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Biomedical subjects

G Sava

Publications and source records attributed to G Sava.

At least 163 records · Page 9Linked to original sources
PubMedDate not supplied

Antimetastatic action of orally administered lysozyme in mice bearing Lewis lung carcinoma.

The pharmacological activity of orally administered lysozyme, for the control of the growth of solid tumor metastases, was examined in mice bearing Lewis lung carcinoma. Groups of at least 10 tumor-bearing mice, fed daily for three consecutive weeks from subcutaneous tumor implantation with lysozyme, prepared from hen egg-white, had a pronounced reduction of the weight of their metastatic tumor to 25-50 per cent of controls within a wide range of doses (25-200 mg/kg/day). The antimetastatic effect was not related to the length of the treatment schedule employed; a short course of 7 days, given on days 1-7 after tumor implantation, proved equally active. The inhibition of the formation of lung metastases, in mice treated with lysozyme prior to tumor inoculation, lasts for at least 2 weeks after discontinuation of treatment, indicating that the antimetastatic activity observed is not associated with cytotoxic activity of the lysozyme, and is probably mediated by the elicitation of host responses. The examination of the therapeutic potential of the antimetastatic action of lysozyme supplied through the usual diet indicates that this treatment synergizes with the antitumor effects of cisplatin, given to mice after surgical removal of the primary tumor, causing a statistically significant prolongation of the survival time of the animals as compared with chemotherapy alone.

Administration, Oral↗
PubMedDate not supplied

Antitumour properties of dimethylsulphoxide ruthenium (II) complexes in the Lewis lung carcinoma system.

The antitumour effects of some ruthenium (II) complexes were tested in mice bearing the solid metastasizing tumour, Lewis lung carcinoma. The toxicity of trans-RuCl2 (DMSO)4 is 10-fold higher than that of its cis-isomer. Qualitatively the antitumour activity of these two complexes is comparable, although trans-isomer is more potent. Both exhibit only marginal effects on primary tumour growth while significantly lowering lung metastasis formation. The effects of trans-RuCl2 (DMSO)4 on primary tumour depend on the inoculum size, being more pronounced with low tumour inocula; significant antitumour effects can be achieved also by replacing Cl with I in the molecule. trans-RuCl2(DMSO)4 markedly reduces the number of lung metastases and particularly their volume; the reduction is comparable to that obtained with equitoxic treatments of cisplatin. Treatment with trans-RuCl2(DMSO)4 for 10 consecutive days, after surgical amputation of primary tumour, significantly prolongs the survival time of the treated mice; cisplatin, at equitoxic doses, is less effective. These data show that dimethylsulphoxide ruthenium(II) complexes possess a significant antitumour and antimetastatic activity in the Lewis lung system, also exhibiting an interesting therapeutic potential when combined with surgical amputation of the primary tumour.

Animals↗
PubMedDate not supplied

Antiinflammatory action of hydrosoluble dimethyltriazenes on the carrageenin-induced edema in guinea pigs.

The antiinflammatory activity of three hydrosoluble aryldimethyltriazenes has been examined on the carrageenin induced edema in guinea pig. The administration of equitoxic dosages of p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt (DM-COOK) and p-(3,3-dimethyl-1-triazeno)sulfonic acid sodium salt (DM-SO3Na) 1 h after carrageenin application, causes 4 h later a similar and statistically significant reduction of paw swelling by about 40% whereas, p-alanylphenyl-3,3-dimethyl-1-triazeno (DM-ALA(OH)) is inactive. Of the two active compounds, DM-COOK displays interesting properties, being rapidly active and causing a peak of inhibition higher than that caused by DM-SO3Na. The antiinflammatory activity of DM-COOK is comparable with that caused by 5 mg/kg indomethacin and 200 mg/kg phenylbutazone. However, DM-COOK, unlike indomethacin, causes an inhibition of leukocyte migration into the peritoneal cavity induced by casein treatment, thus indicating a different mechanism of action. This effect needs clarification and seems not to be correlated to cytotoxicity of the drug for migrating white blood cells, as evidenced by "in vitro' examination.

Animals↗
PubMedDate not supplied

Treatment of metastases of solid mouse tumours by NAMI-A: comparison with cisplatin, cyclophosphamide and dacarbazine.

