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R Cozzi

Publications and source records attributed to R Cozzi.

At least 55 records · Page 3Linked to original sources
PubMed1990

Persistence of azacytidine-induced SCEs and genomic methylation in CHO cells in vitro.

Many carcinogenic agents are able to affect the methylation level in mammalian cells cultivated in vitro. The capacity of azacytidine (AZA) to demethylate DNA can be used to examine the relationship between the genomic methylation level and cytogenetic end-points. Here we compared the sister-chromatid exchange (SCE) level with the genomic % methylcytosine in a Chinese hamster ovary cell line in vitro after giving a single 10-microM pulse of AZA. Both parameters were followed up to 16 cell cycles after the agent was removed. While the SCE level increased starting 2 cycles from the treatment and persisted for the entire 16 cycles, the methylcytosine level, after an initial 50% decrease, approached the control value, completely returning to it after 10 cell cycles. The possibility that the persistence in the SCE increase is an inherited phenomenon is discussed.

5-Methylcytosine↗
PubMed1990

Retinoids as modulators of metabolism: their inhibitory effect on cyclophosphamide and 7,12-dimethylbenz[a]anthracene induced sister chromatid exchanges in a metabolically competent cell line.

Recently, retinoids have been studied for their ability to modify the carcinogenic/mutagenic activity of chemical compounds. Results show that they can inhibit the malignant transformation of cells, the induction of cancer in experimental animals and the mutagenicity of promutagens. Our experiments examine how retinol and retinoic acid can decrease the frequency of sister chromatid exchange (SCE) induced by two indirect mutagens/carcinogens (cyclophosphamide and 7,12-dimethylbenz[a]anthracene) in an epithelial liver cell line of male Chinese hamster (CHEL cells). These cells are metabolically competent and activate different classes of promutagens into biologically active metabolites. Our results are consistent with the suggestion that retinoids modulate the genotoxicity of indirect-acting mutagens by altering their metabolic activation or cellular detoxification processes or both.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Chromatographic and cytogenetic analysis of in vivo metabolites of fluoranthene.

Fluoranthene metabolites in rat serum were analysed by high-performance liquid chromatography (HPLC) with UV and fluorescence detection and compared with in vitro metabolites obtained by incubation with microsomal fraction of rat hepatocytes. In order to resolve very polar fluorescent compounds present in rat serum, a modification of HPLC existing methods for in vitro metabolites separation was necessary. Mutagenic 2,3-dihydrodiol was identified in both in vitro sample and rat serum: this result is in good accord with cytogenetic analysis on rats bone marrow cells, that shows a slight but significant increase of sister chromatide exchanges.

Animals↗
PubMed1987

Sister chromatid exchanges induced by DNA demethylating agents persist through several cell cycles in mammalian cells.

Eukaryotic DNA methylation has been extensively studied in recent years. The ability of many carcinogens to interfere with DNA methylation has not yet been directly related to their tumorigenic activity. Recent data obtained using L-ethionine and 5-azacytidine--both demethylating agents--showed a small but significant increase in the sister chromatid exchange (SCE) rate induced in mammalian cells (human lymphocytes and CHO cells). In this paper we show that the SCE increase induced by both these agents in Chinese hamster ovary (CHO) cells persists for as long as 10 cell cycles. On the other hand mitomycin-C and u.v. light-induced SCEs show a rapid decrease to the control value, as reported for all known SCE inducers. We suggest that DNA demethylation and SCEs are connected through a perturbation of the cell machinery at the level of the replication fork, producing an increase of the error-prone ligation. Since the methylation level is maintained (inherited), the SCE increase produced by these recombinational events will not be corrected through several cell cycles.

Animals↗
PubMed1987

Medical treatment of acromegaly with SMS 201-995, a somatostatin analog: a comparison with bromocriptine.

