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Biomedical subjects

F Spreafico

Publications and source records attributed to F Spreafico.

At least 19 recordsLinked to original sources
PubMed1992

The unique interaction with immunity of FCE 24517, an antitumor drug with a novel mode of action.

The present study was designed to characterize in mice the effects on the immune system of the antineoplastic agent FCE 24517, a benzoic acid mustard derivative of distamycin A with specificity for AT-rich base pair sequences of beta-DNA. At antitumorally therapeutic doses, single injections of FCE 24517 caused profound leukopenia and a decrease of spleen cell numbers. However, primary and secondary antibody production to the T-dependent antigen sheep red blood cells were markedly increased by FCE 24517 given before or together with antigen. Antibody production to the T-independent antigen type III pneumococcal polysaccharide was not appreciably affected by FCE 24517. The delayed type hypersensitivity response to sheep erythrocytes was only marginally decreased, whereas proliferation of spleen cells to mitogens was markedly depressed. The ability of natural killer cells and macrophages to mediate cytotoxicity was not affected by FCE 24517 treatment. The ability of carrier-primed cells from drug-treated mice to cooperate for anti-trinitrophenyl antibody production increased twofold over that of vehicle-injected controls, suggesting an increase in T-helper cell activity. Serum cytokine levels were studied in mice injected with bacterial lipopolysaccharide used as a model stimulus. Peak levels of TNF and IL-6 were not modified by FCE 24517, but at later times higher amounts of cytokines were found in drug-treated mice compared with the control, suggesting a longer exposure of immunocompetent cells to these factors. Two compounds (FCE 24561 and CC-1065), also capable of binding AT-rich sequences in the minor groove of beta-DNA and containing an alkylating moiety, had immunomodulatory activity similar to FCE 24517 in increasing primary anti-sheep erythrocytes response. It is concluded that FCE 24517 exhibits a unique interaction with the immune system, markedly different from that of alkylating agents and may be representative of a novel group of antiproliferative-immunomodulating agents.

Animals↗
PubMed1992

In vivo anti-tumour activity of FCE 23762, a methoxymorpholinyl derivative of doxorubicin active on doxorubicin-resistant tumour cells.

FCE 23762 is a new doxorubicin derivative obtained by appending a methoxymorpholinyl group at position 3' of the sugar moiety. The compound is greater than 80 times more potent than doxorubicin, it is highly lipophilic, and presents equivalent anti-tumour activity when administered by i.p., i.v. or oral route. The pattern of anti-tumour activity of FCE 23762 differs from that of doxorubicin in maintaining anti-tumour activity against two P388 murine leukaemia sublines resistant to doxorubicin and, although at borderline levels of efficacy, against LoVo human colon adenocarcinoma resistant to doxorubicin. FCE 23762 exhibits remarkable efficacy against MX-1 human mammary carcinoma, with most treated mice being cured both after i.v. and oral treatment. Anti-tumour activity was also observed against L1210 murine leukaemia and two sublines resistant to cis-platinum and melphalan, M5076 murine reticulosarcoma, MTV murine mammary carcinoma and N592 human small cell lung cancer.

Animals↗
PubMed1992

Suramin prevents neovascularisation and tumour growth through blocking of basic fibroblast growth factor activity.

Inhibition of angiogenesis through blocking of growth factors involved in this process could be a novel therapeutic approach in several important pathologies, neoplasia among them. Suramin has recently been described to possess antineoplastic activity in animals and humans, and it has been proposed that an important role in this activity is played by antagonism of growth factors and especially bFGF. To investigate this hypothesis in vivo, we used gelatin sponges loaded with bFGF and implanted subcutaneously in mice. Suramin showed an inhibitory activity on bFGF-induced angiogenesis, whereas it was inactive in the case of heparin-complexed bFGF. Suramin was also studied in an in vivo model of tumour-induced angiogenesis using the murine M5076 reticulosarcoma, a tumour producing significant levels of bFGF. Suramin was able to reduce tumour growth and tumour induced angiogenesis, and exogenous administration of bFGF countered suramin effects.

Animals↗
PubMed1992

Selected pharmacologic characteristics of idarubicin and idarubicinol.

