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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

2007; Wiley; Volume: 67; Issue: 7 Linguagem: Inglês

10.1002/pros.20573

1097-0045

Susan L. Dalrymple, Robin E. Becker, John T. Isaacs,

Estrogen and related hormone effects

Abstract 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. Prostate 67: 790–797, 2007. © 2007 Wiley‐Liss, Inc.