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G Pratesi

Publications and source records attributed to G Pratesi.

At least 55 records · Page 3Linked to original sources
PubMed1999

8,11-dihydroxy-6-[(aminoalkyl)amino]-7H-benzo[e]perimidin-7-ones with activity in multidrug-resistant cell lines: synthesis and antitumor evaluation.

The synthesis of dihydroxybenzoperimidine derivatives, which are chromophore-modified dihydroxyanthracenediones with an additional pyrimidine ring incorporated into the chromophore, is reported. These derivatives are structurally related to the antitumor agent mitoxantrone. Their synthesis was carried out by the reaction of 6-amino-8,11-dihydroxy-7H-benzo[e]perimidin-7-one (5) or 6,8, 11-trihydroxy-7H-benzo[e]perimidin-7-one (10) with a number of respective (alkylamino)alkylamines. The dihydroxybenzoperimidine derivatives exhibited in vitro cytotoxic activity against murine leukemia L1210 and human leukemia HL60 cell lines comparable to that of mitoxantrone. These compounds also exhibited a range of in vitro activity against the human MDR-type resistant leukemia K562R cell line with the MDR phenotype. The most active compound of this series, namely 6a, exhibited potent in vitro cytotoxic activity against a panel of human cell lines. Furthermore, in contrast to both mitoxantrone and doxorubicin, it displayed little cross-resistance in cell lines characterized by a MDR phenotype. Cell cycle analysis in the sensitive HT-29 and mitoxantrone-resistant HT-29/Mx (not identified resistance mechanism) cell lines has revealed that both mitoxantrone and 6a induce a G2/M block. However, while the proportion of apoptotic cells after mitoxantrone treatment is similar for both sensitive and resistant cell lines, it is much lower for 6a. Compound 6a tested against P388 murine leukemia in vivo displayed a significant antitumor effect (%T/C 196 at an optimal dose of 10 mg/kg). The property of overcoming the cross-resistance was maintained also in in vivo efficacy studies, where no difference was observed in the antitumor activity of compound 6a against the A2780 human tumor xenograft and its MDR A2780/Dx subline. We conclude that benzoperimidines, if properly substituted, constitute a novel class of compounds that can overcome multidrug resistance.

Animals↗
PubMed1999

Configurational requirements of the sugar moiety for the pharmacological activity of anthracycline disaccharides.

The amino sugar is recognized to be a critical determinant of the activity of anthracycline monosaccharides related to doxorubicin and daunorubicin. In an attempt to improve the pharmacological properties of such agents, novel anthracycline disaccharides have been designed in which the amino sugar, daunosamine, is separated from the aglycone by another carbohydrate moiety. In the present study, we examined the influence of the orientation of the second sugar residue on drug biochemical and biological properties in a series of closely related analogs. This structure-activity relationship study showed that the substitution of the daunosamine for the disaccharide moiety dramatically reduced the cytotoxic potency of the drug in the 4-methoxy series (daunorubicin analogs). In contrast, in the 4-demethoxy series (idarubicin analogs), the C-4 axial, but not the equatorial, configuration conferred a cytotoxic potency and antitumor activity comparable to that of doxorubicin. The configuration also influenced the drug's ability to stimulate topoisomerase II alpha-mediated DNA cleavage. Indeed, the glycosides with the equatorial orientation were ineffective as topoisomerase II poisons, whereas the compounds with axial orientation were active, although the daunorubicin analog exhibited a lower activity than the idarubicin analog. It is conceivable that the axial orientation allows an optimal interaction of the drug with the DNA-enzyme complex only in the absence of the methoxy group. Our results are consistent with a critical role of the sugar moiety in drug interaction with the target enzyme in the ternary complex.

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PubMed1999

A novel taxane with improved tolerability and therapeutic activity in a panel of human tumor xenografts.

