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Antiandrogens have high impact in medicine as they are compounds capable of decreasing the effect of benign prostatic hyperplasia, cancer, and other androgen-dependent diseases that affect a large percentage of the male population in the world. [figure: see text] Dihydrotestosterone, a 5 alpha-reductase metabolite of testosterone, has been implicated as the responsible factor of these androgen abnormalities. This fact indicates that the logical step in the treatment of these diseases is the inhibition of this enzyme activity using molecules that compete selectively with its natural substrates. The study of the pharmacological effect of antiandrogens requires specific animal models using a large number of laboratory animals. On basis of this concept, presently there is a tendency to eliminate studies with animals. In this paper we report a new method for antiandrogenic evaluation using microbial transformations.
The Canadian Prospective Trial of intermittent androgen suppression was a prototype therapeutic initiative started in 1995 for the management of patients in biochemical relapse after radiation for localized prostate cancer. An interim analysis has yielded several observations on the relations between baseline serum prostate specific antigen (PSA), nadir serum PSA, Gleason score, and time off-treatment. In a typical androgen-dependent tumor, the response of serum PSA to androgen withdrawal is biphasic, but with early tumor progression, plateauing of serum PSA is observed. Ligand-independent activation of the androgen receptor, a mechanism subserving the initiation of androgen independence, can be counteracted experimentally with decoy molecules and clinically with nonsteroidal antiandrogens. In some patients, it is possible to lengthen the off-treatment interval by inhibiting the enzyme 5 alpha-reductase, an effect that can be reinforced by lowering serum testosterone with an antigonadotropin. Serial measurements of serum PSA indicate that intermittent androgen suppression engenders a more diverse range of hormone-related responses than previously appreciated. These include: (1) repeated differentiation of tumor with recovery of apoptotic potential; (2) inhibition of tumor growth by rapid restoration of serum testosterone; and (3) restraint of tumor growth by subnormal levels of serum testosterone. These responses are aspects of regulation that should be taken into account when planning long-term treatment of prostate cancer with intermittent androgen suppression.
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We have found that in addition to being potent inhibitors of 17alpha-hydroxylase/C17,20-lyase and/or 5alpha-reductase, some of our novel androgen synthesis inhibitors also interact with the mutated androgen receptor (AR) expressed in LNCaP prostate cancer cells and the wild-type AR expressed in hormone-dependent prostatic carcinomas. The effects of these compounds on the proliferation of hormone-dependent human prostatic cancer cells were determined in vitro and in vivo. L-2 and L-10 are delta4-3-one-pregnane derivatives. L-35 and L-37 are delta5-3beta-ol-androstane derivatives, and L-36 and L-39 are delta4-3-one-androstane-derived compounds. L-2, L-10, and L-36 (L-36 at low concentrations) stimulated the growth of LNCaP cells, indicating that they were interacting agonistically with the mutated AR expressed in LNCaP cells. L-35, L-37, and L-39 acted as LNCaP AR antagonists. To determine whether the growth modulatory effects of our novel compounds were specific for the mutated LNCaP AR, competitive binding studies were performed with LNCaP cells and PC-3 cells stably transfected with the wild-type AR (designated PC-3AR). Regardless of AR receptor type, all of our novel compounds were effective at preventing binding of the synthetic androgen methyl-trienolone[17alpha-methyl-(3H)-R1881 to both the LNCaP AR and the wildtype AR. L-36, L-37, and L-39 (5.0 microM) prevented binding by >90%, whereas L-35 inhibited binding by 30%. To determine whether the compounds were acting as agonists or antagonists, LNCaP cells and PC-3AR cells were transfected with the pMAMneoLUC reporter gene. When luciferase activity was induced by dihydrotestosterone, all of the compounds were found to be potent inhibitors of transcriptional activity, and the pattern of inhibition was similar for both receptor types. However, L-2, L-10, and L-36 were determined to be AR agonists, and L-35, L-37, and L-39 were wild-type AR antagonists. When tested in vivo, L-39 was the only AR antagonist that proved to be effective at inhibiting the growth of LNCaP prostate tumor growth. L-39 slowed tumor growth rate in LNCaP tumors grown in male SCID mice to the same level as orchidectomy, significantly reduced tumor weights (P < 0.05), significantly lowered serum levels of prostate-specific antigen (P < 0.02), and significanty lowered serum levels of testosterone (P < 0.05). L-39 also proved to be effective when tested against the PC-82 prostate cancer xenograft that expresses wild-type AR. These results show that some of our compounds initially developed to be inhibitors of androgen synthesis also interact with the human AR and modulate the proliferation of hormone-dependent prostatic cancer cells. Therefore, compounds such as L-39, which have multifunctional activities, hold promise for the treatment of androgen-dependent prostate tumors.
OBJECTIVE: To develop a neural network model that estimates prostate histology using magnetic resonance imaging (MRI). STUDY DESIGN: Fifty-three men with lower urinary tract symptoms (average age = 63.8 +/- 8.9 years) underwent a prostate MRI (T2) and sextant biopsy of the prostate. Masson Trichome and immunohistochemical prostate-specific antigen staining of the biopsy material were used to calculate the amount of stroma and epithelium in the inner gland (central plus transition zone). MRIs were normalized to the mean intensity of the obturator internus muscle for comparative analyses. Gray scale and texture features were extracted from the inner gland in the midsection transverse MRI slice. Clinical and image variables were used in two neural networks predicting a high amount of stroma and a high amount of epithelium, respectively. RESULTS: The positive and negative predictive values of the stroma and epithelium neural networks were 95%, 69% and 65%, 92%, respectively. CONCLUSION: These data suggest that the combined use of these neural networks may predict patient response to medical therapy targeting prostatic stroma or epithelium.
Benign prostatic hyperplasia (BPH) is a common and highly manageable disorder that affects most men at some point after age 50. Although classic BPH symptoms mimic those of other genitourinary conditions, several straightforward tools are available to aid accurate diagnosis. For patients in whom the condition is identified early in its progression, prudent management includes periodic assessment of disease progression, pharmacotherapy, and phytotherapy. Some patients presenting with BPH may require or request surgical intervention and several minimally invasive procedures are available, although outcomes and complication rates vary for each.