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M Motta

Publications and source records attributed to M Motta.

At least 145 records · Page 8Linked to original sources
PubMed1995

[Modification of cortical and trabecular mineral density of the femur, induced by ipriflavone therapy, Clinical results after 12 months].

In order to evaluate the effects of ipriflavone therapy, a clinical and metabolic study was carried out in a group of female patients with low bone mass. In particular, mineral density of the proximal femur was measured, this being a fundamental factor for the resistance of this district. At the end of the 12-months treatment cycle, reduced plasma concentration of Bone Gla Protein and urinary hydroxyproline/creatinine ratio (indicating reduced bone resorption), and a significant increase of bone density of the femoral neck and of the trabecular substructure of Ward's triangle were found. On the whole, treatment was well tolerated.

Adult↗
PubMed1994

Antiproliferative effects of luteinizing hormone-releasing hormone (LHRH) agonists on human androgen-independent prostate cancer cell line DU 145: evidence for an autocrine-inhibitory LHRH loop.

The therapeutic options for the treatment of androgen-independent prostatic cancers are rather limited; this is mainly because our understanding of the local mechanisms involved in the control of androgen-independent proliferation of the tumor is still very poor. The present experiments have been performed to verify whether luteinizing hormone-releasing hormone (LHRH) agonists may possess a direct effect on the growth of the human androgen-independent prostate cancer cells DU 145 and whether a LHRH growth regulatory system may be present in these cells. The data have shown that two potent LHRH agonists (Zoladex and Buserelin) exert a significant and dose-dependent antiproliferative action on DU 145 cells, after 4 days of treatment. The inhibitory action of Zoladex and Buserelin is completely counteracted by the simultaneous treatment of the cells with a potent LHRH antagonist, suggesting that the action of the LHRH agonists may be mediated by specific receptors. This hypothesis has been confirmed by the demonstration that low-affinity binding sites for 125I-Buserelin are present on DU 145 cell membranes, particularly when cells are cultured in serum-free conditions. By using the reverse transcription-polymerase chain reaction technique, in the presence of a pair of specific oligonucleotide primers complementary to the human LHRH complementary DNA, it has been demonstrated that a mRNA for LHRH is expressed in DU 145 cells. Taken together, these data seem to indicate that an autocrine/paracrine LHRH (or LHRH-like) loop is present in androgen-independent prostate cancer cells, and may participate in the regulation of tumor cell growth. To verify this hypothesis, DU 145 cells have been cultured in serum-free conditions, and treated with a LHRH antagonist for 4 days. The treatment resulted in a significant increase of cell proliferation, suggesting an inhibitory role for the LHRH system in the local regulation of cell growth. In conclusion, these data demonstrate that: (a) LHRH agonists exert a specific antiproliferative action on the human androgen-independent DU 145 cells; (b) an autocrine/paracrine LHRH (or LHRH-like) loop, which seems to be inhibitory on cell proliferation, is expressed in DU 145 cells.

Animals↗
PubMed1994

Evaluation of the reproductive efficiency of simmental and Friesian dairy cows farmed in Friuli (Northeast Italy) by the analysis of progesterone levels.

