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Biomedical subjects

M Grandi

Publications and source records attributed to M Grandi.

At least 19 recordsLinked to original sources
PubMed1992

In vitro activity of novel sulphonic derivatives of distamycin A.

The successful growth of tumors is dependent on the process of vascularization elicited by the tumor itself. As confirmed by many authors, there is a correlation between the presence of factors that stimulate tumor growth and angiogenesis. One of the approaches we have explored to control angiogenesis has been to synthesize compounds able to complex growth factors. A number of sulphonated derivatives of distamycin A were found active in inhibiting the binding of bFGF and PDGF beta on Swiss 3T3 cells with ID50 values ranging between 142-587 microM for bFGF and 28-79 microM for PDGF beta. The effect of these new derivatives in inhibiting angiogenesis was initially explored in the chorioallantoic membrane assay. It was observed that the selected compounds were active in this model system at the concentration of 350 nm/pellet. These new molecules present low or no cytotoxic activity on M5076 murine reticulosarcoma cells, the ID50 values being higher than 60 microM after 72 h continuous exposure in vitro.

3T3 Cells↗
PubMed1992

In vivo activity of novel sulphonic derivatives of distamycin A.

Solid tumor growth can be modulated through inhibition of vascularization elicited by angiogenic factors. With the objective to complex these factors, new derivatives of distamycin A were synthesized and evaluated in vitro [1] and in vivo for their ability, after i.v. administration, to inhibit bFGF-induced vascularization and the growth of M5076 murine reticulosarcoma implanted i.m. The tested compounds were able to block angiogenesis with inhibition values ranging between 70-100%. Moreover, they were found to be capable of inducing tumor inhibition with values ranging between 40% and 95% at non-toxic doses.

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↗
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↗
PubMed1991

Biological profile of FCE 24517, a novel benzoyl mustard analogue of distamycin A.

FCE 24157 (chemically (beta-[1-methyl-4-(1-methyl-4--[1-methyl-4-(4-N,N- bis(2-chloroethyl) amino-benzene-1-carboxy-amido) pyrrole-2-carboxiamido]pyrrole-2-carboxyamido)pyrrole-2-c arboxyamido]) propionamidine, hydrochloride) is a distamycin A (Dista A) derivative bearing a benzoyl mustard moiety instead of the formyl group at the N-terminal. Contrary to Dista A, FCE 24517 has been found to display potent cytotoxic activity on human and murine tumour cell lines. The compound maintains activity on melphalan (L-PAM)-resistant cells, whereas cross-resistance is observed on doxorubicin-(DX)-resistant cells. In vivo, FCE 24517 was found to possess evident antineoplastic activity on a series of murine transplanted solid tumours and human tumour xenografts. The following neoplasms were in fact found to be sensitive to FCE 24517 treatment: M14 human melanoma xenograft, N592 human small cell lung carcinoma, MTV murine mammary carcinoma, Colon 38 murine carcinoma, PO2 murine pancreatic carcinoma and M5076 murine reticulosarcoma. Lower effectiveness was observed against the murine P388 and Gross leukaemia, Lewis lung murine carcinoma, LoVo human colon carcinoma xenografts and A459 human lung adenocarcinoma. Against the murine L1210 leukaemia, FCE 24517 displayed a clear activity only when the tumour was transplanted i.p. and treatment was given i.p., whereas only marginal activity was seen against this leukaemia if transplanted i.v. and the drug was given i.v. As true also in vitro, FCE 24517 was effective against i.p. implanted L1210 leukaemia resistant to L-PAM. The mode(s) of action of this new compound is under active investigation.

Animals↗
PubMed1991

Influence of lipophilicity on cytotoxicity of anthracyclines in LoVo and LoVo/Dx human cell lines.

Quantitative structure-activity relationship studies aimed at improving drug activity profiles require the determination of the physicochemical properties possibly involved in biological action. The lipophilic character of selected anthracyclines has been measured by means of reverse-phase high performance liquid chromatography, selecting appropriate experimental conditions. The capacity coefficients at zero percentage of the organic phase (log K0), which are retention indexes, have been used as lipophilicity descriptors in a QSAR study, involving as biological data the cytotoxicity of anthracyclines in a doxorubicin-sensitive (LoVo) and in a doxorubicin-resistant (LoVo/Dx) human cell lines. The results obtained in these in vitro models indicate that lipophilicity plays a role in anthracycline activity, influencing drug availability at the site of action.

