Neoadjuvant hormonal therapy prior to radical prostatectomy: evaluation of pathological downstaging and biochemical relapse.
(73/384)OBJECTIVES: The effect of neoadjuvant hormonal therapy (NHT) prior to radical prostatectomy (RP) on pathological downstaging of prostate cancer and biochemical relapse of serum prostate specific antigen (PSA) level was evaluated. MATERIALS AND METHODS: Twenty selected patients with prostate cancer, who were treated with hormonal therapy and demonstrated biochemical downstaging by reduction of PSA prior to RP and bilateral pelvic node dissection at the Tohsei National Hospital between January 1997 and August 2001, are reported on. The complete RP specimens of these 20 men were used for accurate evaluation of the pathological stage. All 20 patients received NHT; ten patients were treated with leuprolide plus flutamide and 10 received leuprolide plus chlormadinone acetate (CMA). RESULTS: Decreases in serum PSA values were demonstrated from a pre-hormonal average of 49.7 ng/ml to an average of 0.52 ng/ml after NHT. Of the three clinical stages, A2-C, for cancer patients, two of the 20 patients had stage A2, two had stage B1, nine had stage B2, and seven had stage C. Of the 20 patients with biochemical downstaging, two had pathological stage B1, seven had pathological stage B2, eight had pathological stage C, and three had positive pelvic lymph nodes. Ten (50%) of the 20 patients were reported to have positive surgical margins. Seminal vesical extension was observed in two cases, and penetration was not observed. Positive nodes were identified in three (15%) patients. Among the seven clinical stage C patients, one had pathological stage B1 disease and two had pathological stage B2. Four of nine patients with clinical stage B2 prostatic cancer had pathological stage C disease. The actuarial incidence of a rising PSA at 3 years for the leuprolide plus CMA group was 28.9% compared with 37.5%for the group receiving leuprolide plus flutamide. The cases of biochemical relapse did not necessarily indicate a high stage and had no tendency to be high for baseline PSA level, positive margin rates or Gleason scores. CONCLUSIONS: A significant decrease in the rate of penetration could be observed after NHT, though it was not so effective for pathological downstaging, and changes in the preoperative PSA level did not predict those patients who might have a favorable result. (+info)
Embryonic myosin heavy chain and troponin T isoforms remain in the cremaster muscle of adult rat cryptorchidism induced with flutamide.
(74/384)We examined the immunolocalization of isoforms of muscle proteins, myosin and troponin, in the cremaster muscle of the undescended testis (cryptorchidism). In cryptorchid rats induced by a nonsteroidal androgen antagonist, flutamide, the cremaster muscle contained embryonic myosin and embryonic/cardiac troponin T in both immunofluorescence microscopy and Western blotting using antibodies against myosin and troponin T specific for embryonic, cardiac and fast skeletal muscles. However, in muscles other than the cremaster muscle, i. e., the masseter, pectoral and abdominal muscles, embryonic isoforms of these proteins were undetectable by immunohistochemistry with these antibodies, even in the muscles from cryptorchid rats. Our results showing that high levels of embryonic isoforms of muscle proteins were specifically present in the cremaster muscle of cryptorchid rats induced by flutamide suggest that flutamide treatment of pregnant rats might affect genes controlling the development of the lumbar region of the fetus body resulting in the presence of embryonic protein isoforms in the cremaster muscles which are closely associated with undescended testes. (+info)
Effects of prenatal treatment with antiandrogens on luteinizing hormone secretion and sex steroid concentrations in adult spotted hyenas, Crocuta crocuta.