The present research was conducted 1) to investigate the usefulness of progesterone profiles for the study of reproductive efficiency, 2) to identify new reproductive indexes and 3) to examine the possibility of modelling changes in the biological status of animals. Two groups of dairy cows were chosen for this investigation: Italian Simmental and Italian Friesian cows. Milk samples were taken from each cow every 3 to 4 d between Day 10 and Day 240 after calving, and whey progesterone was determined by RIA. The cows were classified into the following 4 categories on the basis of their luteinic activity: 1) Acyclic cows with P4 values <100 pg/ml; 2) Cyclic cows with a normal cycle (1 or 2 samples <100 pg/ml, followed by 1 sample >/=120 pg/ml, followed by at least 3 samples >/=200 pg/ml, followed by 1 sample <100 pg/ml) or a short cycle (1 or 2 samples <100 pg/ml, followed by 1 sample >/=120 pg/ml, followed by 2 samples >/= 200 pg/ml, followed by 1 sample <100 pg/ml followed by a normal cycle); 3) pregnant cows with P4 values >120 pg/ml at 21 to 24 d from AI; and 4) cows with atypical luteinic activity and P4 values >120 pg/ml in a single sample. Analysis of the P4 frequency distribution indicated that ovarian activity resumed from Day 15 and Day 18 after calving in the Italian Friesian and Italian Simmental cows, respectively, and the highest percentage of cyclic cows was observed on Day 60 for Italian Friesian cows (45%) and Day 70 for Italian Simmental cows (55%). The acyclic phase was considered to be concluded by Day 164 and Day 120 for Italian Friesian and Italian Simmental cows, respectively. By Day 240, 66% of Italian Friesian cows and 79% of Italian Simmental cows were pregnant. The percentage of cows with atypical luteinic activity was almost constant throughout the experiment (Italian Friesian=5 to 10%, Italian Simmental=10 to 15%). The calving-conception interval was 104 d for Italian Friesian cows and 94 d for Italian Simmental cows. In both groups, the area on the P4 frequency diagram representing the acyclic cows was not very different from that representing the cyclic cows, while the area occupied on the diagram by pregnant animals was larger. These results are derived from an accurate mathematical analysis. The average number of times in the acyclic status for both groups of cows was about 3-fold smaller than the average number in the cyclic status.

Journal Article↗
PubMed1994

Androgen metabolism in the human prostatic cancer cell line LNCaP.

The metabolism of androgens in prostatic carcinoma has not been sufficiently studied so far, mainly because of the difficulty in obtaining human tissue specimens. The availability of LNCaP (lymph node carcinoma of the prostate) cells which retain most of the characteristics of the original carcinoma (dependence on androgens, presence of androgen receptors, production of acid phosphatase, etc.) has allowed the present in vitro study designed to characterize the metabolic pathways through which testosterone (T) is metabolized in malignant cells. LNCaP cells have been incubated in the presence of different labelled androgenic precursors to quantitate the formation of the respective metabolites, as indicators of the specific activities of the enzymes involved in such conversions; whenever possible, the kinetic constants (Km and Vmax) of the enzymes have also been calculated. It has been observed that, when [14C] T is used as substrate, the cells form both dihydrotestosterone (DHT) and androst-4-en-3,17 dione (delta 4) with the prevalence of the latter. When [14C] delta 4 is the substrate, T and 5 alpha-androstan-3,17-dione (5 alpha-A) are found with 5 alpha-A representing the major product. In addition, the cells form diols and 5 alpha-A from [14C]DHT as well as androsterone (A) and DHT from [14C]5 alpha-A; there is a prevalence of diols in the former case, and of A in the latter one. The yields of the different metabolites recovered after 2 h of incubation of the cells with the appropriate labelled substrates are therefore in descending order of magnitude: 5 alpha-A > A > diols > delta 4 > DHT > T. These results are also confirmed by the analysis of the rate of production of the different steroids. Taken together the present results suggest that: (a) qualitatively LNCaP cells possess all the major key enzymes involved in androgen processing; (b) the metabolism of androgens in this cell line resembles quantitatively that found in prostatic cancer tissue; all the metabolic steps which contribute to DHT degradation exceed the ones leading to its accumulation; (c) 5 alpha-reductase shows a significantly higher affinity for delta 4 than for T; (d) LNCaP cells may represent a suitable in vitro model for the study of factors controlling the formation and the degradation of androgens in prostatic carcinoma, thus permitting a better understanding of the metabolic processes involved in prostatic benign or malignant (carcinoma) transformation.

17-Hydroxysteroid Dehydrogenases↗
PubMed1994

Androgen-dependent prostatic tumors: biosynthesis and possible actions of LHRH.