Clinically available taxanes represent one of the most promising class of antitumor agents, despite several problems with their solubility and toxicity. In an attempt to improve the pharmacological profile of taxanes, a new series of analogues was synthesized from 14beta-hydroxy-10-deacetylbaccatin III and tested in a panel of human tumor cell lines. On the basis of the pattern of cytotoxicity and lack of cross-resistance in tumor cell lines expressing the typical multidrug-resistant phenotype, a compound (IDN5109) was selected for preclinical development. A comparative efficacy study of IDN5109 and paclitaxel was performed using a large panel of human tumor xenografts, characterized by intrinsic (seven tumors) or acquired (four tumors) resistance to cisplatin or doxorubicin, including four ovarian, one breast, one cervical, three lung, one colon, and one prostatic carcinoma. Drugs were delivered i.v. according to the same schedule (four times every 4th day). IDN5109 achieved a very high level of activity (percentage tumor weight inhibition >70%; log10 cell kill >1) in all but one of the tested tumors. Compared to paclitaxel, IDN5109 exhibited a significantly superior activity in six tumors (including the four tumors that were resistant to paclitaxel) and a comparable activity against the other five paclitaxel-responsive tumors. Additional advantages of IDN5109 over paclitaxel were also suggested by its toxicity profile. IDN5109 was not only less toxic (maximal tolerated doses were 90 and 54 mg/kg for IDN5109 and paclitaxel, respectively), but it also appeared to be endowed with a reduced neurotoxic potential and an improved profile of tolerability compared to the parent drug. Furthermore, the best antitumor efficacy was often already reached with doses lower than the maximal tolerated dose, suggesting an improved therapeutic index for the new drug. In conclusion, the results support the preclinical interest of IDN5109 in terms of the toxicity profile and of the efficacy with particular reference to the ability to overcome multiple mechanisms of drug resistance.

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PubMed1999

A novel charged trinuclear platinum complex effective against cisplatin-resistant tumours: hypersensitivity of p53-mutant human tumour xenografts.

Multinuclear platinum compounds were rationally designed to bind to DNA in a different manner from that of cisplatin and its mononuclear analogues. A triplatinum compound of the series (BBR 3464) was selected for preclinical development, since, in spite of its charged nature, it was very potent as cytotoxic agent and effective against cisplatin-resistant tumour cells. Anti-tumour efficacy studies were performed in a panel of human tumour xenografts refractory or poorly responsive to cisplatin. The novel platinum compound exhibited efficacy in all tested tumours and an impressive efficacy (including complete tumour regressions) was displayed in two lung carcinoma models, CaLu-3 and POCS. Surprisingly, BBR 3464 showed a superior activity against p53-mutant tumours as compared to those carrying the wild-type gene. The involvement of p53 in tumour response was investigated in an osteosarcoma cell line, SAOS, which is null for p53 and is highly sensitive to BBR 3464, and in the same cells following introduction of the wild-type p53 gene. Thus the pattern of cellular response was investigated in a panel of human tumour cells with a different p53 gene status. The results showed that the transfer of functional p53 resulted in a marked (tenfold) reduction of cellular chemosensitivity to the multinuclear platinum complex but in a moderate sensitization to cisplatin. In addition, in contrast to cisplatin, the triplatinum complex was very effective as an inducer of apoptosis in a lung carcinoma cell line carrying mutant p53. The peculiar pattern of anti-tumour activity of the triplatinum complex and its ability to induce p53-independent cell death may have relevant pharmacological implications, since p53, a critical protein involved in DNA repair and induction of apoptosis by conventional DNA-damaging agents, is defective in several human tumours. We suggest that the peculiar DNA binding properties of the triplatinum complex may contribute to the striking profile of anti-tumour efficacy. Taken together, the available information supports that anti-tumour activity of the novel compound is mediated by a mechanism different from that of conventional platinum complexes, and compounds of this series could represent a new class of promising anti-tumour agents.

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PubMed1998

Growth-inhibitory effects of luteinizing hormone-releasing hormone (LHRH) agonists on xenografts of the DU 145 human androgen-independent prostate cancer cell line in nude mice.

