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Biomedical subjects

G Pratesi

Publications and source records attributed to G Pratesi.

At least 73 records · Page 4Linked to original sources
PubMed1996

Biochemical and pharmacological activity of novel 8-fluoroanthracyclines: influence of stereochemistry and conformation.

In an attempt to better understand the role of the cyclohexene ring (ring A) in the biochemical and pharmacological properties of anthracyclines related to doxorubicin and daunorubicin, we investigated the effects of introduction of a fluorine atom at position 8 of idarubicin (4-demethoxydaunorubicin) on drug molecular conformation and biochemical and pharmacological activities. The study showed that the stereochemistry of the substituent at position 8 influenced the "half-chair" conformation, so that in the (8R)-fluoroepimer the A ring retained the alpha half-chair conformation, which is the most stable for natural compounds (i.e., daunorubicin and doxorubicin), and the (8S)-fluoroepimers preferred the beta half-chair conformation. The (8R)-fluoroepimer was more effective than the (8S)-fluoroepimer and idarubicin in stimulating topoisomerase II-mediated DNA cleavage. Similarly, the epimer with the alpha conformation was markedly more potent than the (8S)-epimer as a cytotoxic agent in a variety of human tumor cell lines and was more effective as an antitumor agent in the treatment of an ovarian carcinoma xenograft. In addition, 8-fluoro derivatives were able to overcome the resistance to doxorubicin in a number of human tumor cell lines expressing different mechanisms of resistance. In conclusion, these findings provide evidence that drug interactions involving the external (nonintercalating) moiety of the anthracycline chromophore play an important role in determining pharmacological properties, including drug ability to induce DNA cleavage, and therefore their antitumor efficacy.

Animals↗
PubMed1995

Successful local regional therapy with topotecan of intraperitoneally growing human ovarian carcinoma xenografts.

The therapeutic effects of intraperitoneal topotecan, a water-soluble camptothecin analogue, were investigated in two models of human ovarian carcinoma xenografted intraperitoneally into nude mice: the IGROV-1 tumour, which originated from an untreated patient, and the A2780 tumour, selected for resistance in vitro to cisplatin (A2780DDP). In IGROV-1 tumour-bearing mice, the optimal dose (10 mg kg-1) of topotecan, given intraperitioneally every 4 days for four occasions markedly increased survival time over control mice (300 T/C%) and cured 4/9 mice, and such effects were not achieved by any of the clinically available drugs tested, i.e. cisplatin carboplatin and doxorubicin delivered intraperitonally according to their optimal doses and schedules. In the treatment of A2780DDP tumour-bearing mice, topotecan was very effective since, at dose levels of 6.6 and 10 mg kg-1 every 4 days for four occasions, 15/18 mice survived more than 100 days, and most of them (12/15) were found to be tumour free. The high responsiveness of this tumour to topotecan might be related to the elevated expression of the target enzyme topoisomerase I. From these results, intraperitoneal treatment with topotecan appears to be a promising approach in the therapy of refractory ovarian cancer confined to the peritoneal cavity.

Animals↗
PubMed1995

The role of the glutathione-dependent system in tumor sensitivity to cisplatin: a study of human tumor xenografts.

BACKGROUND: Glutathione, the most important intracellular thiol, has been implicated in modulating tumor cell sensitivity to alkylating agents and cisplatin. However, the role of the glutathione-dependent detoxification system in mediating cisplatin resistance of human tumors remains unclear. DESIGN: Glutathione content and related enzyme activities were assessed in a series of human tumor xenografts representative of responsive (i.e., small-cell lung cancer and ovarian carcinoma) and resistant tumor types (i.e., non-small-cell lung cancer and colorectal carcinoma), in an attempt to establish a correlation with response to cisplatin treatment. RESULTS: The pattern of tumor response to cisplatin treatment for tumors selected in the two panels corresponded to the one expected from the clinical experience, since drug-induced tumor growth inhibition ranged from 70% to 100% in the group of sensitive tumors and from 20% to 60% in the group of resistant tumors. No correlation was observed between glutathione level and cisplatin response in the resistant tumor panel. An inverse correlation was found for glutathione-S-transferase activity level and tumor response only in the panel of chemoresponsive tumors. In the latter panel, the only unresponsive tumor (POCS) showed the highest glutathione level in the entire series investigated. No significant correlation was found between other enzymes investigated and tumor response to cisplatin treatment. In addition, a very low activity of gamma-glutamyltranspeptidase was found to be associated with sensitive tumors. CONCLUSIONS: Although glutathione may have a role in modulating cisplatin cell sensitivity, it is unlikely that alteration in glutathione level and metabolism is a primary mechanism of cisplatin resistance in human tumors, since: a) no significant correlations were found between glutathione level and response to cisplatin treatment in a series of chemosensitive and chemoresistant human tumor xenografts; b) a marked increase in glutathione level might be responsible for cisplatin resistance but, in contrast to findings on cell systems selected in vitro for resistance, it is not a frequent event in human tumors.