The effects of NAMI-A, a novel ruthenium compound endowed with selective antimetastatic action, were tested on solid metastasising tumours of the mouse in comparison to cisplatin, cyclophosphamide and dacarbazine. Each compound was administered i.p. as freshly prepared solutions in isotonic saline in combination with surgical removal of primary tumour, and was used at the maximum tolerated dose. NAMI-A significantly reduced the growth of lung metastases either when given prior to surgery (early growing tumours) on TS/A adenocarcinoma or after surgical ablation of primary tumours (already established lung metasases) on Lewis lung carcinoma. The postsurgical treatment of mice bearing MCa mammary carcinoma caused a significant prolongation of the life-span of the treated animals. In the comparison experiments, dacarbazine was completely ineffective, cisplatin was as active as NAMI-A on MCa mammary carcinoma, slightly less active than NAMI-A on TS/A adenocarcinoma and inactive on Lewis lung carcinoma, and cyclophosphamide was always more active than any other treatment performed. These data stress that NAMI-A, independently of the lack of direct cell cytotoxicity, when compared to the reference drugs, has a potent therapeutic effect in mice bearing solid metastasising tumours.

Animals↗
PubMedDate not supplied

Drug control of solid tumour metastases: a critical view.

Metastasis of solid tumours represent the target of election for the pharmacological treatment of cancer. Nevertheless, commonly used treatments do not represent any selective approach, provided that drugs are mostly unspecific cytotoxics. Today many strategies adopted to interfere with metastasis growth concern the interaction with biological signals of the metastatic cells or of the host. One difference should be made between anti-metastatic and anti-metastasis drugs, in that only the latter realise the goal of selectively destroying metastasis wherever they are. In this context many agents active on newly identified molecular targets are more effective in preventing metastasis formation than in inhibiting their growth. NAMI-A, an innovative ruthenium compound, seems to provide optimism for the future and, in laboratory models, it is very active on lung metastases independently of the stage of their growth. The success of NAMI-A against metastasis should stimulate laboratory studies with appropriate experimental models to predict clinical activity, since the use of experimental conditions closely similar to those of human tumours should help the identification of more active compounds.

Animals↗
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In vitro growth of TS/A adenocarcinoma and of the gene transfected TS/A-IL4 line on biological substrates.

The growth capacity and adaptation of TS/A and TS/A-IL4 lines on laminin, fibronectin, collagens I and IV and matrigel compared to plastics were studied by flow cytometry. On plastic plates, TS/A-IL4 grows in vitro more slowly than the TS/A line and shows a more differentiated phenotype. TS/A-IL4 cells loose the capacity to bind lymphocytes and peroxidase positive cells obtained from mice implanted with the same tumour. The ratio between fibroblast- and epithelial-like cells of TS/A adenocarcinoma is subjected to marked modifications depending on the substrate on which the two cell lines are grown. IL4 release per cell unit is increased by collagen I as is the number of CD54 positive cells, suggesting that, at least in part, the in vivo rejection of TS/A-IL4 tumor might be ascribed to the stimulatory effect of the tissue on the IL4 release by tumor cells. The overall result is that gene modified TS/A-IL4 line shows marked changes of behaviour, most of them depending on the substrate on which tumor cells are growing.

Animals↗
PubMedDate not supplied

Fate of the antimetastatic ruthenium complex ImH [trans-RuCl4(DMSO)Im] after acute i.v. treatment in mice.

The content of ruthenium in blood and different organs of healthy CBA mice was determined by AAS after single i.v. treatment of 200 mg kg-1 of NAMI-A, a new antimetastatic ruthenium compound. Ruthenium concentration in blood falls 5 min after i.v. treatment. In the kidney, ruthenium concentration is markedly higher than in any other analysed tissue. No ruthenium was detected in brains. Pharmacokinetic parameters for a mono- or a bi-compartment model are identifiable: t1/2 is 10.45 h vs 12.02 (t1/2 alpha 0.023 h + t1/2 beta 12 h) with Cltot of 1.60 ml*h-1 vs 1.59); Vd is 24.15 vs 27.48 ml and (model dependent) AUC is 689 vs 694 mg*L-1*h. AUC(0-->infinity) calculated by noncompartmental method (linear trapezoidal rule) is 719.77 mg*L-1*h. NAMI-A is rapidly cleared from the blood compartment immediately after i.v. administration. Apparently, there is no differential accumulation of ruthenium in the lungs which might account for a selective antimetastatic effect caused by a cytotoxic concentration in this site, nor in any other specific organ examined.

Animals↗
PubMedDate not supplied

Increase of tumour infiltrating lymphocytes in mice treated with antimetastatic doses of NAMI-A.

