained suppressed after termination of LY317615 treatment and for the duration of the study (an additional 2 to 3 weeks). Plasma VEGF levels in mice bearing HCT116 xenografts were not altered by LY317615 treatment and plasma bFGF and TGF-beta were not altered by LY317615 in any of the animals. As shown by CD31 immunohistochemical staining, LY317615 decreased intratumoral vessel density by nearly 40% in all three tumors. Only the Caki-1 tumor responded to single-agent LY317615 therapy with a measurable tumor growth delay. Thus, unexpectedly inhibition of PKCbeta in vivo led to decreased VEGF production that persisted after therapy as well as to decreased intratumoral vessels. Plasma VEGF was a weak marker of response to LY317615, and plasma bFGF and TGFbeta were not markers of LY317615 activity.