The pharmacology of ID and IDOL are of interest in light of the potential utility of ID in the treatment of adult and pediatric leukemia patients. Preclinical activity and cellular pharmacology of ID were suggestive of greater clinical activity when compared with several standard anthracyclines. Most intriguing were data comparing in vitro and in vivo activity data and cellular pharmacology of IDOL to other anthracycline alcohol metabolites. Given the pharmacokinetics of IDOL, there is continued interest in the unique aspects of IDOL pharmacology as an important element of ID pharmacology.

Animals↗
PubMed1991

Selective DNA interaction of the novel distamycin derivative FCE 24517.

N-Deformyl-N-(4-N-N,N-bis(2-chloroethylamino)benzoyl)distamy cin A (FCE 24517) is a novel cytotoxic and antitumor agent shortly to be investigated in phase I clinical trials. It was equally effective in inhibiting the growth of the murine L1210 line and of a subline (L1210/PAM) resistant to nitrogen mustards, whereas distamycin A was virtually inactive. The cellular uptake and retention of FCE 24517 and distamycin A were similar, thus excluding the possibility that this marked variation in cytotoxic activity was due to different intracellular concentrations of the two compounds. FCE 24517 did not appear to act as an inhibitor of macromolecule synthesis. As shown by radioactively labeled precursor incorporation only 24 h after drug treatment a significant inhibition of DNA synthesis was observed in L1210 or in L1210/PAM, when a marked proportion of cells was arrested in premitotic phase. FCE 24517 did not cause DNA breaks, DNA interstrand cross-links, or DNA-protein cross-links in L1210 cells exposed to active drug concentrations. A very low amount of radioactivity was found to be bound irreversibly to DNA in L1210 cells exposed for 1 h to [14C]FCE 24517. Using plasmid pBr322 DNA fragments in a modified version of the Maxam and Gilbert DNA sequencing technique we found no detectable binding of FCE 24517 to N-7-guanine (the major site of alkylation for classical alkylating agents), whereas some alkylations to adenine (presumably to N-3-adenine) were demonstrated. Thus it appears that FCE 24517 is a novel antitumor agent with a mode of action different from that of the drugs currently used in the clinic. In summary it is suggested that FCE 24517 acts by causing a few selective alkylations to adenines in the minor groove of DNA, although the precise base sequence necessary has yet to be elucidated.

Alkylating Agents↗
PubMed1991

Reduced cardiotoxicity of doxorubicin given in the form of N-(2-hydroxypropyl)methacrylamide conjugates: and experimental study in the rat.

A rat model was used to evaluate the general acute toxicity and the late cardiotoxicity of 4 mg/kg doxorubicin (DOX) given either as free drug or in the form of three N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. In these HPMA copolymers, DOX was covalently bound via peptide linkages that were either non-biodegradable (Gly-Gly) or degradable by lysosomal proteinases (Gly-Phe-Leu-Gly). In addition, one biodegradable conjugate containing galactosamine was used; this residue was targeted to the liver. Over the first 3 weeks after the i.v. administration of free and polymer-bound DOX, all animals showed a transient reduction in body weight. However, the maximal reduction in body weight seen in animals that received polymer-bound DOX (4 mg/kg) was significantly lower than that observed in those that received free DOX (4 mg/kg) or a mixture of the unmodified parent HPMA copolymer and free DOX (4 mg/kg; P less than 0.01). Throughout the study (20 weeks), deaths related to cardiotoxicity were observed only in animals that received either free DOX or the mixture of HPMA copolymer and free DOX; in these cases, histological investigations revealed marked changes in the heart that were consistent with DOX-induced cardiotoxicity. Sequential measurements of cardiac output in surviving animals that received either free DOX or the mixture of HPMA copolymer and free DOX showed a reduction of approximately 30% in function beginning at the 4th week after drug administration. The heart rate in these animals was approximately 12% lower than that measured in age-matched control rats (P less than 0.05). Animals that were given the HPMA copolymer conjugates containing DOX exhibited no significant change in cardiac output throughout the study (P less than 0.05). In addition, no significant histological change was observed in the heart of animals that received DOX in the form of HPMA copolymer conjugates and were killed at the end of the study. However, these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Acrylamides↗
PubMed1990

In vivo effects of cyclosporin A on murine B-cells responding to type III pneumococcal polysaccharide.

