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Biomedical subjects

L Cusan

Publications and source records attributed to L Cusan.

At least 73 records · Page 4Linked to original sources
PubMed1983

New hormonal treatment in cancer of the prostate: combined administration of an LHRH agonist and an antiandrogen.

At doses which have no or minimal inhibitory effect when administered alone, the LHRH agonist [D-Ser(TBU)6,des-Gly-NH10(2)] LHRH ethylamide (HOE-766) and the antiandrogen RU-23908 administered simultaneously cause a marked inhibition of ventral prostate and seminal vesicle weight after 5 months of treatment. The effect of the LHRH agonist is due to a blockage of the testicular steroidogenic pathway. The same LHRH agonist administered to adult men with cancer of the prostate causes a marked inhibition of serum testosterone and dihydrotestosterone to castration levels within 1-2 weeks. Administration of the pure antiandrogen to men with cancer of the prostate already receiving the LHRH agonist does not interfere with the LHRH agonist-induced blockage of androgen biosynthesis: Moreover, objective signs of remission of the disease were rapidly observed in 8 out of 10 patients. The ease of application of this new form of hormonal therapy which neutralizes androgens from all sources should facilitate its early administration and thus minimize the development of metastases and androgen-resistant cell clones.

Androgen Antagonists↗
PubMed1983

New hormonal therapy in prostate cancer: combined use of a pure antiandrogen and an LHRH agonist.

Treatment with an LHRH agonist (HOE-766) alone causes an almost complete blockage of testicular testosterone formation in rat and man. In order to neutralize androgens of adrenal origin, a pure antiandrogen (RU-23908) was given in combination with the LHRH agonist in the rat. At doses where each drug has no or minimal effect alone, prostate and seminal vesicle weight were reduced to 9 and 15% of control after 5 months of combined treatment, respectively. Among the species studied, man is the most sensitive to the inhibitory effect of treatment with LHRH agonists on testicular steroidogenesis. Near castration levels of serum testosterone and 5 alpha-dihydrotestosterone are obtained within 1-2 weeks of daily subcutaneous administration of the LHRH agonist [D-Ser(tbu)6, des-Gly-NH2(10)]LHRH ethylamide (HOE-766) in adult men with cancer of prostate. The decrease in serum androgen levels is accompanied by objective remission of the cancer in approximately 75% of cases. In a preliminary study where the LHRH agonist was administered in combination with the pure antiandrogen RU-23908, it was shown that the antiandrogen does not interfere with the LHRH-induced inhibition of serum androgen levels. The ease of application of this new form of hormonal therapy should permit its use at early stages of the disease and thus reduce the development of metastases and androgen-resistant cell clones.

Androgen Antagonists↗
PubMed1982

Rat sperm enzymes during epididymal transit.

The activities of cAMP and cGMP phosphodiesterases (EC 3.1.4.1), adenylate cyclase (EC 4.6.1.1) and protein carboxyl-methylase (EC 2.1.1.24) were measured in the particulate and soluble (105 000 g supernatant) fractions of washed spermatozoa isolated from five segments of the adult rat epididymis. The activities of both phosphodiesterases decreased during epididymal transit, whereas adenylate cyclase and protein carboxyl-methylase underwent a progressive increase, the latter showing the most marked alteration. Both cAMP and cGMP phosphodiesterases as well as the adenylate cyclase were all associated primarily with the particulate fraction, and the extent to which these enzymes were associated with the membranes increased as the spermatozoa passed through the epididymis. Sperm protein carboxyl-methylase activity was, on the other hand, predominantly soluble in all segments of the epididymis. Adenylate cyclase, cAMP phosphodiesterase and protein carboxyl-methylase activities were found predominantly in the sperm tails, whereas cGMP phosphodiesterase was equally distributed between heads and tails. These observations imply that the acknowledged increase in intracellular cAMP levels which occurs in spermatozoa during epididymal transit may be a consequence of both increased synthesis (adenylate cyclase) and reduced hydrolysis (phosphodiesterase).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1982

Cellular localization of the Mn2+-dependent adenylyl cyclase in the human testis.

An examination of the activity of the Mn2+-dependent adenylyl cyclase (AC) in fine needle biopsies from human testes was made. Simultaneously the DNA distribution patterns in suspensions of testicular cells derived from the same patients have been determined. The DNA distribution patterns were estimated by microflow fluorimetry (MFF) after straining with fluorochrome (ethidium bromide). Thus, AC activity could be assessed and correlated with the relative number of haploid (1C = spermatids), diploid (2C = spermatogonia and testicular somatic cells), and tetraploid (4C = primary spermatocytes) cells. Testicular Mn2+-dependent AC activities varied between 0 and 8.4 pmol cyclic adenosine monophosphate (cAMP)/mg protein/min and were highly correlated with the contents of haploid (1C) germ cells (spermatids) (r = 0.62, p less than 0.01). There was no correlation between Mn2+-dependent AC activity and diploid or tetraploid cells. This indicates that the Mn2+-dependent AC activity in the human testis, like in the rat and mouse, may be exclusively localized to haploid germ cells. An inverse correlation between plasma FSH and Mn2+-dependent AC activities indicated reduced inhibin secretion in situations where the Sertoli cells did not maintain the testicular germ cell production.