Experiments have been performed to clarify whether LHRH agonists might decrease growth of hormone-unresponsive prostate cancer in vivo. Male nude mice were injected s.c. with the human androgen-independent prostate tumor DU 145 cells; osmotic minipumps releasing the LHRH agonist Zoladex (LHRH-A) for 14 days were simultaneously implanted under the skin. Treatment with LHRH-A induced a significant decrease in tumor growth up to the end of the treatment. In subsequent experiment, minipumps releasing LHRH-A were implanted in nude mice either 7 or 14 days after cell inoculation. When the treatment was started 7 days after inoculation of the cells, tumor growth was significantly decreased up to 28 days; thereafter, tumor volume remained lower than in controls, although not significantly. When LHRH-A was administered beginning 14 days after cell inoculation, tumor growth was not significantly affected at any time interval considered. LHRH-A did not appear to induce apoptosis in DU 145 cells, at least on the basis of the apoptotic index and immunohistochemical staining of the p53 protein. On the other hand, treatment with LHRH-A was accompanied by a significant decrease of the concentration of epidermal growth factor receptors in DU 145 prostate cancer specimens. Our results show that the LHRH agonist used significantly inhibits the growth of DU 145 androgen-independent prostate tumor xenografts in nude mice.

Animals↗
PubMed1998

In vitro and in vivo interaction between cisplatin and topotecan in ovarian carcinoma systems.

Topotecan, a camptothecin analogue, is a specific inhibitor of topoisomerase I approved for use in the treatment of patients with refractory ovarian carcinoma. The drug's mechanism of action suggests a potential efficacy of drug combinations incorporating DNA-damaging agents. In an attempt better to define a rational basis for drug combination we examined the effect of topotecan on the cytotoxicity and antitumor activity of cisplatin in an ovarian carcinoma system growing in vitro and in vivo as a tumor xenograft. The in vitro cell system included a cisplatin-sensitive cell line, IGROV-1, and a cisplatin-resistant subline, IGROV-1/Pt0.5, which is characterized by p53 mutation and loss of normal function of the wild-type gene of the parental cell line. This cell system was chosen since the cell sensitivity to DNA-damaging agents appears to be dependent on p53 gene status. Cytotoxicity was assessed by the growth inhibition assay using different schedules: (a) a 1-h period of cisplatin exposure followed by a 24-h topotecan treatment and (b) a 1-h period of simultaneous exposure to cisplatin and topotecan. In the case of the sequential schedule, an additive interaction was observed in IGROV-1 and IGROV-1/Pt0.5 cells. When the simultaneous schedule was used, a synergistic interaction, more evident for the cisplatin-sensitive cells, was found. On the basis of these observations at a cellular level, the effect of concomitant administration of the two drugs (i.e., the most favorable schedule) was studied in the IGROV-1 tumor xenograft, which is moderately responsive to cisplatin and topotecan. Suboptimal doses of each drug (with a low dose of topotecan, 5.1 mg/kg) achieved an antitumor effect comparable with or superior to that of the optimal dose of a single treatment (tumor weight inhibition, 60%), thus indicating a pharmacological advantage of the combination over the single treatment. However, an increase in the topotecan dose (7.1 mg/kg) was associated with an evident increase in the toxicity of the combination, thereby suggesting that the drug interaction was not tumor-specific. Although the molecular basis of the drug interaction is not clear, it is likely that inhibition of topoisomerase I affects the ability of cells to repair cisplatin adducts. Such findings may have pharmacological implications since they suggest the potential clinical interest of topoisomerase I inhibitors in combination with cisplatin.

Animals↗
PubMed1998

Stimulation of the apoptotic response as a basis for the therapeutic synergism of lonidamine and cisplatin in combination in human tumour xenografts.

