( £ 1.735 nmol/L or £ 500 ng/L) during 9 months (253 days) of treatment. Secondary endpoints were luteinizing hormone levels, bone pain, prostate specific antigen levels, quality of life, testosterone pharmacodynamics, survival, and safety variables. RESULTSIn all, 284 men received either triptorelin (140) or leuprolide (144). The percentage of men with castrate levels of serum testosterone was lower at 29 days for triptorelin than for leuprolide (91.2% vs 99.3%; point estimate -8.0, 95% confidence interval -16.9% to -1.4%), but equivalent at 57 days (97.7% vs 97.1%). The mean (98.8% vs 97.3%) and cumulative (96.2% vs 91.2%) castration maintenance rates between 29 and 253 days were equivalent between the treatment groups. Secondary endpoints were equivalent between treatment groups except for the 9-month survival rate, which was significantly higher for triptorelin than for leuprolide (97.0% vs 90.5%; P = 0.033). Both treatments were well tolerated. CONCLUSIONTriptorelin reduced testosterone concentrations less rapidly, but maintained castration as effectively as leuprolide. There was no evidence that the slower onset of castration caused deleterious effects. KEYWORDSprostate cancer, LHRH agonist, triptorelin pamoate, leuprolide acetate, testosterone OBJECTIVETo compare the efficacy of monthly administrations of the luteinizing hormonereleasing hormone agonists triptorelin pamoate and leuprolide acetate to induce and maintain castrate levels of serum testosterone in men with advanced prostate cancer. PATIENTS AND METHODSMen with advanced prostate cancer were randomly assigned to receive triptorelin 3.75 mg or leuprolide 7.5 mg. The agent was injected intramuscularly every 28 days for nine injections. Primary endpoints were the percentages of men whose serum testosterone concentrations declined to and were maintained at or below castrate levels
The molecular chaperone heat shock protein 90 (HSP90) is involved in folding and stabilization of a wide range of client proteins, including key proteins involved in cancer. Through structure-based design, we synthesized a novel imidazopyridine class of potent HSP90 inhibitors. The synthesis and SAR surrounding this class of compounds will be discussed. The extensive SAR study and lead optimization resulted in the identification of the development candidate CUDC-305, later renamed Debio 0932. Debio 0932 displays high oral bioavailability (96% in mouse), high drug concentrations and a prolonged half-life (20 hr) in tumor tissues. In vitro, Debio 0932 displays potent HSP90 inhibitory activity (IC50, 100 nM) as well as anti-proliferation and apoptosis-inducing activities against a broad range of cancer cell lines (IC50, 40 – 900 nM). In vivo, Debio 0932 is highly effective against various cancer models including NSCLC, AML, breast and colorectal cancers, as well as brain cancers, benefited by its ability to cross the blood-brain barrier to reach therapeutic levels in brain tissue. Debio 0932 also exhibits high selectivity and a favorable safety profile. It was therefore selected as a drug candidate and is currently in Phase 1 clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3249. doi:10.1158/1538-7445.AM2011-3249
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