We studied the effects of acute and chronic sc administration of SMS 201-995 (SMS), a long-acting somatostatin analog, in acromegalic patients. The results were compared with those obtained in the same patients treated with oral bromocriptine (Brc). A single dose of 50 micrograms SMS administered to 28 patients induced a more rapid, greater, and more prolonged reduction in plasma GH levels than did 2.5 mg Brc. Chronic treatment [60-330 days; mean 208 +/- 23 (+/- SEM)] with SMS (100-300 micrograms/day) induced in 16 patients a significantly greater decrease in mean plasma GH and somatomedin-C levels than did 20 mg Brc. Combined treatment with the 2 agents had an additional effect. The clinical and metabolic parameters of acromegaly dramatically improved in all patients whose plasma GH and somatomedin-C levels decreased even if they were not normalized by SMS. Reduction in tumor size occurred in 3 of the 10 patients examined by computed tomography before and during SMS treatment. We conclude that SMS is more effective than Brc and that the 2 drugs may be complementary in the medical treatment of acromegaly.

Acromegaly↗
PubMed1986

An in vitro and in vivo study on mutagenic activity of fluoranthene: comparison between cytogenetic studies and HPLC analysis.

The polycyclic aromatic hydrocarbon, fluoranthene (FT), has been shown to induce SCEs in vitro in CHO cells in the presence of metabolic activation. Negative results were obtained in vivo in mice. The HPLC analysis performed to investigate the presence of metabolites of FT both in the serum of treated mice and in culture medium of CHO cells confirmed some differences between in vitro and in vivo metabolism.

Animals↗
PubMed1986

Bromocriptine does not alter growth hormone (GH) responsiveness to GH-releasing hormone in acromegaly.

GHRH (100 micrograms) and TRH (200 micrograms) were administered to 24 active acromegalic patients before and during chronic bromocriptine (Br) treatment (Br, 10-15 mg/day for 3-5 months) to evaluate the possible effects of the dopamine agonist on GH release induced by these releasing hormones. Mean daily plasma GH levels were reduced by Br treatment from 34 +/- 40 (SD) to 16 +/- 19 ng/ml (P less than 0.01). No significant changes were found when comparing the GH response to GHRH as mean area under the response curve (nanograms per min/ml above the basal) (pretreatment, 5453 +/- 7843; during Br, 7017 +/- 12763 ng/ml . min), and as mean individual peak GH values (pretreatment, 130 +/- 148; during Br, 126 +/- 187 ng/ml) before and during treatment. The percentage GH increase (pretreatment, 340 +/- 354; during Br, 617 +/- 539%) was however significantly higher during Br. Br treatment significantly reduced the GH response to TRH in terms of mean of individual peak levels (from 136 +/- 134 to 60 +/- 52 ng/ml; P less than 0.01) and area under the response curve (from 3142 +/- 3998 to 1331 +/- 1646 ng/min . ml; P less than 0.01). However, the percentage GH increase was not significantly different (pretreatment, 486 +/- 729; during Br, 1059 +/- 1862%). When the patients were divided into Br responders, i.e. mean daily GH reduction during Br of at least 50% below baseline, and nonresponders, the initial response to GHRH was significantly higher in the latter group, but was unaffected by Br treatment in either group. On the contrary, the response to TRH, statistically significant initially only in the Br responder group, was reduced by Br treatment. We suggest that cells sensitive to Br and TRH but not to GHRH (lactotroph-like) and cells sensitive to GHRH but not to Br (pure somatotrophs) may coexist in GH-secreting adenomas.

Acromegaly↗
PubMed1986

Chronic treatment of pathological hyperprolactinemia and acromegaly with the new ergot derivative terguride.

The long term effectiveness and tolerance of terguride, a new ergot derivative, as initial therapy were evaluated in 20 patients with pathological hyperprolactinemia (PHP; group A) and 7 patients with acromegaly. We also studied 10 patients with PHP whose treatment was changed from bromocriptine or lisuride to terguride (group B). Terguride, given for at least 6 months in divided doses ranging from 0.25-1.50 mg/day to group A patients, resulted in normal (11 patients) or markedly reduced plasma PRL levels. Gonadal function was restored in all but 2 patients in this group, and the tumors shrank in 3 of 5 patients with a macroprolactinoma and in 1 of 3 patients with a microprolactinoma. In group B patients, positive effects of the previous treatment on PRL levels, gonadal function, and tumor growth were maintained by terguride. Terguride suppressed plasma GH levels below 50% of baseline in 4 of the 7 acromegalic patients. Two of the 27 patients initially treated with terguride complained of mild nausea and postural hypotension only after the first dose (0.25 mg) of the drug. No patient in group B had any side-effects during terguride, with the exception of 1 patient who was also intolerant to bromocriptine. We conclude that terguride is an effective well tolerated dopaminergic agent in PHP.