NAMI-A is a novel antitumour agent, based on ruthenium, which has proved effectiveness against lung metastases of solid mouse tumours. The study focuses on the effects of NAMI-A on leukocyte infiltration into the primary tumour of MCa mammary carcinoma, implanted subcutaneously (s.c.) or intramuscularly (i.m.) into CBA mice. NAMI-A, given with a cycle of daily treatments for six consecutive days on advanced tumours at 35 mg/kg/day, markedly reduces lung metastasis independently of the tumour type (Lewis lung carcinoma, MCa mammary carcinoma or TS/A adenocarcinoma) being treated and of the site of tumour implantation (s.c. or i.m.). The analysis of leukocyte infiltration of the primary tumour, performed on a single cell suspension of cells isolated from a Ficoll gradient on which a raw suspension of primary tumour cells was layered, showed NAMI-A to significantly increase tumour infiltrating lymphocytes. These lymphocytes are almost all CD3+ cells with a significant increase of the CD8+ over the CD4+ subpopulation that reduces the helper/suppressor ratio from 2.8 to 2.1. These data indicated the absence of toxicity of NAMI-A for tumour infiltrating lymphocytes and suggested that this compound might even synergize in combined treatments with cancer immunotherapy.

Adenocarcinoma↗
PubMedDate not supplied

Blood levels of ruthenium following repeated treatments with the antimetastatic compound NAMI-A in healthy beagle dogs.

NAMI-A is a new generation ruthenium compound which is entering phase-I clinical trials anti-metastatic agent. This study analyses the effects of the i.v. injection of NAMI-A to healthy Beagle dogs at increasing doses from 0.4 (low) 4 (mid) and 8 (high) mg/kg/day, given for 5 consecutive days. Only mild signs of toxicity, consisting of emesis and mucoid faeces, from which animals completely recovered, occurred during treatment at the high dose. Decay of ruthenium concentration from the whole blood, 24 hr after 5-days treatment, was lower than that observed after 1-day treatment. T1/2 was about 20-23 hr, or slightly longer when the animals were hydrated with tap water prior to treatment; Cltot was 21-22 ml*hr-1, decreasing to 13 ml*hr-1 after hydration and increasing to 34 ml*hr-1 with the high dose. AUC was proportional to the dose used. Thus NAMI-A is well tolerated by healthy dogs with blood levels comparable to those obtained in mice treated with an about 10-times higher daily dose.

Animals↗
PubMedDate not supplied

Tumour cell uptake G2-M accumulation and cytotoxicity of NAMI-A on TS/A adenocarcinoma cells.

The ruthenium(III) complex imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate (NAMI-A) was tested on TS/A adenocarcinoma cells to evaluate the relationship between cell uptake, cell cycle arrest and cytotoxicity. The in vitro challenge of TS/A cells with 10(-4) M NAMI-A for 15 minutes to 4 hours showed a partial reduction of cell growth only after 4 hour exposure. In the same experimental conditions NAMI-A caused the increase of cells in G2-M cell cycle phase directly proportional on the length of treatment, and the ruthenium uptake by tumour cells, measured by flameless atomic absorption spectroscopy, that increases up to 2 hours of treatment and then reaches a plateau. The arrest of cell cycle in the pre-mitotic G2-M phase was transient and completely reversed by 48 hours after treatment. This study showed that the effect of NAMI-A on the cell cycle of TS/A cells is not strictly related to NAMI-A uptake as is the effect on tumour cell proliferation.

Adenocarcinoma↗
PubMedDate not supplied

Isolation of a murine metastatic cell line and preliminary test of sensitivity to the anti-metastasis agent NAMI-A.

We have isolated a new cell line (metGM) obtained from the spontaneous lung metastases of the mouse MCa mammary carcinoma. MetGM is a stable cell line which, after one year from its isolation, grows in vitro in suspension, forming cell aggregates, with cells that show irregular blabbing borders, active protein synthesis and convoluted nuclei and which have the capacity of invading matrigel membranes on which they give rise to a network of branching colonies. The preliminary study of the effects of the anti-metastasis ruthenium complex NAMI-A on metGM showed no direct cytotoxicity, with a mild reduction of cell proliferation, independent of the concentration of the ruthenium complex and not evident before 24 hours from treatment. A 10% DNA fragmentation was also measured on metGM cells 24 hours after challenge for 1 hour with 10(-5)M NAMI-A, suggesting that this compound is probably capable of apoptosis in a metastasis-derived cell line. Besides these effects on a limited percent of the cell population, NAMI-A changed the shape of the metGM cells and these alterations might account for the non-cytotoxic anti-metastatic properties of this innovative ruthenium complex. Thus MetGM appears to be a novel cell line suitable for the in vitro study of compounds endowed with anti-metastatic properties and for the development of new drugs with this activity.

