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Biomedical subjects

F Zunino

Publications and source records attributed to F Zunino.

At least 145 records · Page 8Linked to original sources
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↗
PubMed1992

Identification of the product of two oncogenic rearranged forms of the RET proto-oncogene in papillary thyroid carcinomas.

In papillary thyroid carcinomas, we have identified two tumor-specific rearrangements of the RET proto-oncogene leading to the formation of different transforming fusion products sharing the tyrosine kinase (tk) domain of the proto-oncogene and designated ptc-1 and ptc-2. We have analysed ptc-1 and ptc-2 products by immunoprecipitation with specific anti-RET antibodies followed by immunoblotting with the same reagent or with antibodies specific for phosphotyrosine (P-tyr) residues. The anti-RET antibodies were reactive with 64-kDa (p64ptc-1) and 81-kDa (p81ptc-2) proteins from lysates of ptc-1 and ptc-2 transformed cells, respectively, and identified two proteins of 140 kDa and 160 kDa from extracts of SK-N-SH, a neuroblastoma cell line previously shown to express two differently glycosylated forms of the normal RET product. The anti P-tyr antibodies, while detecting the same p64ptc-1 and p81ptc-2 proteins from ptc-1 and ptc-2 extracts, did not show any specific band in the neuroblastoma lysates. An additional set of experiments led us to conclude that, whereas the normal product of the RET proto-oncogene is a membrane-associated receptor-like molecule not intrinsically phosphorylated on tyrosine, both oncogenic forms of RET, ptc-1 and ptc-2, are constitutively phosphorylated on tyrosine, display an 'in vitro' autophosphorylation activity, are translocated from the membrane to the cytoplasm and are apparently unaffected by protein kinase C modulation.

3T3 Cells↗
PubMed1991

Modulation of epidermal growth factor receptor tyrosine phosphorylation by tumor necrosis factor.

The effects of tumor necrosis factor (TNF) on epidermal growth factor (EGF) receptor tyrosine phosphorylation were investigated in Swiss 3T3 cells, which are sensitive to TNF action. At cytotoxic levels, TNF produced an appreciable inhibition of EGF-induced autophosphorylation of the receptor. A similar inhibition was detected even after prolonged treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) which produces down-regulation of protein kinase C (PKC). According to this finding, TNF does not induce phosphorylation of the 80 kDa PKC-specific substrate. These results support the hypothesis that the inhibition of EGF receptor tyrosine phosphorylation is not mediated via stimulation of PKC activity in intact Swiss 3T3 cells.

Animals↗
PubMed1991

Protein kinase C activation by anthracyclines in Swiss 3T3 cells.

The effects of the anti-cancer anthracyclines doxorubicin and daunorubicin on the activity of protein kinase C (PKC) were examined in intact Swiss 3T3 cells. The 2 drugs stimulated the phosphorylation of an 80K phosphoprotein found to be identical to that generated in response to the PKC activator 12-O-tetradecanoylphorbol-13-acetate as indicated by gel electrophoresis and peptide mapping. The effect of doxorubicin was dose-dependent in the range 10(-5) to 10(-3) M and was not associated with a detectable translocation of PKC activity from cytosol to the cell membrane. Doxorubicin and daunorubicin were found to increase the incorporation of phosphate into phosphatidic acid, phosphatidylinositol 4-monophosphate and phosphatidyl inositol 4,5-bisphosphate. In addition, the anthracyclines induced a rise in inositol phosphates, thus indicating a stimulation of the breakdown of phosphoinositides. These data are consistent with an indirect mechanism of PKC activation by anthracyclines. We propose that diacylglycerol, which is derived from the hydrolysis of phospholipids, (including the phosphoinositides), by activation of phospholipases, could mediate PKC activation. The described effects, involving cell-signal-transducing pathways, emphasize a new aspect of the cellular actions of these anti-tumor agents.

Animals↗
PubMed1991

Prevention of doxorubicin-induced cardiomyopathy by reduced glutathione.