The effect of cyclosporin A (CSA) on the antibody response to pneumococcal polysaccharide type III (a T-independent class 2 antigen) was investigated in mice. A single oral CSA administration (50 mg/kg) was able to depress (40%) the primary antibody response evaluated as spleen plaque-forming cells. Repeated treatments (12-50 mg/kg x 5) resulted in a higher degree of inhibition (80%) of anti-SIII response. Both single and repeated CSA treatments were active only when administered concomitantly with or after immunization, whereas no effects were seen with drug pretreatment. Comparable inhibitions of anti-SIII response were observed in control and nude mice suggesting a direct effect of CSA on B-cells.

Administration, Oral↗
PubMed1989

Dechloro teicoplanin antibiotics.

Mono- and didechlorinated derivatives of the antibiotic teicoplanin, its pseudoaglycones and aglycone, and of one amide and ester of deglucoteicoplanin were prepared under selective reductive conditions. The selectivity and rate of dehalogenation were studied and compared to those of vancomycin and deglucovancomycin. The influence of the chlorine substituents on the mechanism of action and antibacterial activity of teicoplanin antibiotics was also investigated.

Animals↗
PubMed1988

Modulation by suramin of NK and monocytic cell-mediated cytotoxicity in human and murine cells.

The in vitro effects of suramin, a compound recently tested in AIDS treatment, were investigated on human and murine NK and monocyte macrophage cytotoxicity and monocyte migratory ability. In a short-term, TNF-dependent assay, pre-exposure (4-18 h) to 100-400 micrograms/ml suramin was associated with a markedly increased cytotoxicity by human monocytes and murine-elicited peritoneal macrophages, paralleled by a greater cytotoxic capacity in the supernates of these effectors. Preincubation with the same pharmacological suramin concentrations also resulted in enhanced spontaneous and directed migration in monocytic cells. Suramin-preincubated human PBL and murine splenocytes were unchanged in their basal NK cytotoxicity but exhibited a deficient response to IFN. Pre- and post-incubations with suramin resulted in increased macrophagic cytotoxicity for TNF-insensitive targets. Conversely, postincubation of effectors with the drug at 100-400 micrograms/ml was associated with profound decreases in both NK and TNF-mediated macrophagic cytotoxicities, and prior exposure to suramin of macrophagic supernates resulted in reduced cytotoxic activity. The mechanisms involved in the complex modulatory activity of suramin for monocyte macrophages and NK cells and the possible therapeutic implications of these findings are discussed.

Animals↗
PubMed1988

In vitro modulation of human monocytes functions by RU 41740 (Biostim).

The in vitro effects of RU 41740, a mixture of two glycoproteins extracted from K. pneumoniae and possessing immunomodulatory activity, on human monocyte's cytotoxic activity, migratory capacity and monokine production were investigated. Exposure to RU 41740 in nanogram concentrations was associated with rapid increases in IL-1 and TNF production and marked augmentation in the monocytes' killing of TNF-sensitive targets, whereas killing of TNF-insensitive targets required longer exposures to microgram concentrations of this drug. Using otherwise effective treatment conditions, RU 41740 did not directly affect monocyte's spontaneous and FMLP-induced migration. The possible role of mononuclear cells stimulation and increased production of effector and regulatory monokines in the immunomodulatory activity of this product is addressed.

Adjuvants, Immunologic↗
PubMed1988

Stimulation of natural host defence mechanisms in rodents by nesosteine.

The effect of Nesosteine, a novel mucolytic agent, on natural host resistance mechanisms was investigated in different organs of mice and rats. Single or repeated administrations of nesosteine by the i.v. or oral route (per os) were associated with significant increases in lung and spleen NK-mediated cytotoxicity, and in alveolar and peritoneal macrophages direct cytotoxicity. In both species the dose-response curve was bell-shaped, and optimal activity on both parameters seen at 1 mg/kg i.v. x 1, 100 mg/kg per os x 1 or 20 mg/kg per os x 5. Increases of at least 100% in lung NK and alveolar macrophages cytotoxicity were found in mice 48 h after single oral dosing at 100 mg/kg. The possible importance of Nesosteine immunostimulatory capacity in the activity of this compound in chronic hypersecretive bronchopulmonary disorders is discussed.