(75/384)Prenatal androgen treatment can alter LH secretion in female offspring, often with adverse effects on ovulatory function. However, female spotted hyenas (Crocuta crocuta), renowned for their highly masculinized genitalia, are naturally exposed to high androgen levels in utero. To determine whether LH secretion in spotted hyenas is affected by prenatal androgens, we treated pregnant hyenas with antiandrogens (flutamide and finasteride). Later, adult offspring of the antiandrogen-treated (AA) mothers underwent a GnRH challenge to identify sex differences in the LH response and to assess the effects of prenatal antiandrogen treatment. We further considered the effects of blocking prenatal androgens on plasma sex steroid concentrations. To account for potential differences in the reproductive state of females, we suppressed endogenous hormone levels with a long-acting GnRH agonist (GnRHa) and then measured plasma androgens after an hCG challenge. Plasma concentrations of LH were sexually dimorphic in spotted hyenas, with females displaying higher levels than males. Prenatal antiandrogen treatment also significantly altered the LH response to GnRH. Plasma estradiol concentration was higher in AA-females, whereas testosterone and androstenedione levels tended to be lower. This trend toward lower androgen levels disappeared after GnRHa suppression and hCG challenge. In males, prenatal antiandrogen treatment had long-lasting effects on circulating androgens: AA-males had lower T levels than control males. The sex differences and effects of prenatal antiandrogens on LH secretion suggest that the anterior pituitary gland of the female spotted hyena is partially masculinized by the high androgen levels that normally occur during development, without adverse effects on ovulatory function. (+info)
Exposure to naturally circulating androgens during foetal life incurs direct reproductive costs in female spotted hyenas, but is prerequisite for male mating.
(76/384)Among all extant mammals, only the female spotted hyena (Crocuta crocuta) mates and gives birth through the tip of a peniform clitoris. Clitoral morphology is modulated by foetal exposure to endogenous, maternal androgens. First births through this organ are prolonged and remarkably difficult, often causing death in neonates. Additionally, mating poses a mechanical challenge for males, as they must reach an anterior position on the female's abdomen and then achieve entry at the site of the retracted clitoris. Here, we report that interfering with the actions of androgens prenatally permanently modifies hyena urogenital anatomy, facilitating subsequent parturition in nulliparous females who, thereby, produce live cubs. By contrast, comparable, permanent anatomical changes in males probably preclude reproduction, as exposure to prenatal anti-androgens produces a penis that is too short and has the wrong shape necessary for insertion during copulation. These data demonstrate that the reproductive costs of clitoral delivery result from exposure of the female foetus to naturally circulating androgens. Moreover, the same androgens that render an extremely unusual and laborious process even more reproductively costly in the female are apparently essential to the male's physical ability to reproduce with a normally masculinized female. (+info)
Abolition of hypertension-induced end-organ damage by androgen receptor blockade in transgenic rats harboring the mouse ren-2 gene.
(77/384)A sexual dimorphism in hypertension has been observed in both human and laboratory animal studies. The mechanisms by which male sex hormones regulate cardiovascular homeostasis are still not yet fully understood and represent the subject of this study. The possible involvement of androgen receptors in the development of hypertension and end-organ damage in transgenic rats harboring the mouse Ren-2 renin gene [TGR(mREN2)27] was studied. Male TGR(mREN2)27 rats were treated with the androgen receptor antagonist Flutamide starting at 4 wk of age. Also, an androgen receptor mutation (testicular feminization mutation [tfm]) was introduced in these rats by crossbreeding male TGR(mREN2)27 rats with tfm rats. The resulting offspring male rats that contain the tfm mutation are insensitive to androgens. Flutamide treatment or tfm mutation produced a significant attenuation of the development of hypertension. Besides a reduction in cardiac hypertrophy, urinary albumin excretion was blunted and no histologic characteristics of end-organ damage were observed in the kidney after Flutamide treatment. Testosterone levels increased 15-fold after Flutamide treatment and 2.7-fold by the tfm mutation. Also, plasma estrogens and luteinizing and follicle-stimulating hormones were significantly increased. Plasma renin concentrations and activity but not plasma angiotensinogen were reduced. Our results indicate that androgens contribute not only to the development of hypertension, but even more importantly to end-organ damage in TGR(mREN2)27 rats. (+info)
Activation of mitogen-activated protein kinase pathway by the antiandrogen hydroxyflutamide in androgen receptor-negative prostate cancer cells.