The pharmacological interest in lonidamine is related to its ability to enhance the cytotoxic effects of several DNA-damaging anti-tumour agents. This study was undertaken to better understand the in vivo interaction between lonidamine and cisplatin in the treatment of human tumour xenografts, including three carcinoma models characterized by a different responsiveness to cisplatin, in spite of the presence of a wild-type p53 gene in all tumours. The drug combination was more effective in tumour growth inhibition than cisplatin alone against MX-1 breast carcinoma and A2780 ovarian carcinoma, both highly responsive to cisplatin, whereas no influence of ionidamine was observed on anti-tumour activity of cisplatin in the treatment of the relatively resistant IGROV-1 ovarian carcinoma. As cisplatin activity is related to induction of apoptosis, the modulation of drug-induced apoptosis by lonidamine was investigated. Under conditions in which lonidamine itself had negligible effects on tumour growth and apoptosis, the modulating agent stimulated the apoptotic response induced by cisplatin in the responsive but not in the resistant tumours. Tumour response was dependent not only on the drug activation of apoptosis, but mainly on the persistence over time of the event. In the breast carcinoma MX-1, hypersensitive to cisplatin and to the lonidamine+cisplatin combination, the efficacy of drug treatment was associated with phosphorylation of bcl-2 followed by down-regulation of the protein. Lonidamine itself caused a delayed phosphorylation of bcl-2. These results are consistent with the interpretation that lonidamine is effective in modulating biochemical factors involved in regulation of apoptosis.

Animals↗
PubMed1998

[Magnesium hydroxide in idiopathic calcium nephrolithiasis].

BACKGROUND: While in vitro the protective effect of magnesium on calcium oxalate crystallization is well known, its clinical relevance in calcium nephrolithiasis is still debated. Therefore, the clinical and metabolic effects of magnesium hydroxide therapy were evaluated in calcium stone formers. METHODS: Nine patients (7 M, 2 F), selected for a low urinary magnesium excretion (uMg 56 +/- 12 mg/day), were given Mg hydroxide (500 mg/day), with clinical and metabolic controls at 3, 12 and 18 months. RESULTS: Urinary Mg/uCreat increased throughout the study; uOx/uCreat decreased significantly; uCa/uCreat increased but not significantly. The stone recurrence rate decreased from 0.75 to 0.11 stones/year/patient, throughout the study period. The decrease of uOx is considered a more important risk factor in calcium stone patients than a similar uCa change; it may be due to a reduced intestinal Ox absorption, for the formation of insoluble and not absorbed Mg oxalate. CONCLUSION: In conclusion, Mg hydroxide therapy was encouraging in patients with calcium nephrolithiasis and low uMg; nevertheless a longer period of treatment is needed to confirm these data.

Calcium↗
PubMed1998

Improved efficacy and enlarged spectrum of activity of a novel anthracycline disaccharide analogue of doxorubicin against human tumor xenografts.

On the basis of a structure-activity study of a new series of anthracycline disaccharides, we recently identified a doxorubicin analogue (MEN 10755) with a promising antitumor activity. In the present study, to better support the pharmacological interest of MEN 10755, we extended the preclinical evaluation of antitumor efficacy to a large panel of 16 human tumor xenografts, which originated from different clinicopathological types. Tumors with typical multidrug-resistant phenotype were excluded because MEN 10755 was found unable to overcome resistance mediated by transport systems. In the doxorubicin-responsive series, MEN 10755 exhibited a higher activity in three of five tumors, as documented by a more marked tumor growth inhibition and an increased value of log-cell kill. In the series of doxorubicin-resistant tumors, MEN 10755 was found effective in 6 of 11 tumors (1 breast, 3 lung, and 2 prostate carcinomas). The overall response rates were 31% and 69% for doxorubicin and MEN 10755, respectively. The improvement in drug efficacy was also supported by a substantial increase in the long-term survivor rate of animals implanted with responsive tumors. Most of the tumors refractory to doxorubicin and responsive to MEN 10755 were characterized by overexpression of the antiapoptotic protein Bcl-2. In one of these tumors (MX-1 breast carcinoma), we examined the ability of MEN 10755 to induce phosphorylation of Bcl-2 after a single treatment with therapeutic doses. The results indicated that, unlike doxorubicin, MEN 10755 induced protein phosphorylation. A similar modification was produced by Taxol, which is known to be very effective against the tumor. The correlation between drug efficacy and Bcl-2 phosphorylation may underly a peculiar feature related to improvement of efficacy of the disaccharide analogue. In conclusion, the present study supports some favorable features of the novel doxorubicin analogue in terms of both efficacy and tolerability with comparison to doxorubicin, although the improvement is somewhat tumor- and schedule-dependent.