Administration, Oral↗
PubMed1988

Immunotoxicology in 1987: problems and challenges.

After the definition of immunotoxicology and of the main current domains of this recently recognized, multifaceted discipline, this article examines the health significance of xenobiotically induced immune abnormalities and considers the possible mechanisms through which damage to the immune system can occur. In the second part of this review, the current status of knowledge and the problems still open with regard to preclinical testing for nonallergic immunotoxicities are examined, and current views on the general strategy for such testing discussed.

Allergy and Immunology↗
PubMed1987

Influence of gangliosides on primary and metastatic neoplastic growth in human and murine cells.

The influence of gangliosides on tumor growth and frequency of metastasis in vivo as well as on growth and motility of neoplastic cells in vitro was tested utilizing human and rodent cell populations. In mice receiving injections of a ganglioside mixture twice daily the tumor volume, the number of spontaneous metastases per animal, and the number of mice with metastasis was approximately double that of controls. Preincubation of neoplastic cells with the ganglioside mixture doubled the number of metastatic foci in the lungs of mice receiving the cells by i.v. injection. Addition of a ganglioside mixture to the culture medium enhanced motility of neoplastic cells about 3-fold. This finding was similar to that observed for capillary endothelium. The presence of gangliosides in the culture media for a 48-h incubation period about doubled the number of neoplastic cells as compared to controls; the same was observed for capillary endothelium. The data are interpreted to indicate that gangliosides improve growth and mobilization of capillary endothelium and neoplastic cells. Both events may concur in enhancing tumor growth in vivo, the first by improving angiogenesis, the second by direct action on the neoplastic cell population.

Animals↗
PubMed1987

Effect of thymostimulin in models of cell-mediated and humoral autoreactivity and on T-dependent suppression.

To explore the therapeutic potential of the thymic hormone preparation thymostimulin (TS) in animal models of cell-mediated and humoral autoimmunity, its effects were investigated on experimental allergic encephalomyelitis in guinea pigs and on anti-erythrocytic autoantibody production in C57B1/6 mice. In both autoimmunity models, TS produced significant therapeutic effects in terms of proportion of diseased animals, disease severity and/or disease duration; however, both the TS dose and the time of treatment start relative to the disease-inducing stimulus critically influenced results. TS effects on the generation and expression of suppressive activity induced in C57B1/6 mice by a supraoptimal immunization with 10(10) SRBC were also examined. TS given after 10(10) SRBC did not influence the level of suppression, and the activity of effectors of suppression was not modified by this agent. Conversely, using a treatment protocol analogous to that effective in reducing murine autoantibody production, TS administration prior to 10(10) SRBC was associated with a significant increase in the subsequent generation of T-dependent, antigen-specific suppressive activity. These findings suggest that effects of TS on the development of suppressor cells may be involved in the activity of this agent in animal models of autoaggression.

Animals↗
PubMed1986

Metastatic growth of a murine tumor: evidence of dissemination to the lungs in the absence of subcutaneous growth.

Growth of MCA-38/B colon adenocarcinoma was detectable 30-33 days after subcutaneous (s.c.) tumor cell inoculation in mice. Seventy percent of the mice receiving 10(7) tumor cells, 50% of those receiving 10(6), and 15% of the mice given 10(5) cells developed s.c. tumors (mean of 4 experiments, total of 80 mice per group). Metastases in the presence of a primary tumor were observed in 11% of 10(7) and in 10% of 10(6) tumor-cell injected animals. Lung metastases were detected in the absence of tumor growth at the site of s.c. cell injection in 19% of 10(7), in 8% of 10(6) and in 5% of 10(5) and 10(4) tumor-cell inoculated mice. In parallel experiments an intravenous (i.v.) inoculum of tumor cells produced lung colonies in 40% of 10(6) and in 14% of 10(5) tumor-cell injected animals. Smaller inocula did not give rise to lung colonies, thus making it unlikely that accidental i.v. inoculations of tumor cells during the s.c. injections caused the observed metastatic dissemination to the lungs.

Adenocarcinoma↗