Animals↗
PubMed1994

Preclinical phase II studies in human tumor xenografts: a European multicenter follow-up study.

BACKGROUND: The EORTC New Drug Development Office has initiated a multicenter collaborative program to evaluate the use of human tumor xenografts to predict phase II clinical activity. A first study confirmed the efficacy of doxorubicin and inactivity of amsacrine against human tumor xenografts (Boven et al., Cancer Res: 52, 5940, 1992). In the follow-up study reported here, the activities of cisplatin, AZQ (diaziquone), pazelliptine and retelliptine have been evaluated against a panel of 40 established tumor lines grown subcutaneously in nude mice. DESIGN: The xenografts used represent carcinomas of the breast, colon, head+neck, ovary, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) and melanoma. Drugs were administered intravenously on days 0 and 7. Doses were for cisplatin 5 mg/kg, AZQ 3-7 mg/kg, pazelliptine 20-80 mg/kg and retelliptine 6-12.5 mg/kg and were selected to give a median loss of about 10%-15% body weight. RESULTS: When activity was defined as a specific growth delay > 1 and a tumor growth inhibition > 50%, then cisplatin demonstrated activity in 15 of 40 xenografts tested (3 of 5 breast, 1 of 6 colon, 0 of 5 head+neck, 2 of 6 NSCLC, 4 of 7 SCLC, 1 of 5 melanoma and 4 of 6 ovarian cancers); AZQ was active in 23 of 38 xenografts (2 of 3 breast, 2 of 7 colon, 4 of 5 head+neck, 3 of 6 NSCLC, 6 of 6 SCLC, 2 of 5 melanoma, 4 of 6 ovarian cancers); pazelliptine was active in 2 of 38 xenografts (1 of 5 breast cancers, 1 of 5 melanoma) while retelliptine was active in 1 of 39 xenografts (a breast cancer xenograft) tested. CONCLUSIONS: These results are reasonably consistent with the clinical activity of cisplatin, but overpredict the clinical efficacy of AZQ. Since pazelliptine and retelliptine are investigational compounds, the clinical phase II studies will provide a prospective test for this model. The results of the present study and the previous one indicate that the human tumor xenograft model could be suitable for predicting the activity of novel compounds to be developed for treatment of cancer patients.

Animals↗
PubMed1994

[Arterial pressure in idiopathic calcium nephrolithiasis].

Hypertension and calcium nephrolithiasis show some common features, such as the high prevalence of hypercalciuria and of elevated urinary sodium excretion. 28 patients with idiopathic calcium stone disease and 17 normals were studied: all the subjects were evaluated for the mean arterial pressure, and for the metabolic risk factors for calcium stone disease. The mean arterial pressure proved to be higher in patients with calcium nephrolithiasis than in normals. In normals the mean arterial pressure showed a direct relationship with the urinary calcium, while in the group of stone patients it had a direct relationship with the urinary sodium excretion. The lack of relationship between the mean arterial pressure and calcium excretion, in patients with calcium stones, suggests an impaired tubular calcium handling in such patients.

Blood Pressure↗
PubMed1994

Amyloid bone disease and highly permeable synthetic membranes.

The effect of different highly permeable membranes on amyloid bone disease (ABD) was retrospectively evaluated in patients on renal replacement therapy (RRT) in our Unit with a dialytic age of more than 4 years. A group of 36 patients (age 60 +/- 12 years) after a variable period (28 +/- 29 months) on hemodialysis with cuprophane membrane (CU-HD), were moved to HDF with a reinfusate volume of 22 +/- 1 1/session, for a period of 65 +/- 26 months using the following membranes: AN69 1.6 m2, PAN 1.8, PMMA 2.1, PS 1.3, polyamide (PA) 1.3 and 1.6. Bone x-rays of wrists, hips and shoulders were taken annually and the presence of ABD was evaluated according to generally accepted criteria. ABD occurred in 4 patients after a period of 73 +/- 30 months on CU-HD only; it developed in 4/7 patients an AN69, in 4/6 on PAN, in 3/5 on PMMA, in 3/5 on PS; no patient of the 13 on PA developed ABD. Comparing patients on PA with those on other synthetic membranes, no significant difference was found in dialysis time (73 +/- 19 vs 83 +/- 28 months) as well as in age (59 +/- 13 vs 61 +/- 11 years) at ABD on set, when present. These data strongly encourage prospective studies enrolling more patients for a longer period of observation in order to evaluate possible differences on ABD development among various synthetic membranes.