The aim of the present investigation was to evaluate the potential cardioprotective effect of reduced glutathione (GSH) against the delayed cardiomyopathy induced by doxorubicin (DXR) in a well-documented rat model. DXR was administered i.v. at a weekly dose of 3 mg/kg for a total of 4 doses; 250 or 500 mg/kg of GSH was given i.v. 10 min before and 2 h after each DXR injection, resulting in a total weekly dose of 500 or 1000 mg/kg, respectively. The development of cardiotoxicity was monitored in vivo by means of electrocardiography (QaT duration), and was evaluated by measuring the contractile performance of isolated atria and by light and electron microscopy of left ventricular samples excised 5 weeks after the last DXR administration. DXR was found to impair body weight gain and to produce an irreversible and time-dependent prolongation of QaT, a decrease in myocardial contractility of isolated atria and typical morphologic alterations, including myocyte vacuolization and myofibrillar loss. Pretreatment with GSH at a dose of 500 mg/kg x 2, but not at 250 mg/kg x 2, partially prevented the impairment of body weight gain, QaT prolongation in ECG and the decrease in myocardial contractility of isolated atria induced by DXR. Alterations of the morphologic pattern were also significantly reduced in animals receiving the higher dose of GSH. Determinations of the cardiac non-protein sulfhydryl group content showed that GSH, at doses higher than or equal to 500 mg/kg, significantly increased this parameter, irrespective of the presence of DXR. In conclusion, the present data indirectly support the hypothesis that oxidative damage is involved in DXR cardiotoxicity and indicate that maintenance of the reduced thiol pool could be an important issue in myocardial protection.

Animals↗
PubMed1991

The role of topoisomerase II in drug resistance.

The conventional laboratory approach to study the mechanisms of drug resistance has been the selection of drug-resistant cell lines by continuous exposure to cytotoxic agents. Such lines, which are selected for resistance to a single agent, frequently display cross-resistance to a number of cytotoxic agents that are unrelated in both structure and proposed mechanism of action. Multidrug-resistant cells display reduced drug accumulation, which is the result of overexpression of a surface glycoprotein (P170). Although resistance to multiple antitumor agents is a common clinical problem in the treatment of cancer, the precise role of the P-glycoprotein-mediated mechanism in human tumors remains to be established. Many alterations in multidrug-resistant cells selected in vitro have been identified. The concomitant expression of multiple phenotypic differences, which appear to be favored by continued and prolonged drug exposure, makes analysis of critical individual resistance pathways more difficult. However, multiple factors may also be involved in the development of clinical resistance. Recent studies have identified alterations in DNA topoisomerase II activity and function as an alternative mechanism that contributes to the multidrug-resistance phenomenon or is responsible for a different type of drug resistance. The precise nature of these changes remains unclear. Available evidence supports the view that expression of the enzyme is an important determinant of cell sensitivity to DNA topoisomerase poisons, but that other changes involved in regulation of enzyme function and/or in the cellular processing of drug-induced DNA damage may be critical in determining the differential pattern of cell response to antitumor agents.

Animals↗
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

A feasibility study of high-dose cisplatin and 5-fluorouracil with glutathione protection in the treatment of advanced colorectal cancer.

On the basis of previous studies supporting that glutathione (GSH) reduced cisplatin nephrotoxicity we have designed a new regimen in the treatment of advanced colorectal cancer, which included GSH as a modulator of cisplatin-induced toxicity. Eleven untreated patients with measurable metastatic colorectal cancer received 5-fluorouracil (750 mg/m2, daily continuous infusion for days 1-5) and cisplatin (40 mg/m2 1 hour-infusion for days 6-8) given every 4 weeks. Reduced glutathione (2.5 g) was delivered i.v. prior to each cisplatin infusion. Toxicity was minimal and reversible and included nausea/vomiting (11 cases), mild neurotoxicity (4 cases) and leukopenia (2 cases); only 2 patients showed moderate and transient increases of serum creatinine (less than 2 mg/dl) and BUN. Renal function impairment was also monitored by magnesemia levels and urinary marker enzymes indicating minimal cumulative nephrotoxicity. Out of 10 evaluable patients, only 2 partial responses were observed. The median survival was 9 months (range 5-26). The study was closed, since the preliminary results do not suggest any therapeutic advantage in adding cisplatin to 5-fluorouracil in the present schedule, even using an intensive regimen. Indirect evidence suggests that these disappointing results are not the consequence of interference of GSH on the cytotoxic efficacy of cisplatin. The lack of incidence of severe toxicity of this regimen supports the role of reduced glutathione as a potential protective against cisplatin nephrotoxicity. Although these preliminary results suggest that further studies with the present regimen in this disease are not warranted, in view of its safety this program deserves evaluation in the treatment of neoplastic diseases responsive to 5-fluorouracil/cisplatin.

