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G Pratesi

Publications and source records attributed to G Pratesi.

At least 91 records · Page 5Linked to original sources
PubMed1990

Evaluation of a platinum-doxorubicin complex in experimental tumor systems.

On the basis of previous observations indicating that the platinum (II)-doxorubicin complex (coordinated via the amino sugar) was active against resistant ascitic leukemias, the preclinical evaluation of this complex was extended to a variety of experimental tumors, including solid doxorubicin-resistant tumors (P388/DX, B16 melanoma with acquired resistance, and MXT mammary carcinoma with natural resistance). In the treatment of sensitive tumors (Gross leukemia and Lewis lung tumor) the complex provided efficacy comparable to that of doxorubicin. Among resistant models, only P388/DX, which is only weakly responsive to cisplatin itself, showed significant sensitivity to the platinum complex. Since all resistant tumors were transplanted in the same site (s.c.) of the same mouse strain, it is likely that the different tumor response reflects different underlying mechanisms of cell resistance rather than alterations in pharmacologic behavior of the anthracycline after covalent binding to platinum. The data reported in this preclinical study support the potential value of this approach to overcome selected manifestations of resistance to anthracyclines. In contrast to the highly toxic doxorubicin/cisplatin combination, doxorubicin complexation with platinum was not associated to an increase in toxicity.

Animals↗
PubMed1990

Role of T cells and tumour necrosis factor in antitumour activity and toxicity of flavone acetic acid.

To investigate the importance of natural killer (NK) and T cells in the inhibition of tumour growth by flavone acetic acid (FAA), colon 26 murine carcinoma was grafted subcutaneously in euthymic and athymic mice. FAA was active in euthymic but not in athymic mice (ratio between tumour weight in treated vs. control animals [T/C %], 27% and 92%, respectively). NK cell activity was increased in both mouse strains, indicating a lack of major involvement of this lymphocyte population in FAA efficacy. In euthymic mice tumour-specific T cells were activated, and after in vivo depletion of lymphocyte subpopulations (L3T4 and Lyt2), tumour inhibition by FAA was abrogated (T/C %, 88%). Antitumour efficacy of FAA was also reduced when the treatment was followed by injection of antitumour necrosis factor alpha (TNF alpha) antibodies. FAA toxicity depended on tumour weight at the time of treatment: 200 mg/kg caused 0 and 100% mortality in mice bearing tumour nodules under 50 and over 300 mg, respectively. When anti-TNF alpha antibodies were given after FAA treatment, the toxicity was greatly reduced (3/14 mice died compared with 10/15).

Adenocarcinoma↗
PubMed1990

Different interaction of cisplatin and etoposide on in vivo and in vitro tumor systems.

The effect of cisplatin (CDDP) in combination with etoposide (VP16) was examined on four human cell lines (one colon adenocarcinoma, LoVo; one ovarian carcinoma, IGROV-1; two small cell lung cancers, NCI-H146 and NCI-N592; and two murine leukemias, P388 and L1210). Simultaneous exposure to CDDP and subtoxic concentrations of VP16 for 1 h produced a cell killing in all cell lines comparable to that achieved by CDDP alone. Sequential exposure of NCI-H146 and NCI-N592 to CDDP for 1 h followed by VP16 for 96 h again produced an additive effect. When two of these cell lines were treated in in vivo models (i.p. P388 leukemia, s.c. NCI-N592) with suboptimal doses of the two drugs, a potentiation of the antitumor effects of the two drugs in simultaneous combination was evidenced by the increase in survival time and in the number of 'cures' in P388 leukemia bearing mice and by the inhibition of tumor size in NCI-N592. This comparative study, using the same cell lines in vitro and in vivo, indicates that the CDDP-VP16 potentiation observed in vivo does not reflect a specific interaction at the cellular-biochemical level. The results support the therapeutic interest of this combination (presumably as a result from favorable pharmacological interactions) even despite the lack of potentiation at cellular level, under comparable conditions of treatment.

Animals↗
PubMed1989

In vivo and in vitro growth of SCLC cells derived from biopsies.