Animals↗
PubMedDate not supplied

Metal complexes of ruthenium: a potential class of selective anticancer drugs.

Metal complexes of ruthenium were subjected to a number of studies concerning their chemical behaviour and their potential role in medical applications. Particular emphasis was given to the examination of the antineoplastic properties of ruthenium complexes with a number of ligands of biological interest. The possibility of obtaining compounds of potential value in the chemotherapeutic approach to neoplastic disease is supported by observations that ruthenium compounds could interact with tumor cells better than with normal tissues. This interaction can be considered the result of the chemical characteristics of ruthenium ions which can confer much more selectivity than do the actually available and clinically used organic compounds or cis-dichlorodiammine-platinum (II). Thus, ruthenium-based compounds represent the way for introducing a new class of antitumor drugs endowed with a great potential for the management of human tumors.

Animals↗
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Observations on the antimetastatic action of lysozyme in mice bearing Lewis lung carcinoma.

The effects of the oral administration of 100 mg/kg/day of lysozyme chloride on lung metastasis development were studied in mice bearing Lewis lung carcinoma. Lysozyme was administered to mice by supplying the daily amount of lysozyme with the powdered food. Lysozyme treatment reduces lung metastasis development, by significantly reducing the number of metastases of large dimension (diameters greater than 2mm) and by causing a significant increase of the percentage of animals free of large metastases, as compared with untreated controls. Correspondingly, the same animals show a pronounced increase of the number of multinuclear giant cells in the spleen; this parameter appears to be inversely correlated with the antimetastatic effect. These effects support the hypothesis that the antimetastatic effect of orally administered lysozyme depends upon spleen activation and perhaps upon induction of multinuclear giant cells of macrophage origin. This effect is consistent with previous findings indicating the occurrence of host-mediated effects in the antitumor action of lysozyme administered through the oral route.

Animals↗
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Lysozyme and cancer: role of exogenous lysozyme as anticancer agent (review).

The use of lysozyme preparations in the treatment of tumor diseases is based on more than 30 years' experience, using different methodologies and showing various results from which suggestions on the mechanism of action were derived. Lysozymes have no established place in the treatment of human tumors in spite of some interesting findings described in some reports. Nevertheless, many studies have confirmed the tumor-inhibitory activity of lysozyme treatment in a number of experimental tumors. The first half of the sixties saw increased attention on the part of scientists to the antitumor activity of lysozyme in many in vivo experimental systems of animal tumors. All of them emphasized tumor inhibitory effects after administration of lysozyme by various routes including admixture with tumor cells, peritumor and intratumor treatments, or indirectly by systemic injections and oral treatment. From these observations, at least two possible mechanisms of action can be derived, both involving the activation of the immune reactivity of the host. Lysozyme can directly activate immune cells or it can increase tumor cell immunogenicity. Alternatively, lysozyme can liberate substances from bacteria (peptidoglycans and/or polyribopyrimidinic acids) responsible for immunopotentiation and therefore antitumor activity. The present work will focus on the possibilities offered by the use of lysozyme(s) in cancer management, citing the evidence to be found in the literature with the aim of contributing to a better understanding of the activity and the role of lysozyme in the treatment of neoplastic diseases.

Animals↗
PubMedDate not supplied

Inhibition of carrageenin paw edema by pyridinalalkylimine rhodium(I) complexes.

The effects of a series of pyridinalalkyl-1,5-cyclooctadiene Rhodium(I) complexes were studied on the carrageenin paw edema model, using Sprague-Dawley rats. The series of compounds used were administered at 35, 70 and 140 mumol/kg i.p. 1hr before carrageenin application, and the effect was measured 4hr after carrageenin. The 1,5-cyclooctadienepyridinalaldoxime Rhodium(I) complex proved to be the most active compound, effective also when administered 1hr after carrageenin induction of paw swelling. However, the effects of this complex are not superior to those reported for the methyl derivative, and the overall antiinflammatory activity is inferior to that of this latter compound, particularly when the number of dosages causing at least 80% inhibition are compared. These data are consistent with those obtained in a previous investigation indicating that Rhodium(I) complexes have potential antiinflammatory properties, susceptible of further investigations extended also to other models of inflammatory disease.

Animals↗