Testosterone (T) is the major exogenous stimulus for the growth of prostatic carcinoma. It is believed that the proliferative action of T may be mediated by locally expressed growth modulatory factors. Recent evidence from our laboratory suggests that a LHRH (or a LHRH-like) loop might be expressed in human prostatic tumor cells. To verify this hypothesis, we have studied whether a mRNA for LHRH is expressed in the human androgen-responsive prostatic cancer cell line LNCaP, using the reverse transcription-polymerase chain reaction technique in the presence of a pair of specific oligonucleotide primers. A cDNA band of the expected size was obtained from LNCaP cells; this band hybridized with a 32P-labeled LHRH oligonucleotide probe and its sequence showed a complete match with the reported sequence of the human placental LHRH cDNA. These observations indicate that the mRNA coding for LHRH is expressed in LNCaP cells and suggest that a LHRH (or a LHRH-like) peptide might be produced by these cells. To clarify the possible action of this peptide, LNCaP cells were grown in a steroid-free medium and treated with a LHRH antagonist. The treatment resulted in a significant increase of tumor cell growth. These data clearly indicate that the LHRH system expressed in LNCaP cells plays an inhibitory role on cell proliferation, and that this system seems to be regulated in a negative way by steroids. An EGF/TGF alpha autocrine stimulatory loop (peptides, receptors, intracellular signals) is also functional in these cells. Treatment of LNCaP cells grown in serum-free conditions (i.e. in the absence of exogenous growth factors) with a monoclonal antibody against the EGF receptor, or with immunoneutralizing antibodies against EGF or TGF alpha, resulted in a significant decrease of cell proliferation. T positively regulates this EGF/TGF alpha system by increasing the concentration of EGF binding sites. The present data indicate that an inhibitory LHRH (or LHRH-like) system is expressed in LNCaP cells and participates in the local mechanisms regulating tumor cell proliferation together with an EGF/TGF alpha stimulatory loop. Both systems appear to be modulated by T.

Androgens↗
PubMed1994

Effect of the in vivo treatment with the synthetic steroid 17 beta-methoxy-17-methyl-(5 alpha)-1 H'-androstane-(3,2-c) pyrazole (17MM) on the in vitro formation of DHT in the epididymis of the rat.

Adult male Sprague-Dawley rats were injected subcutaneously (s.c.) for 21 days either with the synthetic steroid 17 beta-methoxy-17-methyl-(5 alpha)-1 H'-androstane-(3,2-c) pyrazole (17MM) at two dose levels (0.1 and 1 mg/kg/day) or with the vehicle used to dilute the steroid. At autopsy, caput epididymes and ventral prostates were removed and incubated in vitro. The effect on the 5 alpha-reductase (5 alpha-R) activity was evaluated by measuring the amounts of DHT formed from 14C-testosterone (14C-T) used as the substrate. The in vivo administration of 17MM at the dose of 0.1 mg/kg/day resulted in a significant decrease in the formation of DHT at the level of the epididymis, while there was no effect on the prostate. The dose of 1 mg/kg/day did not induce any modification in the formation of DHT in either organ. The determination of serum LH showed that the treatment with either dose did not alter serum LH titers. These findings suggest that the in vivo treatment with 17MM lowers the in vitro formation of DHT from T at the epididymal, but not at the prostatic level and consequently suggests a selective inhibitory effect of 17MM on the 5 alpha-R present in the epididymis.

5-alpha Reductase Inhibitors↗
PubMed1993

Characterization of a soluble LHRH-degrading activity in the rat ventral prostate.

Recent evidence supports the hypothesis of a direct action of LHRH at the level of the prostate. Since peptidases able to degrade the hormone are present in several LHRH target structures, it was deemed of interest to investigate whether the prostate of adult normal male rats might possess LHRH degrading activities (LHRH-DA). Through the use of RP-HPLC, it has been observed that LHRH-DA is present in the soluble fraction of the rat ventral prostate homogenate, and is able to hydrolyze synthetic LHRH and to generate fragments 1-3 and 1-5 of the decapeptide. The degradation of [pGlu-3H]LHRH is inhibited by LHRH itself, and affected by several LHRH agonists and antagonists with different kinetics and potencies. TRH, the enkephalin analog [D-Ala2-D-Leu5]enkephalin and rat prolactin do not inhibit the degradation of [pGlu-3H]LHRH by the soluble fraction of prostate homogenate; on the contrary, this is inhibited by graded doses of somatostatin. The prostatic LHRH-DA is also inhibited, in a dose dependent manner, by bacitracin, serine protease inhibitors (diisopropylfluorophosphate and phenylmethansulfonylfluoride), the metal chelating agent EDTA, HgCl2, and dithiothreitol. No inhibitory effect on [pGlu-3H]LHRH hydrolysis was observed after incubation of the prostatic extract in the presence of captopril. The prostatic LHRH-DA seems to be different from that present in other tissues of the rat (e.g., hypothalamus, pituitary, gonads), and to be decreased by castration performed 3 weeks before. These results suggest that (1) an LHRH-DA is found in the soluble fraction of rat prostate homogenate; (2) this enzymatic activity exhibits the characteristics of a metallo- and thiol-dependent neutral endopeptidase; (3) it appears to be different from similar hydrolytic activities found in other tissues; and (4) it is influenced by the hormonal milieu, since castration causes a significant decrease of its activity.