In order to increase the availability of SCLC cells derived from biopsies, in vivo and in vitro growth methods were investigated. The cells grown in both conditions were periodically monitored for reactivity with 2 monoclonal antibodies (MAbs): MLuC1 directed against SCLC cells and IM1 which recognizes the class II antigen on activated lymphocytes and macrophages. About 50% of the 28 analyzed SCLC specimens were found to proliferate in one or both systems. The in vitro-grown cells exhibited the same heterogeneity found in the original cell suspensions and moreover, in some cases only normal cells were recovered after several in vitro passages. From the subcutaneous transplanted tumors a large number of MLuC1-positive tumor cells could easily be recovered, thus indicating the validity of the in vivo methodology. The MBr1 MAb, directed against an epithelial antigen, was found to react with about 50% of the 26 tested tumors, mainly those which demonstrated in vivo and/or in vitro growth capacity. These data suggest that only some tumors, presumably with peculiar biological characteristics, can efficiently grow in these artificial systems.

Adult↗
PubMed1989

An exponential-Gompertzian description of LoVo cell tumor growth from in vivo and in vitro data.

The data of nine monolayer cultures, 48 multicellular spheroids, and 19 s.c. xenografts of LoVo cells were fitted, on an individual basis, by exponential and Gompertzian equations, respectively. The mean growth parameters alpha 0 (initial growth rate) and beta (retardation factor) of the three experimental systems presented a strong linear correlation alpha 0 = 6.88 beta + 0.56, r = 0.9843. This implies that, at the particular tumor size of 155 microns in diameter (mean +/- SD = 50-310 microns), the tumor growths described by Gompertzian curves (from spheroids as well as from s.c. xenografts) have the same growth rate as monolayer cultures. This occurrence strongly supports an exponential-Gompertzian growth model, where an exponential monolayer-like phase changes to a Gompertzian growth, controlled by environmental conditions, when the tumor size has reached a critical value.

Carcinoma↗
PubMed1989

Relative role of host and tumor in the growth pattern of murine and human neoplasms following subcutaneous transplantation in mice.

The growth patterns of two murine and eight human tumors, bilaterally implanted into subcutaneous tissue of groups of recipient mice, were studied. A Gompertz equation was fitted to experimental data for each individual implant and the Gompertz parameters were utilized as quantitative growth characteristics. The relative roles of the tumor-implanted flank (right versus left), of the individual host and of the tumor were analyzed by the paired t-test, simple linear regression model, one-way and two-way analysis of variance. Sixty pairs of Gompertz curves were obtained in seventy animals. Heterogeneity was the main characteristic of the growth pattern in all tumors under study, with a wide variability among the Gompertz parameters. Statistical analysis of experimental data showed that only the tumor systematically influenced the growth characteristics, whereas neither the tumor-implanted flank nor the individual host played a significant role. These results have both theoretical and practical implications.

Analysis of Variance↗
PubMed1989

Effects of 5-FU and cis-DDP combination on human colorectal tumor xenografts.

The antitumor efficacy of the cis-diamminedichloroplatinum (cisDDP) and 5 fluorouracil (5FU) combination was evaluated in a panel of eight human colorectal carcinoma xenografts. Tumors differed in origin (primary or metastatic), differentiation degree and chemotherapy treatment. Xenografts were treated with repeated i.v. injections of cisDDP, 5FU, or both drugs at 24-h interval. Compared with controls, cisDDP achieved a significant tumor growth inhibition in five out of eight tumor lines, and 5FU in four out of seven. One of two unresponsive tumor lines was significantly inhibited by the combination, that was also more effective than either drug alone (p less than 0.05) in one responsive xenograft. Comparing the effects of the combination according to which drug was administered first, lower drug doses were tolerated using the cisDDP-5FU sequence, but the antitumor effects were similar at equitoxic doses. These results indicate a potential therapeutic benefit of the cisDDP-5FU combination for colorectal carcinoma patients and show that toxicity of the combination is influenced by the drug sequence.

Adult↗
PubMed1989

Protective effect of reduced glutathione against cisplatin-induced renal and systemic toxicity and its influence on the therapeutic activity of the antitumor drug.

