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T Giraldi

Publications and source records attributed to T Giraldi.

103 records · Page 6Linked to original sources
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Metastasis and neuroendocrine system in stressed mice.

The effects of experimental stressors have been examined for their differential effects on primary tumor growth and spontaneous lung metastasis in syngeneic mice bearing the weakly immunogenic tumor Lewis lung carcinoma. The effects caused by the early weaning, physical restraint and foot-shock are in general small, and affected by a high variability. On the contrary, spatial disorientation reproducibly causes a specific increase in tumor metastases. The effects of spatial disorientation are sensitive to the inhibition by treatment with bromocryptine and guanethidine, and particularly by a central and peripheral adrenergic neuron blocking agent reserpine. The use of different lighting conditions and assay of urinary melatonin excretion reveal an association between pineal gland function and effects of spatial disorientation on metastasis.

Adrenal Glands↗
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Melatonin and oxidative damage in mice liver induced by the prooxidant antitumor drug, adriamycin.

Antioxidant properties have been attributed to melatonin; it seemed therefore worthwhile to determine its effects in relation to the prooxidant action of adriamycin, which contributes to its toxic and therapeutic effects. Melatonin effectively acts as a direct free radical scavenger in the concentration range of 20-100 microM as determined in vitro, using Fenton reaction as a source of free radicals that were determined by EPR using spin trapping method. Following the administration of a single i.v. dose of 28 mg/Kg or of 3 repeated i. p. doses of 5 mg/Kg adriamycin to CBA mice, glutathione levels in the liver cells were significantly reduced. When the treatment with adriamycin was preceded by the s.c. administration of 2 mg/Kg melatonin, the decrease in total and reduced glutathione concentrations was significantly prevented. A significant increase in lipid peroxidation was observed in liver cells after a single administration of adriamycin which was not attenuated by pretreatment with melatonin. These results indicate that further examination of the possible protective action of melatonin on the toxic effects of prooxidant antitumor drugs on normal and neoplastic tissues would be of interest also in relation to their chronotoxicological properties.

Animals↗
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Cytofluorimetric analysis of a renal tubular cell line and its resistant counterpart.

P-glycoprotein (P-gp) and multidrug resistance related protein (MRP) overexpression is often responsible of the development of multidrug resistance in cancer therapy. These proteins are also expressed in normal tissues, where their physiological role is related to the extrusion of endogenous toxins or to secretory function in liver and kidney. The LLC-PK1 cell line is derived from normal pig proximal renal tubule and physiologically expresses low levels of P-gp and MRP. A resistant cell line (LLC-PK1/ADR) has been established in our laboratory by chronic exposure to increasing doses of doxorubicin. Cytofluorimetric analysis of P-gp and MRP expression performed by C219 and MRPm6 immunofluorescence detection showed that these cells overexpress P-gp but not MRP. The uptake of doxorubicin and rhodamine 123 has been quantified in LLC-PK1 and LLC-PK1/ADR cells and compared with data obtained using other tumor cell lines commonly used as reference for studying P-gp or MRP overexpression. P388 sensitive cells and its resistant counterpart P388/ADR cells, which overexpress P-gp and PANC-1 cells, which express high levels of MRP were used. A lower fluorescence intensity was evident with both doxorubicin and rhodamine 123 in LLC-PK1/ADR as well as in P388/ADR cells, that overexpresses P-gp, in comparison with the parental lines. The uptake was increased by a pretreatment with verapamil. Verapamil was completely ineffective on PANC-1 cells, confirming a selective effect of this inhibitor on P-gp. Propidium iodide staining, performed after doxorubicin treatment, confirmed a higher cytotoxicity of the antineoplastic drug in the LLC-PK1 cells compared with the resistant counterpart.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Activity and inhibition by cytotoxic and antimetastatic drugs of cathepsin B-like cysteine proteinase in transplantable leukemias in mice.

The cellular levels of cathepsin B-like cysteine proteinases have been determined in a panel of transplantable mouse leukemias possessing a different potential to metastatize to the liver after i.p. implantation. The higher enzymatic activity observed in L1210 leukemic cells matches their higher capacity for hepatic infiltration. No significant difference is observed for TLX5 lymphoma and P388 leukemia, in spite of their different liver invasiveness, and their enzymatic levels do not significantly differ from that of the non-invasive Ehrlich ascitic carcinoma. The in vivo administration of the antimetastatic drugs ICRF159 and DM-COOK, or of the cytotoxic drugs cyclophosphamide, cisplatin, CCNU and GANU, does not cause a pattern of enzyme inhibition matching the tumor metastatic potential and the increase in life-span of the treated tumor bearing mice, indicating that the inhibition of cathepsin B-like cysteine proteinase is not involved in either their cytotoxic or their antimetastatic action.

Animals↗
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Proteinases and proteinase inhibition by cytotoxic and antimetastatic drugs in transplantable solid metastasizing tumors in mice.