Animals↗
PubMed1993

Differences in the time course of the effects of oophorectomy in women on parameters of bone metabolism and interleukin-1 levels in the circulation.

Interleukin-1 is a cytokine with bone-resorbing activity which is claimed to play a role in the pathogenesis of osteoporosis and of post-oophorectomy bone loss. We measured plasma levels of interleukin-1 (IL-1) in 16 women who underwent hysterectomy and bilateral oophorectomy and in 12 women with hysterectomy alone before surgery and 7, 15, 30, 45 and 60 days after surgery. Only oophorectomized patients showed a significant increase of circulating interleukin-1 levels. This increase was significant only 30 days after surgery, whereas a rise at 7 days (P < 0.001) was observed for serum calcium and hydroxyproline/creatinine and calcium/creatinine ratios. These data do not indicate a definite role of IL-1 in promoting bone resorption in estrogen-deficient women in vivo.

Adult↗
PubMed1993

Expression of luteinizing hormone-releasing hormone mRNA in the human prostatic cancer cell line LNCaP.

Recent evidence suggests that LHRH or a LHRH-like peptide might be produced by human prostatic tumor cells. To test this hypothesis, we have studied whether a mRNA for LHRH is expressed in the human prostatic cancer cell line LNCaP, by means of the RT-PCR (reverse transcription-polymerase chain reaction) technique. For these experiments, mRNA was extracted from LNCaP cells, from rat hypothalami and from rat pituitaries, reverse transcribed to cDNA and amplified via the PCR utilizing a pair of oligonucleotide primers complementary to the LHRH cDNA. Following gel electrophoresis, a band of the expected size of 228 base pairs was found in LNCaP cells as well as in the rat hypothalamus, but not in the rat anterior pituitary. This 228 base pair band from LNCaP cells and from the rat hypothalamus specifically hybridized to a 32P-labeled LHRH oligonucleotide probe. The cDNA band obtained from LNCaP cells was subcloned into a plasmid vector, and the analysis of its sequence showed a complete match with the authentic human placental LHRH cDNA. These observations clearly demonstrate that a mRNA for LHRH is expressed in human prostatic cancer cells, and suggest that LHRH or a LHRH-like peptide may be produced by these cells. To test the hypothesis whether this material might act as a local growth regulating factor on tumor cell proliferation, LNCaP cells, grown in a steroid-free medium, were treated daily with a potent LHRH antagonist. After 9, 12 and 15 days, the treatment resulted in a significant increase of tumor cell proliferation. These data clearly suggest that the LHRH mRNA expressed in LNCaP cells is possibly translated into LHRH or a LHRH-like peptide which probably functions as a local growth inhibitory factor on prostatic tumor cell proliferation, by acting on LHRH receptors.

Animals↗
PubMed1993

Direct inhibitory effect of somatostatin on the growth of the human prostatic cancer cell line LNCaP: possible mechanism of action.