Reduced glutathione has been shown to be an effective protector against cisplatin-induced nephrotoxicity of potential clinical value, since it does not reduce antitumor activity of the cytotoxic drug. This paper extends previous observations on the protective potential of reduced glutathione against cisplatin-induced nephrotoxicity, in different rodent models. Following i.v. administration, glutathione protection against cisplatin-induced nephrotoxicity was found to be critically dependent on timing of thiol administration. Whereas the sulfhydryl compound provided almost complete protection in CD rats, the protective effect against toxic renal damage was only partial in mice of different strains. In spite of the modest protection against kidney toxicity, glutathione reduced lethal toxicity in the mouse. Under the same experimental conditions at protective dose levels, the tripeptide thiol did not interfere with the antitumor effectiveness of cisplatin, in any of the tumor models examined. The kidney content of non-protein sulfhydryls of CD rats produced by the effective dose of glutathione was markedly higher than that found in the mouse treated with the same dose. This finding is consistent with a differential protection provided by glutathione against cisplatin-induced renal toxicity in these species.

Animals↗
PubMed1989

Improvement of anemia in patients on chronic dialysis treated by hemodiafiltration.

A group of patients with severe anemia on standard hemodialysis were transferred to polyacrylnitrile hemodiafiltration (HDF), which was arranged in order to obtain an ultrafiltration rate (UF) higher than 100 ml/min. During HDF, despite a significant reduction of the dialysis time, all patients had a significant decrease of predialytic BUN and serum creatinine, and a significant improvement of anemia. Furthermore, a close direct correlation was detected between the percent increase of hemoglobin and the length of time on HDF. Therefore, high-UF HDF represents a valid dialytic strategy to improve anemic states, permitting a significant reduction of the dialysis time and, thus, offering a better life quality for the patients.

Anemia↗
PubMed1989

Effects of tauromustine, a water-soluble nitrosourea compound on NMU-1 murine lung tumor.

This study assessed the antitumor activity of 1-(2-chloroethyl)-3-/2-(dimethylaminosulfonyl)ethyl-1-nitrosourea (TCNU), a newly soluble nitrosourea, on NMU-1 lung tumor, a transplantable murine model poorly sensitive to BCNU. TCNU delivered orally was more effective after weekly than after biweekly treatments. When TCNU was given weekly intravenously, its therapeutic index was higher than after oral treatment. Compared with BCNU, TCNU showed superior antitumor effects on NMU-1 murine lung tumor. In this experimental model, TCNU activity was comparable to that of drugs active on human lung cancer.

Animals↗
PubMed1989

Serum magnesium and nerve conduction velocity in uraemic patients on chronic haemodialysis.

In 18 patients on regular haemodialysis treatment, the dialysate magnesium concentration (dMg) was lowered (from 0.5 to 0.25 mmol/litre) and the correlation between serum Mg level (sMg) and nerve conduction velocity was investigated before and one year after dMg variation, in order to ascertain whether hypermagnesaemia plays a role in the pathogenesis of peripheral neuropathy in patients on regular dialysis. The normalization of sMg (from 1.27 +/- SD 0.16 to 0.98 +/- 0.09 mmol/litre) did not result in any improvement in nerve conduction velocity, though such improvement has previously been reported; however, this discrepancy could be explained by the fact that sMg was not excessively high at the beginning of the study.

Adult↗
PubMed1989

Nucleoside analogues: 8. Some isomers of B.3839, the original 5-fluorouracil/nitrosourea molecular combination, and their effect on colon, breast and lung tumours in mice.

This study describes the manipulation of secondary products arising from the synthesis of the prototypical molecular combination of 5-fluorouracil (5-FU) and chloroethylnitrosourea (CNU), B.3839, in order to investigate the effects produced by connecting the C-S-C-C-CNU chain to the 5-FU ring in different ways. The isolation of phthalimide precursors of these compounds and the transformation into CNUs is described. Anti-tumour activity of these molecular combinations against a series of experimental murine colon, lung and mammary tumours is presented. The spectrum of anti-tumour activity displayed is interesting but defies simple explanation without further detailed in vivo pharmacokinetic and metabolism studies in order to define optimal profiles for activity.

Adenocarcinoma↗
PubMed1989

Nucleoside analogues. 9. Seco-nucleoside analogues of some 5-fluorouracil/nitrosourea molecular combinations having uracil as base: synthesis and anti-tumour activity.

