acyline and Prostatic-Neoplasms

GnRH analogs are useful for the treatment of prostate cancer, but require parenteral administration. The peptide GnRH antagonist acyline potently suppresses luteinizing hormone (LH) and testosterone in man; however, its clinical utility is limited by the requirement for frequent injections. The use of a proprietary enhancer system called GIPET, which is based on medium-chain fatty acids, facilitates the oral bioavailability of peptides. We hypothesized that GIPET enhancement would allow for the safe oral dosing of acyline for the treatment of prostate cancer.. We enrolled eight healthy young men in a pharmacokinetic and pharmacodynamic study of 10, 20 and 40 mg doses of GIPET-enhanced oral acyline. Blood for measurement of serum LH, FSH, testosterone and acyline was obtained prior to each dose of GIPET-enhanced oral acyline and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48 h after dosing.. Serum LH, FSH and serum testosterone were significantly suppressed by all doses of GIPET-enhanced oral acyline after 6 h, with suppression reaching a nadir 12 h after dosing. In addition, the 20 and 40 mg doses demonstrated sustained suppression of testosterone for 12-24 h. All hormone concentrations returned to normal 48 h after administration. There were no treatment-related serious adverse events, and laboratory assessments, including liver function tests and creatinine, were unaffected by treatment.. Oral administration of GIPET-enhanced acyline significantly suppresses testosterone and gonadotropins in normal men without untoward side effects and might have utility in the management of prostate cancer.

Topics: Administration, Oral; Adult; Biological Availability; Dose-Response Relationship, Drug; Fatty Acids; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Oligopeptides; Prostatic Neoplasms; Tablets; Testosterone; Time Factors; Young Adult

Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer. The efficacy of ADT has not been rigorously evaluated by demonstrating suppression of prostatic androgen activity at the target tissue and molecular level. We determined the efficacy and consistency of medical castration in suppressing prostatic androgen levels and androgen-regulated gene expression. Androgen levels and androgen-regulated gene expression (by microarray profiling, quantitative reverse transcription-PCR, and immunohistochemistry) were measured in prostate samples from a clinical trial of short-term castration (1 month) using the gonadotropin-releasing hormone antagonist, Acyline, versus placebo in healthy men. To assess the effects of long-term ADT, gene expression measurements were evaluated at baseline and after 3, 6, and 9 months of neoadjuvant ADT in prostatectomy samples from men with localized prostate cancer. Medical castration reduced tissue androgens by 75% and reduced the expression of several androgen-regulated genes (NDRG1, FKBP5, and TMPRSS2). However, many androgen-responsive genes, including the androgen receptor (AR) and prostate-specific antigen (PSA), were not suppressed after short-term castration or after 9 months of neoadjuvant ADT. Significant heterogeneity in PSA and AR protein expression was observed in prostate cancer samples at each time point of ADT. Medical castration based on serum testosterone levels cannot be equated with androgen ablation in the prostate microenvironment. Standard androgen deprivation does not consistently suppress androgen-dependent gene expression. Suboptimal suppression of tumoral androgen activity may lead to adaptive cellular changes allowing prostate cancer cell survival in a low androgen environment. Optimal clinical efficacy will require testing of novel approaches targeting complete suppression of systemic and intracrine contributions to the prostatic androgen microenvironment.

Topics: Adult; Androgens; Gene Expression Regulation, Neoplastic; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Neoadjuvant Therapy; Oligonucleotide Array Sequence Analysis; Oligopeptides; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; Testosterone