The tissue levels of two proteolytic enzymes, plasminogen activator and cathepsin B - like cysteine proteinase, which were found to be increased in malignant tumors and to be proportional to tumor metastatic potential in some instances, have been determined in a panel of solid metastasizing tumors in mice. The examination of B16 melanoma, MCa mammary carcinoma and of two lines of Lewis lung carcinoma with widely different potential to spontaneously metastasize, showed no correlation between metastatic potential and the tissue content of the proteinases considered. The treatment of the animals with cytotoxic antitumor drugs (CCNU, GANU, cisplatin, and cyclophosphamide) or with antimetastatic drugs acting with a mechanism unrelated with cytotoxicity (ICRF 159 and DM-COOK) caused only marginal inhibition in some instances, whereas no meaningful pattern of inhibition either based in terms of metastatic potential of the tumor or on drug mechanism of action was recognizable. A direct involvement of the two proteinases examined in the process of metastasis in the tumor panel used is thus not apparent, although a more complex interaction with other latent proteinases and inhibitors might be operative.

Animals↗
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Primary tumor growth and formation of spontaneous lung metastases in mice bearing Lewis carcinoma treated with proteinase inhibitors.

The differential effects on primary tumor growth and on the formation of spontaneous pulmonary metastases have been determined for a series of proteinase inhibitors. The substances included the gold compounds, aurothioglucose and aurothiomalate, D(-)penicillamine, phosphoramidon and an egg-white inhibitor of cysteine proteinase (EWI). The i.p. administration of these substances to mice bearing s.c. Lewis lung carcinoma cause varying degrees of antineoplastic effects; the most pronounced effects on metastases are caused by phosphoramidon. The inactivity of EWI on tumor progression is concomitant with an inhibition to 50% of cathepsin B in tumor homogenates. The selective antimetastatic action of phosphoramidon is in agreement with the crucial role proposed for tumor collagenases in tumor dissemination.

Animals↗
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Seasonal dependency of the effects of experimental stressors on tumor metastasis in mice bearing Lewis lung carcinoma.

Increasing evidence indicates that the application of stressor paradigms in experimental animals affects tumor incidence and progression. However, a high heterogeneity appears both for the animal-tumor system used and for the characteristics of the stressor employed. A high variability was observed also with the application of rotational stress, a carefully and widely characterized mild psychological stressor, to mice bearing Lewis lung carcinoma. The aim of this work has been therefore to examine the possible seasonal dependency of the effects of experimental stressors (rotational stress, forced immobilization and electric foot shock) on spontaneous lung metastasis formation in mice bearing Lewis lung carcinoma. The possible participation of pineal gland and of melatonin have also been examined including in the experimental protocol the measurement of melatonin urinary excretion. The stressor paradigms used significantly increased metastasis weight in spring, in comparison with non-stressed animals. When examined in winter, rotational stress and foot shock significantly decreased metastasis formation, in comparison with non-stressed mice. The effects of forced immobilization were not season-dependent. The melatonin urinary excretion has been measured in relation to the seasonal effects of rotational stress. Nocturnal melatonin excretion is markedly increased by rotational stress in spring and is remarkably decreased in winter. These variations in endogenous melatonin levels caused by rotational stress appear to directly correlate with the effects of the stressor or metastasis. These results lend support to the view that the mechanisms underlying the tumor enhancing action of stressors involve the psychoneuroendocrine network, and indicate the relevance of chronobiology in experimental cancer research and neuro-immuno-modulation.

Animals↗
PubMedDate not supplied

Blockers of adrenergic neurons and receptors, tumor progression and effects of rotational stress in mice.

The aim of this work was to determine the possible participation of adrenergic responses to the increase in tumor dissemination induced by rotational stress using drugs affecting monoaminergic function. The growth of the primary tumor and the formation of lung metastasis were determined in mice implanted with Lewis lung carcinoma, subjected to rotational stress and treated with the adrenergic neuron blocker reserpine, the alpha-receptor blocker phenoxybenzamine, and the beta-blocker propranolol. Treatment with reserpine markedly reduced the formation of spontaneous lung metastasis and completely abolished the increase in metastases caused by rotational stress without direct effect on tumor cells or blood vessels. Phenoxybenzamine and propranolol caused opposite effects on tumor progression. Previous immunosuppression by cyclophosphamide in mice with tumors reduced the antimetastatic effects of reserpine. These results suggesting the importance of the adrenergic modulation of immune resistance factors in controlling metastasis development and indicate a possible role in monitoring the use and effects of monoaminergic drugs in cancer patients.

Adrenergic Agents↗
PubMedDate not supplied

Survival time in mice bearing TLX5 lymphoma subjected to rotational stress and chemotherapy with CCNU.

The effects of a psychological stress model rotational stress were examined in mice bearing TLX5 lymphoma. The survival time of the animals was determined as a function of tumor inoculum size and treatment with the antitumor drug, CCNU. Rotational stress significantly decreased the mean survival time of mice implanted with 10 or 10(2) tumor cells, and significantly increased tumor takes in mice implanted with 10 cells. Treatment with CCNU significantly prolonged the survival time of the treated animals; the application of rotational stress significantly attenuated the increase in survival time caused by CCNU. These results indicate that in mice with a limited tumor burden, psychological stress favors the progression of TLX5 lymphoma, and reduces the effectiveness of the antitumor drug, CCNU. Moreover, the experimental model employed may provide a tool useful for investigating the mechanisms involved in the sensitivity of lymphoma to psychosocial stress.

Animals↗