Acromegaly↗
PubMed1986

Relationship between somatomedin-C and growth hormone levels in acromegaly: basal and dynamic evaluation.

The relationship between basal and stimulated plasma GH and somatomedin-C (SmC) levels in acromegalic patients was evaluated. The basal plasma SmC levels of 66 patients were significantly correlated (P less than 0.01) with mean daily plasma GH levels, but not with the percent GH increase after GH-releasing hormone or TRH or the GH decrease after acute bromocriptine administration. Bromocriptine (7.5-15 mg/day) administration for 9.2 +/- 0.9 (+/- SD) months in 20 patients significantly (P less than 0.05) decreased GH levels. SmC decreased significantly [from 9.8 +/- 1.9 to 5.1 +/- 0.7 U/ml (mean +/- SE)] only in the 10 patients who had the more marked GH inhibition. The administration of a somatostatin analog, SMS 201-995 (100 micrograms twice daily), to 12 patients for 16 weeks significantly decreased plasma GH and SmC levels beginning on the second day of therapy; normal SmC levels were achieved in 5 of 12 patients. Pituitary adenomectomy resulted in normal GH and SmC levels in 10 of 12 and 8 of 12 patients, respectively. Our data indicate an overall dependency of plasma SmC levels on plasma GH levels in acromegaly, although similar GH levels may have differing somatomedin-stimulating activities. A derangement in the feedback mechanisms controlling GH secretion is indicated by the failure of elevated SmC levels to influence the GH responsiveness to releasing hormones. In evaluating pharmacological or surgical treatments of acromegaly, a single plasma SmC value can reliably replace several plasma GH determinations.

Acromegaly↗
PubMed1986

Serum type III procollagen propeptide levels in acromegalic patients.

Serum type III procollagen propeptide (PIIIP) is a reliable index of tissue collagen synthesis. Since in acromegaly there is increased collagen production, we measured serum PIIIP in acromegalic patients before any treatment (basal), during medical treatment with the somatostatin analog SMS 201-995, and after pituitary adenomectomy. In all patients, serum GH and plasma somatomedin-C (SmC) levels were also measured. Basal serum PIIIP levels were significantly (P less than 0.01) higher in acromegalic patients (mean +/- SEM, 22.7 +/- 2.1 ng/ml) than in normal subjects (n = 30; 9.7 +/- 0.5 ng/ml), and they were significantly correlated with plasma SmC values (r = 0.31; P less than 0.05). A significant (P less than 0.01) reduction in PIIIP levels occurred in patients treated with SMS 201-995 or surgery (from 24.3 +/- 2.7 to 12.4 +/- 1 ng/ml) as well as in GH and SmC levels. The maximum percent decrease in serum PIIIP was significantly correlated with those in GH (r = 0.65; P less than 0.01) and SmC (r = 0.60; P less than 0.01). Serum PIIIP levels did not change in those patients in whom neither GH nor SmC were decreased by treatment. In conclusion, serum PIIIP levels are elevated in acromegalic patients, and they decline in parallel with GH and SmC during medical or surgical treatment. Serum PIIIP measurements may be useful in the evaluation of acromegalic patients to gain information on the biological activity of GH and in monitoring the course of the disease.

Acromegaly↗
PubMed1985

Low doses of dopamine agonists in the long-term treatment of macroprolactinomas.

To evaluate the long-term effects of dopamine agonists in the treatment of macroprolactinoma, we studied prolactin levels and tumor size for 30 to 88 months (57 +/- 14, mean +/- S.D.) in 38 patients treated with bromocriptine or lisuride. Elevated prolactin levels became normal in 30 patients, and the tumor shrank in 29. After two years of treatment, we attempted to reduce the maintenance dose (5 to 20 mg of bromocriptine per day or 0.4 to 0.8 mg of lisuride per day); in 21 patients no changes in prolactin levels or tumor size were observed over 6 to 52 months with 0.625 to 10 mg of bromocriptine per day or 0.05 mg of lisuride per day. However, it was possible to withdraw the drug in only one patient. We conclude that dopamine agonists are usually effective treatments for macroprolactinoma and that after a response has been obtained, it can be maintained in many patients with a greatly reduced dose.