Amyloidosis↗
PubMed1993

Importance of orthotopic implantation for human tumors as model systems: relevance to metastasis and invasion.

Transplantation of human tumors into immunodeficient athymic nude mice has become an important experimental approach to study the biology and the treatment of human cancer. Most human tumor xenograft experiments have employed subcutaneous injection procedures, but the main limit of this technique is the lack of metastasis from the subcutaneous site. The possibility of producing experimental metastasis by intravenous injection of cells in the animals has been known for a long time, and it has been recently reported that tumorigenic properties and metastatic ability of human cancer can be altered by transplantation of the tumor into its organ or tissue of origin in the recipient animals (orthotopic transplantation). In this paper we review (1) the principal techniques of orthotopic injection of most solid tumors, (2) the most recent techniques to achieve experimental metastases, and (3) the methods for preparing tumor cell suspensions from human surgical specimens suitable for transplantation into animals. These animal models should be used for a more appropriate evaluation of new antitumor treatments including the ones targeted to inhibit metastatic spread.

Animals↗
PubMed1993

New reinfusate composition in high UF haemodiafiltration: electrolyte solution combined with bicarbonate.

When high-permeability membranes are employed, high UF should be used in order to obtain optimal uraemic toxin removal and to avoid backfiltration. A high UF requires the infusion of an electrolyte solution including Ca2+ and Mg2+ which cannot be associated with bicarbonate in prepackaged solutions because of the risk of precipitation; therefore acetate or lactate are used as buffers. This study evaluated whether bicarbonate can be infused together with an electrolyte solution in high UF HDF, and if so, the clinical advantages that could be obtained by substituting acetate with bicarbonate in the reinfusate. In 12 patients on postdilutional high UF (121 +/- 10 ml/min) HDF (Qb 400, Qd 500 ml/min, dialysate containing Na, 141 +/- 2; K, 2.5; Ca, 3.5; Mg, 0.7; Cl, 111 +/- 2; acetate, 3; bicarbonate, 34 mEq/l; TMP 400 mmHg), an acid bag (Na, 128; K, 4; Ca, 7; Mg, 2; Cl, 141; acetate, 8 mEq/l), and a basic bag (Na, 150; HCO3, 80; Cl, 70 mEq/l), each containing 2 litres, were simultaneously infused through a Y connection. The final composition of reinfusate at the drip-chamber, combined with the above dialysate, allowed a negative intradialytic mass balance for Na, K, Mg and a positive one for Ca, acetate, to maintain prepostdialytic plasma values of these ions as well as bicarbonate close to normal limits. Furthermore, in five high-risk patients, clinical data were evaluated on high UF HDF, infusing a solution containing either acetate or bicarbonate, and an improvement of vascular stability was observed with the bicarbonate reinfusate.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1993

Nucleoside analogues. 13. The effect on anti-tumour activity of varying the uracil 5-substituent and the point of attachment (N1 or N3) of the uracil moiety in seco-nucleoside nitrosoureas.

The high activity against colon tumours in the mouse of nitrosoureas linked to seco-nucleosides with 5-fluorouracil or uracil as base component led us to synthesize and test similar drugs carrying other 5-substituted uracils attached by either N1 or N3. Not only were some of the new drugs active against the solid MAC 13 and against mammary and lung tumours, but unlike earlier compounds were particularly effective (especially N3 and alkoxy drugs like B.4083) against the ascitic MAC 15A, causing some cures. Further, these agents are valuable tools in the study, using modern techniques, of bifunctional alkylation of biological macromolecules, a vital principle of experimental cancer chemotherapy about which our knowledge is still very incomplete.

Animals↗
PubMed1992

Current approaches to new drug development in cancer chemotherapy.

This review summarizes and discusses current developments of new antitumor agents, with particular reference to mechanism of action, preclinical efficacy and interest for clinical evaluation. A progress is appreciable in the study of analogues of existing agents and in the identification of new series of cytotoxic compounds with a mechanism of action somewhat similar to that of conventional cytotoxic drugs. Advances in knowledge of tumor cell biology and biochemistry offer the prospect of identifying new targets for a selective drug action. The value of this new drug discovery approach remains to be established.

Animals↗
PubMed1991

The exponential-Gompertzian tumor growth model: data from six tumor cell lines in vitro and in vivo. Estimate of the transition point from exponential to Gompertzian growth and potential clinical implications.