Antibiotics, Antineoplastic↗
PubMed1991

[Obesity: relationships with the endocrine system].

In this study we have examined the relationship between obesity and endocrine glands. We have underlined that obesity can be a symptom of some endocrine diseases and that, on the other side, only a few number of cases with excessive weight have a true endocrine pathogenesis. The endocrine implications of essential obesity, only detectable with appropriate dynamic tests, are sometimes expression of an altered peripheral metabolism. The more relevant hormonal data that we will examine in details are: increase of insulin plasma levels, altered hypothalamic neuroregulation with consequence on the gonadotropin secretion and values of prolactin, growth hormone and cortisol.

Endocrine Glands↗
PubMed1990

In vitro bone marrow purging of multidrug-resistant cells with a mouse monoclonal antibody directed against Mr 170,000 glycoprotein and a saporin-conjugated anti-mouse antibody.

Selective elimination of multidrug resistance-positive cells (LoVo/Dx) was obtained by using the monoclonal antibody MRK 16, which recognizes a surface epitope of the Mr 170,000 glycoprotein, and a sheep anti-mouse immunoglobulin antibody, conjugated to the ribosome-inactivating protein saporin 6. The killing was greatly decreased or even abolished by adding the monoclonal antibody at a 100-fold concentration. Both the MRK 16 and anti-mouse saporin 6 conjugate did not show any killing activity when they were used separately. In cell suspensions composed of 90% normal bone marrow cells and 10% multidrug resistance-positive cells, the monoclonal antibody MRK 16 followed by the anti-mouse immunotoxin caused the elimination of 99% multidrug resistance-positive cells, as revealed by immunofluorescence and immunocytochemistry as well as by a clonal assay. Human normal hematopoietic precursors (granulomonocytic colony-forming units, erythroid burst-forming units, and multipotent granulomonocytic, erythroid, and megakaryocytic-forming units) were not affected by the MRK 16 plus immunotoxin treatment. This technique might be suitable for ex vivo bone purging in an appropriate clinical setting, such as autologous bone marrow transplantation.

Antibodies, Monoclonal↗
PubMed1990

Effects of football on the pituitary-testicular axis (PTA): differences between professional and non-professional soccer players.

Basal levels of LH, FSH, PRL and T, as well as LH, FSH and PRL relative maximum responses (RMRs = peak values/basal values) to an iv bolus of GnRH (0.1 mg) plus TRH (0.2 mg) were evaluated in 7 professional soccer players (PSP) examined on 3 occasions: after a 30 days rest period and 14-15 h from the end of both a customary training session and a strenuous football match, performed at the end of a 3 months regular training program. In 5 out of the 7 PSP a semen analysis was carried out after each endocrine evaluation. The results were compared with those obtained in 10 non-professional soccer players (NPSP) subjected to a similar study protocol, and with the data from 10 healthy, sedentary men. Basal LH values in the rest period were significantly higher (P less than 0.05) in PSP than in control men, whereas LH RMR and sperm motility were significantly lower (P less than 0.02) in the former group. No significant differences in basal hormone concentration and in the RMRs to GnRH-TRH were observed between PSP and NPSP. The training session performed by the PSP after 3 months of regular training did not significantly affect the hormonal parameters. In contrast, the football match induced a significant increase in PRL basal levels (P less than 0.02 vs. controls) and a significant fall in PRL RMR (P less than 0.02 vs. controls).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

[Sex change in children with Morris syndrome].

Eleven boys with Morris syndrome underwent feminizing genitoplasty utilizing a segment of the sigmoid colon for neovaginal reconstruction. Bilateral orchiectomy was performed for cosmetic reasons and to prevent neoplasms. Patient follow-up ranging from 6 months to 13 years have demonstrated good results were obtained. No intra- or postoperative complications were observed. Patient psycho-social-sexual identification and satisfaction were achieved.

Adolescent↗
PubMed1989

Cellular and molecular pharmacology of 4'-epidoxorubicin in HeLa cells. Comparison with its parent drug, doxorubicin.