Adult↗
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↗
PubMed1990

Photodynamic therapy by topical meso-tetraphenylporphinesulfonate tetrasodium salt administration in superficial basal cell carcinomas.

The efficacy of an originally developed photodynamic approach, using topical administration of tetraphenylporphinesulfonate as the photosensitizer, was evaluated in a series of 292 basal cell carcinoma lesions (less than 2-mm thick) in 50 treated patients. The lack of indication for conventional therapies was the main selection criterion. The photosensitizing agent (2% solution) was topically applied at 0.1 ml/cm2, followed by light irradiation with a dye laser emitting at 645 nm (120 or 150 J/cm2). After initial treatment, all lesions responded, with 273 (93.5%) complete responses. Recurrences were observed in 29 (10.6%). A second application of photoradiation was performed in 15 persistent lesions and 11 relapsed lesions, producing 19/26 complete responses. Our results suggest that this technique can be considered a promising alternative treatment modality in selected cases of superficial basal cell carcinomas.

Aged↗
PubMed1990

Comparison of DNA cleavage induced by etoposide and doxorubicin in two human small-cell lung cancer lines with different sensitivities to topoisomerase II inhibitors.

In an attempt to clarify the role of drug-induced protein-associated DNA breaks (i.e., DNA topoisomerase II-mediated DNA cleavage) in the cytotoxic activity of doxorubicin and etoposide, their cellular effects were compared in 2 human small-cell lung cancer (SCLC) lines, characterized by differential sensitivity to DNA topoisomerase II inhibitors. These drugs were selected for comparative studies since they are among the most effective agents in the treatment of SCLC. H146 and N592 cell lines were obtained from pleural effusion and bone-marrow aspirate of pretreated patients, respectively. Both cell lines grew as floating aggregates with similar doubling times (30 and 33 hr for N592 and H146 cells, respectively). Although, immediately after 1 hr exposure to equitoxic drug levels, the extent of DNA cleavage produced by doxorubicin was markedly lower than that produced by etoposide, DNA lesions produced by doxorubicin persisted and even increased following drug removal. In contrast, an almost complete disappearance of etoposide-induced DNA breaks was noted 1 hr after drug removal. Resealing of strand breaks was faster in N592 than in H146 cells. These findings suggest that reversal of these lesions plays a major role in cell survival rather than the occurrence of DNA breaks immediately following drug exposure. This observation is consistent with the view that inhibition of DNA re-ligation rather than stimulation of DNA cleavage is the critical step for drug action. The different response of these cell lines to cytotoxic action of the topoisomerase inhibitors is associated with a differential drug effect on DNA integrity (detected as DNA double-strand breaks and DNA-protein cross-links). However DNA lesions were comparable when cells were exposed to equitoxic drug levels. The observation that etoposide-induced DNA breaks were similar in isolated nuclei from both cell lines suggests that drug-target interaction is modulated in a different manner in the intact cell. As indicated by doxorubicin uptake and retention, cellular drug pharmacokinetics do not account for the different drug response of the studied SCLC lines, presumably, reflecting a different extent of DNA break formation and/or a different cytotoxic consequence of DNA damage.

Carcinoma, Small Cell↗
PubMed1990

Sequence-selective topoisomerase II inhibition by anthracycline derivatives in SV40 DNA: relationship with DNA binding affinity and cytotoxicity.