Animals↗
PubMed1997

Doxorubicin disaccharide analogue: apoptosis-related improvement of efficacy in vivo.

BACKGROUND: Although doxorubicin remains one of the most effective agents for the treatment of solid tumors, there is an intensive effort to synthesize doxorubicin analogues (compounds with similar chemical structures) that may have improved antitumor properties. We have synthesized a novel doxorubicin disaccharide analogue (MEN 10755) and have characterized some of its relevant biochemical, biologic, and pharmacologic properties. METHODS: The antitumor activity of this compound (MEN 10755) was studied in a panel of human tumor xenografts, including xenografts of A2780 ovarian tumor cells, MX-1 breast carcinoma cells, and POVD small-cell lung cancer cells. MEN 10755 was compared with doxorubicin according to the optimal dose and schedule for each drug. The drug's cytotoxic effects, induction of DNA damage, and intracellular accumulation were studied in A2780 cells. DNA cleavage mediated by the enzyme topoisomerase II was investigated in vitro by incubating fragments of simian virus 40 DNA with the purified enzyme at various drug concentrations and analyzing the DNA cleavage-intensity patterns. Drug-induced apoptosis (programmed cell death) in tumors was determined with the use of MX-1 and POVD tumor-bearing athymic Swiss nude mice. RESULTS: MEN 10755 was more effective than doxorubicin as a topoisomerase II poison and stimulated DNA fragmentation at lower intracellular concentrations. In addition, MEN 10755 exhibited striking antitumor activity in the treatment of human tumor xenografts, including those of the doxorubicin-resistant breast carcinoma cell line MX-1. CONCLUSIONS: The high antitumor activity of MEN 10755 in human tumor xenografts, including doxorubicin-resistant xenografts, and its unique pharmacologic and biologic properties make this disaccharide analogue a promising candidate for clinical evaluation.

Animals↗
PubMed1997

Cytotoxic and antitumor activity of MEN 10710, a novel alkylating derivative of distamycin.

MEN 10710 is a new synthetic distamycin derivative possessing four pyrrole rings and a bis-(2-chloroethyl)aminophenyl moiety linked to the oligopyrrole backbone by a flexible butanamido chain. Its biological properties have been investigated in comparison with the structurally related compound, tallimustine (FCE24517), and the classical alkylating agent, melphalan (L-PAM). Cytotoxic potency of MEN 10710 was increased from 10- to 100-fold, as compared to tallimustine or L-PAM in murine L1210, human LoVo and MCF7 tumor cell lines. MEN 10710 was still active against L1210/L-PAM leukemic cells, while a partial cross-resistance was observed in LoVo/DX and in MCF7/DX cells selected for resistance to doxorubicin and expressing a MDR phenotype. Treatment with verapamil (VRP) reduced the resistance to tallimustine, but not to MEN 10710, in MCF7/DX cells. The cytotoxic effects reflect in vivo antitumor potency and toxicity in the treatment of human tumor xenografts. MEN 10710 was more effective in A2780/DDP, an ovarian carcinoma selected for resistance to cisplatin. On the other hand, the IC30 for inhibiting murine granulocyte/macrophage colony formation was 50 times higher for MEN 10710 than for tallimustine, suggesting a lower myelotoxic potential. In conclusion, the particular biological profile of MEN 10710 characterized by a marked cytotoxic potency, an interesting antitumor efficacy and a reduced in vitro myelosuppressive action may represent a further improvement in the rational design of a novel distamycin-related alkylating compound.