The effects of somatostatin-14 (S) on the proliferation of the human prostatic cancer cell line (LNCaP, lymph node carcinoma of the prostate) and on the amount of proteins secreted by these cells have been studied. LNCaP cells were treated for 3 days with different doses of S. The hormone significantly inhibits cell proliferation at doses comprised between 0.4 and 2 nmol, as indicated by a significant decrease in the incorporation of 3H-thymidine as well as in the uptake of [alpha-32P]dATP. The direct antiproliferative effect of S is reversible, since cell proliferation returns to normal 4 days after withdrawal of the hormone from the medium. This action of S is not due to cytotoxic side-effects, since no changes in the incorporation of 35S-methionine are observed. Total RNA and protein synthesis do not appear to be modified by the hormone in vitro. The hormone probably exerts its antiproliferative effect on LNCaP cells by stimulating phosphotyrosyl protein phosphatases, since the inhibition of growth induced by S (1 nmol) is reversed by sodium vanadate (2 and 4 mumol), a potent inhibitor of the process of tyrosine dephosphorilation. In addition, S (1 nmol/L) induces a significant decrease in the amounts of proteins secreted by LNCaP cells. Also the antisecretory action of S seems to be mediated by the activation of phosphotyrosyl protein phosphatases, since sodium vanadate is able to reverse the action of S on this parameter. In conclusion, the present data suggest for the first time that S exerts a direct inhibitory effect on LNCaP cell proliferation and protein secretion, two effects probably mediated by the activation of phosphotyrosyl protein phosphatases.

Cell Division↗
PubMed1993

Immunotactoid glomerulopathy (ITGP): a not fully defined clinicopathologic entity.

Immunotactoid glomerulopathy is characterized by the ultrastructural finding of fibrillary or microtubular deposits in patients without systemic diseases such as SLE, diabetes, paraproteinemias, cryoglobulinemia, or amyloidosis. These deposits correspond in most (but not all) cases to immunoglobulin and complement deposits as shown by immunohistochemical techniques. Different light microscopic patterns (mesangioproliferative, membranous, membranoproliferative, and crescentic) have been reported. Clinical presenting feature is characterized by proteinuria (often of nephrotic range), hematuria, and hypertension in most cases. Chronic renal failure requiring hemodialysis or transplantation is described in more than half the patients. Pathogenesis has not yet been elucidated and only some speculative hypotheses have so far been suggested. At present there is no clear evidence that we are dealing with a new pathologic entity, but larger series must be collected and studied in order to find a correct taxonomic collocation of this glomerulopathy.

Adult↗
PubMed1993

Membranous glomerulonephritis (MGN) in transplanted kidneys: morphologic investigation on 256 renal allografts.

Twenty-two cases of membraneous glomerulonephritis (MGN) were identified among 256 bioptically investigated transplanted patients. MGN was defined as de novo in 15 patients and recurrent in three. The type of MGN could not be ascertained with certainty in the other four. Several morphologic features unusual for the idiopathic form of MGN were found. Most cases disclosed focal segmental distribution of subepithelial deposits and showed the contemporaneous presence of different stages of the disease according to Ehrenreich and Churg classification. In addition mild-to-moderate mesangial cell proliferation was found in about one third of de novo MGN biopsies. Endocapillary hypercellularity was observed in 14 specimens and held to be due to an excess of mononuclear blood cells, related to a concomitant episode of rejection. Chronic transplant glomerulopathy was found in 47% of patients with de novo MGN and in 66% of those with recurrent MGN, being more frequently observed in specimens with diffuse distribution of deposits. Repeated biopsies showed progression of the stage and extension of deposits to a large number of capillary loops in four out of six patients. De novo MGN was documented 1 to 54 mo (mean value 20.2 mo) after transplantation, and the recurrence was observed after 12, 15, and 42 mo. All but two patients (who were anuric) complained of proteinuria, which was in the nephrotic range in 12. Apart from the significantly higher frequency in de novo MGN patients of DR4 antigen, whose significance must in any case be re-evaluated in a larger series, none of the factors so far suggested to be linked to the onset of de novo MGN has found further support in our study. On the contrary, relevance in favoring the appearance and the evolution of MGN has to be attributed to transplant glomerulopathy, which, moreover, seems to be more important than MGN itself in causing the unfavorable outcome of the graft.

Adult↗
PubMed1993

Ageing of the neuroendocrine system in the brain of male rats: receptor mechanisms and steroid metabolism.