Topoisomerase II mediated double-strand breaks produced by anthracycline analogues were studied in SV40 DNA. The compounds included doxorubicin, daunorubicin, two doxorubicin stereoisomers (4'-epimer and beta-anomer), and five chromophore-modified derivatives, with a wide range of cytotoxic activity and DNA binding affinity. Cleavage of 32P-end-labeled DNA fragments was visualized by autoradiography of agarose and polyacrylamide gels. Structure-activity relationships indicated that alterations in the chromophore structure greatly affected drug action on topoisomerase II. In particular, removal of substituents on position 4 of the D ring resulted in more active inducers of cleavage with lower DNA binding affinity. The stereochemistry between the sugar and the chromophore was also essential for activity. All the active anthracyclines induced a single region of prominent cleavage in the entire SV40 DNA, which resulted from a cluster of sites between nucleotides 4237 and 4294. DNA cleavage intensity patterns exhibited differences among analogues and were also dependent upon drug concentration. Intensity at a given site depended on both stimulatory and suppressive effects depending upon drug concentration and DNA sequence. A good correlation was found between cytotoxicity and intensity of topoisomerase II mediated DNA breakage.

Amsacrine↗
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

Fluorinated anthracyclines: synthesis and biological activity.

A number of fluorine containing derivatives of daunomycin and Adriamycin have been synthesised with a fluorine substituent located on the C-9 side chain. They included the p-trifluoromethyl-(4) and p-fluorobenzoate (3) esters of Adriamycin and the trifluoro-ethyl-hydrazones of Adriamycin (2) and daunomycin (1). The less polar derivatives (esters 3 and 4) appear to enter HeLa cells more readily than the polar derivatives (hydrazones 1 and 2) as indicated by the rates and extent of cellular uptake and the uptake was by facilitated diffusion. All four fluorinated derivatives were less active than their parent anthracyclines, but the difference was less pronounced when considering specific potency. The fluorinated derivatives (1-4) behave sufficiently similar to daunomycin and Adriamycin to enable their use as fluorine probes in 19F NMR physicochemical and cellular studies of anthracyclines.

Antibiotics, Antineoplastic↗
PubMed1990

Efficacy and safety of high-dose cisplatin and cyclophosphamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer.

Recent efforts to improve the response rates in advanced ovarian cancer with the use of high-dose cisplatin have been limited by unacceptable toxicity. Based on experimental and clinical studies indicating that reduced glutathione (GSH) is a protective agent against cisplatin-induced toxicity, a new high-dose regimen including GSH as a chemoprotector was designed in an attempt to improve the efficacy and therapeutic index of cisplatin. A total of 40 consecutive patients with stage III (bulky) and IV ovarian carcinoma were treated with cisplatin (40 mg/m2 daily for 4 consecutive days) and cyclophosphamide (600 mg/m2 i.v. on day 4). The treatment was repeated every 3-4 weeks for five courses unless progression or severe toxicity occurred. Before each cisplatin administration, patients received GSH (1,500 mg/m2) i.v. over 15 min, with a standard i.v. hydration (2,000 ml fluid) without diuretics. Debulking surgery was initially attempted in 18 patients and, after 2-3 courses, in 16 patients; it could not be carried out in 6 patients. Three patients were not evaluable for response because they prematurely discontinued their treatment. In all, 23 patients (62%) achieved complete clinical remission (negative second-look laparotomy in 16), with an overall (complete + partial) response rate of 86%; 2 patients achieved disease-free status following second surgery. Nausea/vomiting was the most severe acute toxic effect; myelosuppression was acceptable. Renal impairment was effectively prevented by GSH. Neurotoxicity that was not associated with motor dysfunction was the most significant cumulative toxicity in patients (24/32) receiving 4-5 courses. The results of this study indicate that the use of GSH is a safe new method for high-dose cisplatin administration. This regimen is well-tolerated and very effective in ovarian cancer patients with bulky disease and warrants further evaluation.

Adult↗
PubMed1990

Effect of amrinone on anthracycline-induced lethal and cardiac toxicity in mice and rats.

The protective role of amrinone against toxicity of anthracyclines was examined in both mice and rats. These two anthracyclines were selected since they are characterized by different patterns of toxicity. In contrast to doxorubicin, the 4'-deoxy derivative did not cause delayed mortality. The results of this investigation indicate that amrinone is an effective protective agent against acute lethal events induced by both anthracyclines. However, the inotropic agent did not reduce the delayed mortality produced by doxorubicin. This parallels the apparent lack of prevention of doxorubicin-induced myocardial toxicity in CD rats, as determined by ECG changes and by morphologic alterations following multiple drug administrations. The administration of amrinone did not interfere with the antitumor activity of 4'-deoxy-doxorubicin against C-26 colon tumor.

Amrinone↗