Adenylyl Cyclases↗
PubMed1982

Desensitization of FSH-responsive adenylyl cyclase in cultured immature Sertoli cells by homologous hormone.

Sertoli cell monolayers were prepared from 19-day-old rat testes. On day 7 of culture cells were incubated for 24 hr in the presence or absence of ovine follicle stimulating hormone (oFSH). Cells were harvested, and adenylyl cyclase responses of the membrane particles to FSH, human chorionic gonadotropin (hCG), isoproterenol, and fluoride (F-) were examined in the presence of either GTP or the nonhydrolyzable guanylyl nucleotide GMP-P(NH)P. Culturing the cells in presence of FSH caused a hormone specific desensitization of FSH-responsive adenylyl cyclase, whereas responses to isoproterenol and fluoride were unaffected. Activation of Sertoli cell adenylyl cyclase by GTP and GMP-P(NH)P showed no difference between cells preincubated with or without FSH, indicating that FSH did not change the activity of the G/F (or N) component or its interaction with the catalytic subunit of the adenylyl cyclase. FSH-responsive adenylyl cyclase in cultured Sertoli cells has been shown to be selectively desensitized by homologous hormone. The mechanism may involve alteration or loss of the FSH receptor or changes in the "coupling" of the FSH receptors to the G/F component of the adenylyl cyclase, since there was no alteration in the guanylyl nucleotide and fluoride activation.

Adenylyl Cyclases↗
PubMed1982

Adenylyl cyclase and protein carboxyl methylase in human spermatozoa.

Adenylyl cyclase (AC) and protein carboxyl methylase (PCM) activities in human ejaculated spermatozoa were measured in 31 men being evaluated for infertility at the Infertility Clinic. The spermatozoal Mn2+-sensitive AC activities ranging between zero and 1.4 nmol cyclic adenosine monophosphate (cAMP)/10(9) cells/min, was positively correlated with motility index [% motile sperm X degree (0-4)] (r = 0.72, rho less than 0.05). This confirms a role for cAMP in human sperm motility. PCM activities, ranging between zero and 160 pmoles (CH3OH/10(9) cells/min), were significantly correlated with AC activities (r = 0.86, p less than 0.001). However, PCM activities were not positively correlated with motility index (p = 0.065). PCM most probably is a factor involved in spermatozoal motility since two patients suffering necrospermia possessed spermatozoa deficient in both AC and PCM activities.

Adenylyl Cyclases↗
PubMed1982

Changes in protein carboxyl-methylase isoenzymes during testicular development in the rat.

Measurements of total rat testicular protein carboxyl-methylase (PCM) activity at various ages ranging from 10 to 90 days showed a rapid (fivefold) increase between 20 and 30 days, coincident with the occurrence of haploid germ cells. When partially purified testicular enzyme, at different ages, was fractionated by isoelectric focusing, the activity of the individual PCM isomers displayed clear differences in the time at which maximal activity was reached. The most acid PCM isoenzyme (pI 6.1) was the dominant isoform in the immature testis and exhibited the highest increase in activity between 20 and 30 days of age. During the same age interval, the activity of the other two isoenzymes (pI 6.7 and 7.4) increased only slightly. At 50 days, while the isofocusing profile revealed no additional increase in the activity of the acid isoform (pI 6.1) and only a doubling in the activity of the second isomer (pI 6.7), the most basic isoenzyme displayed a drastic increment in specific activity (approximately sixfold when compared to 30 days). This indicates that the PCM isozymes have different cellular localization in the seminiferous tubules. The acid isomer (pI 6.1) appears to be associated to the early stages of spermatogenesis and may represent both germ cell and somatic cell PCM. The basic isomer (pI 7.4) may be specific for germ cells (spermatids), and is most likely associated with the later stages of germ cell maturation.

Animals↗
PubMed1982

New hormonal therapy in prostatic carcinoma: combined treatment with an LHRH agonist and an antiandrogen.