The work described in this article gives information on the effects of ageing on the hypothalamo-pituitary-testicular axis in rats. The hypothalami of young and old male rats contain similar amounts of luteinizing-hormone-releasing hormone (LHRH); when perifused in vitro they release comparable amounts of LHRH under basal conditions and in response to K+. The addition of an LHRH analogue to the perifusion medium blocks the release of LHRH induced by K+ from the hypothalami of young and old male rats, indicating that the ultrashort feedback mechanism controlling LHRH release functions normally in aged male rats. Ageing also exerts important effects on the density of mu- and kappa-opioid receptors in the brain. The number of hypothalamic mu-opioid receptors was significantly decreased in aged animals; a replacement treatment with testosterone does not reverse this decrease, indicating that the decline of hypothalamic mu receptors and of serum titres of testosterone in old rats are independent phenomena. The number of kappa-opioid receptors in the brain increases in the amygdala and in the thalamus with ageing. Apparently ageing does not influence the number of delta receptors in any of the brain areas investigated. The number of pituitary LHRH receptors decreases in old animals, which might explain the low serum concentration of gonadotrophins in aged rats caused by an inadequate response of the pituitary to hypothalamic LHRH. The impaired secretion of testosterone in aged male rats is accompanied by an increase in the number of testicular LHRH receptors, indicating that the intratesticular mechanisms controlling testosterone release also undergo significant alterations during ageing. The rate of conversion of testosterone to dihydrotestosterone (DHT) and 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) is the same in the hypothalami of young and old rats. However, the yields of DHT obtained from the pituitaries of aged male rats are significantly lower than those recorded in the pituitaries of young animals. These results show that the enzymes necessary for metabolizing testosterone via the 5 alpha-reductase pathway are maintained both in the hypothalamus and in the anterior pituitary of aged male rats. However, the 5 alpha-reductase activity of the anterior pituitary of senescent animals appears to be lower than that in the younger controls.

Aging↗
PubMed1992

Selective inhibition of the 5 alpha-reductase of the rat epididymis.

The effect of several synthetic steroids belonging either to the 4-aza-3-oxo-steroid family or to androstene and androstane derivatives was investigated "in vitro" on the epididymal as well as prostatic 5 alpha-reductase activity. For this purpose rat caput epididymis and prostate were incubated with the different steroidal compounds at molar concentrations of 10(-7), 10(-6), and 10(-5) in the presence of labelled testosterone as substrate. The steroids 4-MA (17 beta, N,N-diethyl-carbamoyl-4-aza-5 alpha-androstan-3-one) and 4-OH-A (4-hydroxy-androstenedione), already known to be effective 5 alpha-reductase inhibitors at the level of the prostate, have been used as reference molecules. The 5 alpha-reductase activity was evaluated by measuring pg of dihydrotestosterone (DHT) formed in 2 h of incubation by mg of tissue. The steroids A, B, C, F, G and I inhibit the formation of DHT in the rat epididymis although to different extents; they are also equally effective on the formation of DHT in the rat prostate. The steroids D, E, H and L are devoid of any inhibitory property on the formation of DHT in both the rat epididymis and prostate. The most interesting results were obtained with compound M which exhibits a dose-dependent and significant inhibitory effect on the formation of DHT in the epididymis, but it is inactive at the level of the prostate. These findings suggest that it is possible (a) to selectively interfere with the 5 alpha-reductase of the epididymis without affecting that present in the prostate, and (b) consequently to envisage new ways to regulate male fertility.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1992

Treatment of pre-menopausal advanced breast cancer with goserelin--a long-acting luteinizing hormone releasing hormone agonist.

Twenty-two pre-menopausal evaluable patients with advanced breast cancer (median age 39 years; ER positive 19, unknown three; prior adjuvant chemotherapy 16) were treated with the LHRH agonist goserelin depot (Zoladex). Serum levels of 17 beta-estradiol and progesterone were suppressed by goserelin within 3-4 weeks of therapy, while serum leuteinizing hormone and follicle stimulating hormone titers remained in the low level of the normal range. Complete or partial response was documented in seven of 22 cases (32%) and occurred in all major sites of disease. Tumor response was documented in women regularly menstruating at the start of therapy. Median time to disease progression was 23 weeks; median duration of response was 64 weeks; overall survival was 141 weeks. Zoladex was well tolerated: only hot flushes in 82% and reversible cutaneous pigmentation in the site of injection in 45% of the patients were observed. In our experience the activity of Zoladex was comparable to that of oophorectomy, without the psychological trauma and the morbidity related to surgical castration.