The published growth data were examined for six tumor cell lines (FSA, Line 1, MCA-11, EMT6/RO, MGH-U1, MLS) grown in vivo and in vitro as monolayer cultures and as multicell spheroids cultured under different experimental conditions. Serial estimates of tumor sizes were fitted by Gompertzian equations obtained with a non-linear computerized program. When the growth equations of the same tumor growing in different experimental conditions were compared, the Gompertzian parameters alpha 0 (initial specific growth rate) and beta (retardation factor) showed a strong linear correlation in all the examined lines, with no exception. This occurrence supports the exponential-Gompertzian growth model, where an early exponential phase (which is virtually not influenced by exogenous factors) is followed by a Gompertzian phase, the characteristics of which are greatly dependent on environmental conditions. The transition between the two phases was estimated to occur when tumor size reached 10(2)-10(4) cells, depending on the cell line. This kinetic change in tumor growth may be clinically relevant as regards cytotoxic treatments. It could explain some consequences of delays in adjuvant (postoperative) chemotherapy observed in clinical trials on primary breast cancer.

Animals↗
PubMed1991

Anti-tumour activity of flavone acetic acid (NSC 347512) in mice--influence of immune status.

Flavone acetic acid (FAA) is a synthetic flavonoid with dramatic pre-clinical anti-tumour activity involving a vascular component in its mechanism but no clinical effects have been seen to date. As FAA also has immunomodulatory activity, immunological factors might explain differences in activity between mouse and man. This study examines the influence of host immune status on the anti-tumour activity of FAA. Two human colon tumour xenografts (COBA, HT-29) fail to respond to FAA in nude mice. The lack of activity of FAA against HT-29 xenografts cannot be explained on the basis of limited drug bioavailability as achievable plasma, and tumour levels of FAA are similar to those seen in sensitive murine colon tumours. The immune status of the host also influences the activity of FAA against two transplantable tumours of the mouse colon. Both these tumours are highly responsive to FAA in their normal NMRI hosts, but neither tumours exhibited significant growth delay in thymectomised NMRI or nude hosts. Histological examination of treated tumours revealed significant areas of haemorrhagic necrosis in all three hosts. These data suggest a clear immunological component in the mechanism of action of FAA which is separate from the previously described haemorrhagic necrosis.

Adenocarcinoma↗
PubMed1991

Differential efficacy of flavone acetic against liver versus lung metastases in a human tumour xenograft.

A human ovarian carcinoma, IGROV-1, was xenografted into different sites (i.p., s.c., i.v., and intrasplenically) in nude athymic female mice to investigate the pattern of antitumour efficacy of FAA and compare it to that of doxorubicin and cisplatin, two established cytotoxic drugs. Ascitic and lung-growing tumours totally failed to respond to FAA, whereas s.c. and liver-growing tumours were significantly growth inhibited. This pattern of activity differs from that achieved by the two conventional cytotoxic drugs, which were active against the IGROV-1 tumour growing in all of the tested sites. These studies indicate that cytotoxicity is not the major determinant of FAA antitumour efficacy even against human tumour xenografts. Moreover, the dramatic difference between the sensitivity of lung and liver tumour colonies demonstrates the great importance of the site of tumour growth for FAA efficacy.

Animals↗
PubMed1990

Relationships among tumor responsiveness, cell sensitivity, doxorubicin cellular pharmacokinetics and drug-induced DNA alterations in two human small-cell lung cancer xenografts.

In an attempt to understand the underlying cellular/biochemical factors of sensitivity/resistance in human small-cell lung cancer (SCLC), 2 SCLC tumor lines were compared with respect to tumor responsiveness to drug treatment, cell sensitivity, cellular doxorubicin accumulation, and DNA topoisomerase-II-mediated DNA cleavage. The tumor lines growing in nude mice with similar growth characteristics (doubling time around 10 days) were selected since one (POCI tumor) was found to be hypersensitive and the other (POSG tumor) resistant to doxorubicin treatment. The pattern of anti-tumor drug response of the doxorubicin-resistant tumor was atypical (i.e., non-adherent to the well-characterized multi-drug-resistant phenotype), since it responded to vincristine. The markedly different in vivo tumor response reflected the intrinsic cellular sensitivity to doxorubicin. No correlation was found between cellular drug accumulation and doxorubicin sensitivity following in vitro exposure to the drug. In agreement with this observation, the expression of mdr-I gene was undetectable in these tumors. Thus, in the POSG tumor, resistance to doxorubicin occurred without expression of the P-glycoprotein and reduction of cellular drug accumulation. In contrast, the extent of DNA cleavage produced by doxorubicin was markedly higher in the doxorubicin-hypersensitive than in the doxorubicin-resistant tumor. These results, taken together with previous observations in SCLC cell lines, support the important role of DNA topoisomerase-mediated effects in the sensitivity of SCLC to doxorubicin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