The effects on cellular DNA and cytotoxicity produced by doxorubicin (Dx) and its epimer 4'-epidoxorubicin (4'E-Dx) were investigated in cultured HeLa cells. 4'E-Dx was 2.3 times more cytotoxic than Dx after 1 h of treatment, but the two anthracyclines were equally cytotoxic on longer-term (24 h) drug exposure. The different kinetics of cell lethality were related to pharmacodynamic differences between the two drugs. In fact, cellular uptake and efflux rates of 4'E-Dx were faster than those of Dx on 1 h of drug exposure but similar after 24 h of treatment. 4'E-Dx caused more protein-concealed strand breaks in DNA (single and double) than did Dx, despite a lower potency for free-radical formation. The degree of strand breakage by 4'E-Dx was not a linear function of exposure time and, in fact, the rate of strand-break induction declined continuously with time. In contrast, Dx caused an almost linear increase in DNA single-strand breaks with time during 1 h of drug exposure; this was apparently due to its slower uptake. There was little repair of the DNA single-strand breaks produced by Dx upon postincubation for 5 h in a drug-free medium, whereas DNA lesions caused by 4'E-Dx were removed with a t1/2 of about 1.7 h. These findings underline the importance of the cellular pharmacokinetics of anthracyclines in relation to their cytotoxic and DNA-damaging effects.

DNA Damage↗
PubMed1989

The pituitary-testicular axis in non-professional soccer players.

In European countries, football is one of the most popular forms of physical exercise. However, the possibility that endocrine changes can arise in football players has not been investigated completely. Therefore, the aim of the present study was to evaluate the effects of a training program and the consequences of a football match on the pituitary-testicular axis in ten trained non-professional soccer players. Basal levels of LH, FSH, PRL and T, as well as LH, FSH and PRL responses to an iv bolus of GnRH (0.1 mg) plus TRH (0.2 mg), were measured in each subject. The endocrine evaluation was performed before the beginning of the seasonal training (after a 30 days rest period), and repeated on 2 consecutive days at the end of a 3 months regular training program, 14-15 h from the end of both a customary 3 h training session and a 90 min strenuous soccer match. In 5 out of the 10 athletes a semen analysis was performed after each endocrine evaluation. Ten age-matched, healthy, sedentary men served as a control group. Basal serum levels of LH (10.4 +/- 1.3 mIU/ml), FSH (8.7 +/- 1.1 mIU/ml), PRL (9.7 +/- 1.6 ng/ml) and T (6.3 +/- 0.9 ng/ml) measured in the soccer players before the beginning of the seasonal training were similar to those found in the control subjects (LH = 9.2 +/- 1.7 mIU/ml, FSH = 8.5 +/- 1.4 mIU/ml, PRL = 8.8 +/- 1.8 ng/ml, T = 6.4 +/- 1.1 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Intracellular doxorubicin concentrations and drug-induced DNA damage in a human colon adenocarcinoma cell line and in a drug-resistant subline.

The mechanisms of resistance to doxorubicin (DX) were investigated using a human colon adenocarcinoma cell line (LoVo) and a subline approximately 30 times less sensitive to doxorubicin. LoVo and LoVo/DX were similar in terms of DNA and protein content, cell volume, duration of S phase and the generation time, and proportion of cycling cells. LoVo/DX showed cross-resistance to other anthracyclines, to vinca alkaloids, epipodophyllotoxin derivatives, 4'-(9-acridinylamino-methanesulfon-m-aniside) and actinomycin D. LoVo/DX was equally sensitive to melphalan and showed collateral sensitivity to cis-platinum and 1-beta-D-arabinofuranosylcytosine. On exposing LoVo and LoVo/DX to 1.25 and 40 micrograms/ml DX respectively, for 4 hr, similar DX intracellular concentrations were reached in the two cell lines. In these treatment conditions protein associated DNA-single strand breaks or DNA-double strand breaks, assessed by alkaline elution methods were only slightly less in LoVo/DX than in LoVo cells. In LoVo/DX cells, however, DNA breaks disappeared very quickly after drug removal whereas they persisted longer in LoVo cells. This persistance is probably related to the much slower DX efflux from LoVo than LoVo/DX. When verapamil was combined with DX it inhibited the rapid DX efflux from LoVo/DX and reversed the resistance in this cell line, but it had no significant activity on LoVo cells. Verapamil also increased DX-induced DNA-single strand breaks and DNA-double strand breaks in LoVo/DX cells, but not in LoVo cells.

Adenocarcinoma↗