Adenoma↗
PubMed1981

Size reduction of macroprolactinomas by bromocriptine or lisuride treatment.

We have administered to 29 patients with macroprolactinoma the dopamine agonists bromocriptine and lisuride for 1-50 months (mean +/- SE, 12.7 +/- 1.8) in order to assess the effects of these drugs on tumor size. Fourteen patients were treated with bromocriptine (dose range, 7.5-20 mg/day), 12 patients were treated with lisuride (0.6-2 mg/day), and 3 patients were given both drugs. Computed tomography performed before and during treatment showed the occurrence of tumor shrinkage in 18 patients (62%), but in no case was a complete disappearance of the tumor observed. In 5 of these patients, it was even possible to document tumor shrinkage within the first month of treatment with low doses of the dopamine agonists, whereas in other patients, tumors shrank only after prolonged treatment with higher doses. Visual field and acuity improved or normalized in 8 of the 13 patients with visual defects; in some cases, the improvement was reported as early as 2 days after the treatment was started. Plasma PRL levels fell in all patients who showed a reduction in tumor size; in 2 other patients, PRL levels were only poorly suppressed, and tumor size remained unchanged. In the remaining patients, PRL levels were lowered without convincing evidence of tumor shrinkage. In considering the high percentage of patients showing tumor shrinkage under medical treatment, we propose a course with dopamine agonists as the first step in the management of patients with macroprolactinomas regardless of the presence of visual impairments.

Adolescent↗
PubMed1980

Chromosomal aberrations induced by caffeine in somatic ganglia of Drosophila melanogaster.

Nerve ganglia of third-instar larvae were treated with various doses of caffeine (5 X 10(-4), 10(-3), 5 X 10(-3), 10(-2) and 2 X 10(-2) M) for 2 h at 25 +/- 1 degrees C. The ganglia were fixed at set time intervals after treatment so that the effect of caffeine in different stages of the cell cycle could be observed. Chromatid aberrations were induced only when the caffeine was administered in G2 or approaching mitosis. No aberrations were observed after treatment in S or early G2. In relation to the different doses administered, a threshold effect was evidenced, the number of aberrations increasing in a marked way at doses exceeding 5 X 10(-3) M. These data indicate that the effect observed in Drosophila melanogaster is similar to that described by Kihlman in animals and plants treated with caffeine at temperatures below 30 degrees C. Results obtained in non-cytological tests (non-disjunction, chromosome loss, lethal recessives, dominant lethals) have so far given incomplete indications as to the mutagenicity of caffeine in Drosophila. The results we have obtained with the cytological test seem to contribute to a better definition of the mutagenicity.

Animals↗
PubMed1980

Size reduction of a prolactin secreting adenoma during long-term treatment with the dopamine agonist lisuride.

A 38-year-old amenorrhoeic woman suffering from a prolactin (PRL) secreting adenoma, which had suprasellar extension as shown by caroe agonist (lisuride). PRL levels were lowered and after 1 year of treatment CAT showed a marked reduction of the tumour size. After 2 years of treatment menstruation returned and CAT demonstrated a further reduction of the adenomatous tissue. This study supports the suggestion that dopamine agonists possess an anti-proliferative effect on tumoural lactotrophic cells of humans.

Adenoma↗
PubMed1980

Homogeneity in the growth hormone-lowering effect of dopamine and somatostatin in acromegaly.

We have studied the effect of maximally inhibiting doses of dopamine (DA) or somatostatin on GH levels in 39 acromegalic patients. The GH-lowering effects of the two drugs were highly variable in different patients. A significant correlation (r = 0.45; P < 0.01) was found between the percent changes obtained during the infusions of DA (500 microgram/min) and somatostatin (3.33 microgram/min). Pretreatment with L-sulpiride markedly blunted the inhibitory effect of DA but did not affect the response to somatostatin. We conclude that the GH-secreting cells of acromegalic patients contain separate receptors for DA and somatostatin. We hypothesize that the partial or total lack of responsiveness to DA or somatostatin may be due to the loss of receptors for these agents on the GH-secreting neoplastic cells.

Acromegaly↗