Adult↗
PubMed1992

Antiproliferative effects of luteinizing hormone-releasing hormone agonists on the human prostatic cancer cell line LNCaP.

Highly potent LH-releasing hormone (LHRH) agonists have been recently introduced in therapy for the treatment of the carcinoma of the prostate, an androgen-dependent pathology. These peptides are believed to act mainly by inhibiting the pituitary-testicular axis and, consequently, by reducing testosterone levels. The recent observation that binding sites for LHRH analogs are present on prostatic tumor tissue suggests that these drugs could also act directly on the tumor. To verify this hypothesis, the effects of two potent LHRH agonists [Zoladex (Z) and Buserelin (B)] have been studied on the proliferation of the human prostatic cancer cell line LNCaP (lymph node carcinoma of the prostate). LNCaP cells were treated for 9 days with different doses of either Z or B (concentrations from 10(-12)-10(-6) M). Both analogs significantly inhibited cell proliferation at doses between 10(-9)-10(-6) M. The antiproliferative action of the two LHRH agonists was shown to be dose dependent, with IC50 values of 0.82 and 1.79 nM for Z and B, respectively. A similar treatment with B was without any significant effect on the proliferation of a mouse embryo fibroblast cell line (Swiss 3T3), which was used as a nontumoral control. The inhibitory action of both LHRH agonists (10(-8) M) on LNCaP cell proliferation was completely antagonized by the simultaneous treatment of the cells with a potent LHRH antagonist (Nal-Arg-LHRH; 10(-8) M); when given alone at the dose selected, the antagonist did not affect cell growth. These results clearly suggest that the antiproliferative effect of LHRH agonists on LNCaP cells may be mediated by specific receptors. The presence of binding sites for [125I]B was consequently demonstrated on the membranes of LNCaP cells cultured in a medium containing charcoal-stripped fetal calf serum, i.e. in the absence of steroids. The affinity of these binding sites for the ligand was lower than that observed for the same receptors on rat pituitary membranes. To clarify the mechanism of the antiproliferative action of the LHRH agonists, the effects of both Z and B on the incorporation of [3H]thymidine and [14C]methionine into LNCaP cells were investigated. During a short incubation period (3 h), the two LHRH agonists rapidly inhibited [3H]thymidine incorporation into the cells. The same treatment did not affect the incorporation of [14C]methionine into proteins.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Agents↗
PubMed1992

[Retrospective survey of pharmacologic tolerance in the prevention of neoplastic recurrence of superficial urothelioma].

As from June 1989 all superficial bladder tumours (regardless whether treated by surgery or endoscopy) have been included in 5 different chemo, immuno or chemoimmunoprophylactic protocols of therapy against neoplastic recurrence. The protocols considered: mitomycin alone and in association with alpha 2a IFN; epirubicin alone and in association with alpha 2b IFN; immunomodulating alpha 2a IFN. The administration procedures adhered to those set down in the literature and late treatment modalities were used for the associations. The aim of the study was to perform a retrospective evaluation of the intravesical therapies regarding local and systemic tolerability to various drugs and disregarding any evaluation of drug efficacy, i.e. the percentage of patients free from recurrence. We evaluated 92 patients and a total of 1028 instillations carried out prior to June 1991. The number of patients in each protocol was: 31 on IFN; 13 on mitomycin; 24 on epirubicin; 14 on the immunomodulator plus with mitomycin; 10 on the immunomodulator associated with epirubicin. Treatment was suspended in 11/92 patients (11.9%). The highest percentage of interruptions (21.4%) was observed in the mitomycin plus IFN protocol, while the lowest (6.4%) was seen in the IFN monoprotocol. The percentage of patients who presented no side effects during prophylaxis was similar in all protocols studied (50% of patients on the two associations and 54.8% on IFN alone) with the exception of the epirubicin protocol patients who showed lower tolerance (41.6%). The number of "irritable" instillations in each protocol group was analyzed. The lowest number (9/162 = 5.5%) was conserved in the epirubicin plus IFN protocol, while the highest (19/108 17.5%) was seen in the mitomycin group.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intravesical↗