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.
OBJECTIVE
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.


METHODS
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.
Dalrymple
Susan L
SL
Department of Urology, The Sidney Kimmel Comprehensive Cancer Center and the Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Becker
Robin E
RE
Isaacs
John T
JT
D000728:Androgens / Q000502:physiology*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood / Q000098:blood supply / Q000188:drug therapy*; D011804:Quinolines / Q000627:therapeutic use*; D015363:Quinolones; D016019:Survival Analysis; D043823:Taxoids / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D011804:Quinolines; D015363:Quinolones; D043823:Taxoids; D000077143:Docetaxel; C516109:tasquinimod; D017430:Prostate-Specific Antigen