Animals↗
PubMed1997

Apoptosis as a determinant of tumor sensitivity to topotecan in human ovarian tumors: preclinical in vitro/in vivo studies.

Preclinical and clinical studies have documented the pharmacological interest in camptothecin derivatives in the treatment of resistant tumors. In particular, topotecan, a water-soluble derivative, exhibited promising activity in pretreated ovarian carcinoma. The present study investigated the pattern of tumor response in two human ovarian carcinoma xenografts and in their cisplatin-resistant sublines characterized by different mechanisms of drug resistance. In IGROV-1/Pt1 cells, cisplatin resistance has been ascribed to a reduced susceptibility to apoptosis as a consequence of p53 mutation and inactivation of its function. In the A2780 cisplatin-resistant subline, which retained the wild-type p53 gene status, the development of resistance has been possibly related to increased cell ability to repair drug-induced DNA damage. The in vivo results of the present study showed that topotecan could overcome the resistance in A2780/CP but not in IGROV-1/Pt1 tumor xenografts. The pattern of tumor response following in vivo topotecan treatment correlated with drug ability to induce apoptosis but not with its in vitro antiproliferative activity. The antitumor efficacy of topotecan in the four tumors reflected a different cell response to drug-induced DNA damage, as suggested by different perturbations of cell cycle progression. Indeed, only in the subline refractory to topotecan in vivo, IGROV-1/Pt1, did we observe a persistent arrest of the cells in the S-phase, resulting in a cytostatic and not a cytotoxic effect, since a low level of apoptosis was induced by the drug. In conclusion, the current results support that determination of drug-induced apoptosis is a useful predictor of tumor response to topotecan in ovarian carcinomas and suggest that p53 gene status may be a critical determinant of cell response to topoisomerase inhibitors.

Animals↗
PubMed1996

Spontaneous lung metastases in a human lung tumor xenograft: a new experimental model.

The cell line NIH-H460, derived from a human large-cell carcinoma of the lung, because metastatic in the lung of athymic mice after S.C. injection. Using serial S.C. passages of the lung metastasis, a cell line was selected, H460M, which was characterized by an increased metastatic potential compared to the parental cells after s.c. (Spontaneous metastases) or i.v. injection (experimental metastases). For the high frequency of lung metastases in the mouse and the short time required to develop metastatic foci, the H460M cells transplanted in nude mice represent a unique preclinical model for biological and therapeutic studies. The paper describes the growth and some biological properties (invasion and migration capability, membrane profile) of this experimental in vivo model.

Animals↗
PubMed1996

Efficacy of lonidamine combined with different DNA-damaging agents in the treatment of the MX-1 tumor xenograft.

Lonidamine is an antitumor agent with a peculiar mechanism of action, since it differentially impairs the energy metabolism of normal and neoplastic cells. We investigated the effects of lonidamine on the activity of DNA-damaging antitumor agents against the MX-1 human breast carcinoma xenograft. Athymic mice bearing measurable s.c. tumors were treated by a single injection of doxorubicin (i.v.), cyclophosphamide (i.v.), or cisplatin (i.p.) followed by repeated daily injections of lonidamine (i.p. or p.o.). A potentiation of the activity of all these DNA-damaging drugs was achieved when each was given in combination with lonidamine, but for doxorubicin and cyclophosphamide the increase in antitumor activity paralleled the increase in lethal toxicity. In contrast, a therapeutic advantage of the combination was achieved for cisplatin and lonidamine as compared with cisplatin alone. Indeed, 6 mg/kg of cisplatin plus lonidamine cured all tumors, whereas the maximum tolerated dose of cisplatin alone (12 mg/kg) cured only six of eight tumors. In addition, the study indicated that the duration of lonidamine administration after injection of the cytotoxic drug influenced the tumor response and that prolonged treatment resulted in greater efficacy. These results document the ability of lonidamine to modulate the pharmacological activity of DNA-damaging drugs, thus suggesting that lonidamine may be a clinically useful cisplatin modulator.

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