The quinoline-3-carboxamide anti-angiogenic agent,tasquinimod, enhances the anti-prostate cancer efficacy of androgen ablation and taxotere without effecting serum PSA directly in human xenografts
The quinoline-3-carboxamide anti-angiogenic agent,tasquinimod, enhances the anti-prostate cancer efficacy of androgen ablation and taxotere without effecting serum PSA directly in human xenografts
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DOI：
10.1002/pros.20573
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发表时间：
2007-05-15
期刊：
影响因子：
2.8
通讯作者：
Isaacs, John T.
中科院分区：
文献类型：
--
作者：
Dalrymple, Susan L.;Becker, Robin E.;Isaacs, John T.
目的。他喹莫特是第二代口服活性喹啉-3-甲酰胺类似物，通过其抗血管生成活性增强了抗前列腺癌的效力。它目前正在进行临床试验。雄激素消融和紫杉烷是转移性前列腺癌的标准治疗方法。这就提出了这样一个问题，即他喹莫特与这两种方法中的任何一种联合使用是否会提高治疗效果。一系列人前列腺癌移植瘤(CWR-22Rv1，CWR-22R-H，LAPC-4，LNCaP，PC-3和DU-145)在雄性裸鼠体内的肿瘤生长被评估为解决这些问题的模型系统。结果：这些研究证明，每天口服他喹莫特持续、统计学地(P<；0.05)抑制每一种移植瘤的生长，这种抑制是通过剂量依赖的抗血管生成反应(P<；0.05)肿瘤血管密度降低。当他奎尼莫特与雄激素消融术联合应用时，其抗前列腺癌的效果会增强，甚至在雄激素消融术之后或在他斯奎尼莫特治疗后进行的情况下也能观察到这种增强。此外，他喹莫特与雄激素消融加泰索帝联合应用时，对肿瘤的生长抑制和生存期也有增强作用。相伴的研究证明，在这些异种移植中，他奎莫特对血清PSA没有直接影响。结论：这些结果证明，在接受他喹莫特治疗的宿主中，血清PSA的差异与抑制肿瘤生长有关。这表明，在临床试验中，PSA斜率或倍增时间的变化可以指示他喹莫特的疗效。
PURPOSE. Tasquinimod is a second-generation orally active quinoline-3-carboxamide analog with enhanced potency against prostate cancer via its anti-angiogenic activity. It is presently undergoing clinical trials. Androgen ablation and taxanes are standard therapies for metastatic prostate cancer. This raises the issue of whether combining tasquinimod with either of these approaches enhances therapeutic efficacy.EXPERIMENTAL DESIGN. The tumor growth of a series of human prostate cancer xenografts (CWR-22Rv1, CWR-22R-H, LAPC-4, LNCaP, PC-3 and DU-145) in male nude mice given nothing versus tasquinimod alone or in combination with androgen ablation or with androgen ablation plus taxotere were evaluated as model systems to resolve these issues.RESULTS. These studies documented that daily oral treatment with tasquinimod consistently, statistically (P < 0.05) inhibited the tumor growth of each of the xenografts in a dose-dependent manner via an anti-angiogenic response as monitored by a significant (P < 0.05) decrease in the tumor blood vessel density. Tasquinimod's anti-prostate cancer efficacy is enhanced when combined with androgen ablation and this enhancement was observed even when androgen ablation was either subsequent to or proceeded by tasquinimod treatment. In addition, tasquinimod also enhanced the tumor growth inhibition and survival when combined with androgen ablation plus taxotere. Companion studies documented that tasquinimod has no direct effect on serum PSA in these xenografts.CONCLUSIONS. These results documented that differences in serum PSA in tasquinimod-treated hosts are related to inhibition in tumor growth. This suggests that in clinical trials, changes in PSA slope or doubling time are indicative of therapeutic response to tasquinimod.