Joseph I B, Isaacs J T
Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Cancer Res. 1997 Mar 15;57(6):1054-7.
Linomide is a p.o. active antiangiogenic agent that has been demonstrated to be effective in suppressing the in vivo growth of rat and human prostatic cancer xenografts. The present studies were conducted to determine whether the angiogenic molecules, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) and basic fibroblast growth factor (bFGF) are expressed in vitro by DU-145, PC-3, TSU-PR1, and LnCaP human prostate cancer cell lines and whether Linomide inhibits the secretion of these angiogenic molecules. Additionally, two different androgen-responsive human prostatic cancer xenograft models (i.e., PC-82 and A-2) were used to determine whether androgen ablation-induced reduction in tumor growth is associated with a reduction in tumor VEGF and/or bFGF levels. These studies demonstrated that both VEGF and bFGF proteins are expressed to different degrees in the human prostatic cancer cell lines. The secretion of VEGF but not bFGF is up-regulated by hypoxia. Linomide is unable to inhibit either basal or hypoxia-induced secretion of VEGF. Linomide also has no effect on secreted bFGF levels. Castration inhibited tumor VEGF but had no effect on bFGF levels in both the androgen-responsive PC-82 and A-2 human prostatic cancers when grown in severe combined immunodeficient mice. When given in combination, castration potentiated the inhibition of tumor growth induced by Linomide alone. This potentiation is not due to a further inhibition in tumor VEGF levels induced by castration. Although both castration and Linomide inhibit angiogenesis, the former accomplishes it by inhibiting VEGF secretion, whereas the latter has multiple effects at several steps in the angiogenic process other than VEGF secretion. Based on their different but complementary mechanisms of action, simultaneous combination of androgen ablation with Linomide enhances the anti-prostatic cancer efficacy compared to either monotherapies alone and warrants testing in humans.
来那度胺是一种口服有效的抗血管生成剂，已被证明能有效抑制大鼠和人前列腺癌异种移植瘤在体内的生长。本研究旨在确定血管生成分子血管内皮生长因子/血管通透因子（VEGF/VPF）和碱性成纤维细胞生长因子（bFGF）是否在DU-145、PC-3、TSU-PR1和LnCaP人前列腺癌细胞系中体外表达，以及来那度胺是否抑制这些血管生成分子的分泌。此外，使用两种不同的雄激素反应性人前列腺癌异种移植模型（即PC-82和A-2）来确定雄激素去除诱导的肿瘤生长减少是否与肿瘤VEGF和/或bFGF水平降低有关。这些研究表明，VEGF和bFGF蛋白在人前列腺癌细胞系中均有不同程度的表达。缺氧上调VEGF而非bFGF的分泌。来那度胺无法抑制VEGF的基础分泌或缺氧诱导的分泌。来那度胺对分泌的bFGF水平也没有影响。去势抑制了在严重联合免疫缺陷小鼠中生长的雄激素反应性PC-82和A-2人前列腺癌的肿瘤VEGF，但对bFGF水平没有影响。联合使用时，去势增强了来那度胺单独诱导的肿瘤生长抑制作用。这种增强作用不是由于去势进一步抑制肿瘤VEGF水平。虽然去势和来那度胺都抑制血管生成，但前者通过抑制VEGF分泌来实现，而后者在血管生成过程中除VEGF分泌外的几个步骤具有多种作用。基于它们不同但互补的作用机制，与单独的单一疗法相比，雄激素去除与来那度胺同时联合使用可增强抗前列腺癌疗效，值得在人体中进行测试。