The synthesis of representative seco-nucleoside analogues of 5-fluorouracil (5-FU)/nitrosourea molecular combinations having uracil (U) as base instead of 5-FU is described. The anti-tumour activity of corresponding pairs of drugs is compared in experimental tumours of the mouse colon, lung and breast. These studies have demonstrated that the presence of a hydrogen or fluorine atom at pyrimidine C-5 is unimportant for the activity shown against most of the experimental tumours employed, rather that the pyrimidine cyclic urea and/or alkylthio functionalities may constitute the critical factors. One exception is the prototypical compound B.3839 and its U analogue B.3912. B.3839 is highly active against colon 38 adenocarcinoma, a tumour which is highly responsive to 5-FU, whereas most of the activity is lost in B.3912. The 5-FU release profile of some of these molecular combinations could be adequate or effective in treatment of slow-growing clinical tumours.

Adenocarcinoma↗
PubMed1989

Nucleoside analogues: 7. Effect on colon, breast and lung tumours in mice of 5-fluorouracil/nitrosourea molecular combinations incorporating alkoxy and oxidized sulphur functions.

This study considers further changes in the carrier moiety of molecular combinations of the pyrimidine antimetabolite 5-fluorouracil (5-FU) and the alkylating group chloroethylnitrosourea (CNU). Detailed chemical syntheses are described of compounds incorporating (a) a simpler alkoxy group in the 'sugar' fragment, (b) attachment of the 5-FU residue to the C-X-C-C chain on the side of the heteroatom X distal from the CNU group, and (c) higher oxidation states of the sulphur atom in the prototypical compound B.3839. Anti-tumour activity of these analogues against a series of experimental murine colon, lung and mammary tumours is described. The pattern of activity reveals that the carrier moiety is important but further pharmacokinetics and metabolism studies are required to determine structure-activity relationships.

Adenocarcinoma↗
PubMed1988

Sequence dependence of the antitumor and toxic effects of 5-fluorouracil and cis-diamminedichloroplatinum combination on primary colon tumors in mice.

Primary colon tumors of different sizes and malignancy, chemically induced by methylazoxymethanol in outbred CF-1 mice, were used to investigate the antitumor effects of 5-Fluorouracil (5FU) and cis-diammine-dichloroplatinum (DDP), given weekly i.v. as single agents or in combination. When single-drug chemotherapy was tested, DDP showed higher efficacy than 5FU. In fact, in two separate experiments a significant reduction (P less than 0.05) of tumor number (TN) and tumor burden was obtained by treatment with the optimal dose of DDP (4.5 mg/kg per injection) and not by that of 5FU (52 mg/kg). When the two drugs were combined (24-h interval), studies carried out on healthy mice treated weekly i.v. showed a lower toxicity with the same doses given in the sequence 5FU-DDP than in the opposite sequence. The two drugs, delivered in the sequence 5FU followed by DDP, statistically reduced the TN and total tumor burden compared to control mice (P less than 0.05). On the other hand, the same doses in the sequence DDP followed by 5FU did not attain significant tumor reduction. The sequence dependence of the activity and toxicity of the 5FU and DDP combination observed in this experimental model should be taken into account in the design of clinical trials.

Animals↗
PubMed1988

Response of chemically induced primary colon tumours of the mouse to flavone acetic acid (NSC 347 512).

Flavone acetic acid (FAA) is a compound with proven activity against various transplantable colon cancers in mice. In this study it was evaluated against primary colon tumours, chemically induced by methylazoxymethanol in outbred CF1 mice. FAA was given i.v. at doses of 70 or 100 or 150 mg kg-1 every 7 days for 6 weeks. Only 4 out of 60 FAA treated mice died of toxicity. FAA reduced tumour number and tumour burden compared to control mice (P less than 0.05 at least), with no apparent dose-response relationship. Antitumour activity of FAA was comparable to that of 5-fluorouracil (5-FU) used as standard. Moreover, FAA was more effective that 5-FU against large tumours. FAA levels in plasma and different tissues (including colonic neoplastic lesions) after a single i.v. dose of 150 mg kg-1 were investigated. Tumour FAA levels appear insufficient to be responsible for the antitumour activity based only on a direct FAA cytotoxic effect. The results confirm clinical interest in FAA and suggest that mechanisms other than direct cytotoxicity may be involved in its activity.

Animals↗