In order to block the influence of androgens from all sources on the growth of prostatic cancer, we have used a new hormonal therapy based on medical castration achieved with the potent LHRH agonist [D-Ser(TBU)6, des-Gly-NH2(10)]LHRH ethylamide (HOE-766) combined with the administration of a pure antiandrogen that neutralizes the action of adrenal androgens as well as those still secreted in low amounts by the testis during LHRH agonist treatment. This study was performed in ten patients with advanced prostatic carcinoma (9 at stage D2 and one at stage C). Bone pain, prostatism and general well-being were 60 to 90% improved within one month after starting treatment in all patients. After 2 months of treatment, minimal bone pain remained only in one patient who was originally bedridden. Bone scanning showed a 70 to 90% decrease in uptake after 3 to 5 months of treatment in the patients studied. Acid phosphatase levels were 60 to 90% reduced after 2 months of treatment in 3 out of the 4 patients who had elevated levels before therapy. Marked objective and subjective improvement was thus rapidly observed in 9 out of 10 patients treated with the combined therapy, while, in the other patient at stage C, subjective improvement could be documented. Although preliminary, this study indicates that a combined hormonal therapy which neutralizes all androgenic influences on peripheral tissues is of potential benefit in prostatic cancer. Moreover, the ease of application as well as the lack of secondary effects of the present approach should make possible its use early in the disease and should thus minimize the development of metastases and androgen-resistant cell clones. Randomized prospective studies on this potentially beneficial therapy are warranted.

Adenocarcinoma↗
PubMed1981

Additive inhibitory effects of treatment with an LHRH agonist and an antiandrogen on androgen-dependent tissues in the rat.

Combined treatment of adult male rats with the LHRH agonist, [D-Ser(TBU)6, des-Gly-NH2(10)]LHRH ethylamide, and a non-steroid antiandrogen, RU 23908, led to a rapid and marked atrophy of the ventral prostate and seminal vesicles. Treatment with the LHRH agonist decreased androgen secretion and thus facilitated the action of the antiandrogen in androgen-dependent tissues. Such a combined treatment could be useful in the treatment of androgen-dependent pathologies in man, particularly in prostatic adenocarcinoma and possibly benign prostatic hyperplasia.

Animals↗
PubMed1981

Effects of castration, sex steroids, LHRH and glucocorticoids on LHRH binding in the anterior pituitary of male rats.

In the present study we have examined the effects of gonadotrophin releasing hormone (LHRH), sex steroids and glucocorticoids on the binding of LHRH to receptors in the pituitary of male intact and castrated rats. In intact rats, LHRH (10 microgram/day) treatment for 11 days caused a significant increase in LHRH binding, whereas testosterone (500 microgram/day) or oestradiol (50 microgram/day) were inhibitory. 17-hydroxyprogesterone and dexamethasone were without effects. In castrated rats, LHRH caused a marginal decrease in LHRH binding. Much greater inhibition was observed with testosterone and oestradiol. 17-hydroxyprogesterone reduced binding to that of intact controls, whereas dexamethasone was ineffective. When different doses of sex steroids were tested, both oestradiol, testosterone and 5 alpha-dihydrotestosterone inhibited LHRH in a dose-dependent manner. The lowest doses of steroids causing significant inhibition of LHRH binding in castrated animals were 0.5, 50 and 500 microgram/day for oestradiol, 5 alpha-dihydrotestosterone and testosterone, respectively. The present study shows that pituitary receptors for LHRH are regulated both by sex steroids and LHRH itself.

Animals↗
PubMed1981

Characterization of protein carboxyl methylase activities in rat testis: presence of testis specific charge isomers.

The physicochemical and molecular properties of testicular Protein Carboxyl Methylase (PCM) have been studied. The testicular enzyme was stable at high ionic strength, independent of metal ions and resistant to reducing or alkylating agents, and displayed a narrow pH optimum of pH 5.8-6.0. The enzyme had a molecular weight of approximately 25,000 daltons and a Km for S-adenosyl-L-methionine (SAM) of 1.3 microM. Varying concentrations of gelatine (exogenous methyl acceptor protein) did not change the affinity of the enzyme for SAM. The molecular properties of the enzyme were characterized using gel filtration, hydroxyapatite and DEAE-cellulose chromatography, and isoelectric focusing. Three charge isomers exhibiting PCM activity were isolated with pI values of 6.1, 6.7, and 7.35 while comparative data from the pituitary gland revealed primarily the presence of the most acid isozyme (pI 6.1). These results suggest that the different testicular charge isozymes may be involved in the selective methylation of specific testicular proteins.

Animals↗
PubMed1981

Effect of an LHRH analog on growth and hormone receptor levels in DMBA-induced mammary tumors in the rat.

Dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in the rat are well known to be hormono-dependent. Daily injections of an LHRH agonist, [D-Ala6, des-Gly-NH2(10)]LHRH ethylamide (LHRH-A), 1 microgram daily, for 38 days results in a 35% decrease in the number of tumors present at the beginning of the experiment compared to a decline of 45% after ovariectomy and of 8% in the control group. This is accompanied by a marked reduction in ovarian LH and FSH receptors. LHRH-A treatment also resulted in reduction in the number of progesterone and prolactin receptors in the tumors. In addition, an increase in plasma LH and FSH and a decline in plasma prolactin (PRL) concentrations are observed. The mechanisms by which the LHRH agonist induces its antitumoral effect probably relate to an ovarian desensitization to LH and FSH with a concomitant decrease in circulating levels of estrogen and prolactin, two well known stimuli for the growth of DMBA-induced mammary tumors.

9,10-Dimethyl-1,2-benzanthracene↗