(78/384)Whereas hydroxyflutamide (HF) has been used as an antiandrogen to block androgen-stimulated prostate tumor growth, the antiandrogen withdrawal syndrome that allows antiandrogens to stimulate prostate tumor growth still occurs in many patients treated with androgen ablation therapy. This was previously explained by mutations in the androgen receptor (AR) and/or modulation from AR coregulators, so that HF becomes an AR agonist. Using immunohistochemical analysis, we analyzed four prostate cancer patients undergoing androgen ablation therapy with flutamide and compared their phospho-extracellular signal-regulated kinase 1/2 levels in prostate cancer biopsies before receiving HF and after experiencing disease progression while taking HF. We found a significant increase of activated mitogen-activated protein (MAP) kinase in prostate tumors from patients receiving HF during androgen ablation therapy. In vitro studies showed that HF induced a rapid activation of the Ras/MAP kinase pathway in human prostate cancer DU145 cells which lack the AR, as well as in PC-3AR2 and CWR22 cells which express the AR. Cycloheximide failed to inhibit this activation, but both AG1478, an inhibitor of the epidermal growth factor receptor (EGF-R), and an EGF-R-neutralizing antibody blocked this HF-mediated activation of MAP kinase, which suggests that the activation of Ras/MAP kinase by HF is a membrane-initiated, non-AR-mediated, and nongenomic action. The consequence of this activation may result in increasing cell proliferation and cyclin D1 expression. This raises a concern for using HF in the complete-androgen-ablation therapy in prostate cancer treatment and provides a possible pathway that might contribute to the HF withdrawal syndrome. (+info)
Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor.
(79/384)The purposes of the present studies were to examine the androgen receptor (AR) binding ability and in vitro functional activity of multiple series of nonsteroidal compounds derived from known antiandrogen pharmacophores and to investigate the structure-activity relationships (SARs) of these nonsteroidal compounds. The AR binding properties of sixty-five nonsteroidal compounds were assessed by a radioligand competitive binding assay with the use of cytosolic AR prepared from rat prostates. The AR agonist and antagonist activities of high-affinity ligands were determined by the ability of the ligand to regulate AR-mediated transcriptional activation in cultured CV-1 cells, using a cotransfection assay. Nonsteroidal compounds with diverse structural features demonstrated a wide range of binding affinity for the AR. Ten compounds, mainly from the bicalutamide-related series, showed a binding affinity superior to the structural pharmacophore from which they were derived. Several SARs regarding nonsteroidal AR binding were revealed from the binding data, including stereoisomeric conformation, steric effect, and electronic effect. The functional activity of high-affinity ligands ranged from antagonist to full agonist for the AR. Several structural features were found to be determinative of agonist and antagonist activities. The nonsteroidal AR agonists identified from the present studies provided a pool of candidates for further development of selective androgen receptor modulators (SARMs) for androgen therapy. Also, these studies uncovered or confirmed numerous important SARs governing AR binding and functional properties by nonsteroidal molecules, which would be valuable in the future structural optimization of SARMs. (+info)
Caffeine test in predicting flutamide-induced hepatic injury in patients with prostate cancer.
(80/384)The caffeine test measures the activity of cytochrome p450 (CYP1A2) which is a major enzyme involved in the activation of flutamide. The usefulness of this test in predicting flutamide-induced hepatic injury in patients with prostate cancer was examined. The subjects were: (1). five patients whose aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level rose to 100 IU/l or higher following the start of flutamide (moderately injured group); (2). four patients whose AST and ALT levels were higher than normal but less than 100 IU/l (mildly injured group); and (3). two patients whose hepatic function remained normal (normal group). The subjects were each given canned coffee to drink. Urinary caffeine (137X), paraxanthine (17X) and 1, 7-dimethyluric acid (17U) levels were measured 4-5 h later. The metabolite ratio, (17U+17X)/137X, was calculated to serve as an indicator of CYP1A2 activity. The metabolite ratio for the moderately injured group (3.98+/-1.56) and the mildly injured group (5.55+/-1.42) were lower than that for the normal group (9.56). The results suggest that a decrease in CYP1A2 activity is involved in the onset of flutamide-induced hepatic injury, and that the caffeine test seems to provide a useful means of its prediction. (+info)