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Biomedical subjects

G Giaccone

Publications and source records attributed to G Giaccone.

At least 199 records · Page 11Linked to original sources
PubMed1995

Teniposide for brain metastases of small-cell lung cancer: a phase II study. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: Here we report the results of a phase II study of teniposide, one of the most active drugs against small-cell lung cancer (SCLC), in patients with brain metastases. PATIENTS AND METHODS: Patients with SCLC who presented with brain metastases at diagnosis (n = 11) or during follow-up evaluation after treatment (n = 69) were treated with teniposide at a dose of 150 mg/m2 intravenously on days 1, 3, and 5 at 3-week intervals in an outpatient setting. Response in the brain was evaluated by brain computed tomography (CT) after two, six, and 12 courses. RESULTS: In 26 of 80 assessable patients, an intracranial response was seen, with a response rate of 33% (95% confidence interval, 22% to 44%). The median response duration was 5.4 months for patients with a complete response (CR) and 4.2 months for patients with a partial response (PR). Patients who required corticosteroids for peritumoral edema had a significantly lower response rate than patients who did not receive corticosteroids. Neurologic function at the start of treatment had a significant influence (neurologic function 1 better than 2, respectively, better than 3 and 4; P < .001), as did the number of cycles of previous chemotherapy (0 better than 1 to 5 cycles, respectively, better than > 5 cycles; P = .043). Grade 3/4 leukocytopenia and thrombocytopenia were seen in 3% and 39%, respectively, of 80 patients. Toxicity-related death was seen in eight patients, seven of whom were previously treated with chemotherapy. CONCLUSION: Teniposide is active against brain metastases of SCLC. It is a suitable drug for palliation, especially of patients without extensive pretreatment and with a good neurologic function and performance status. Patients previously treated with cranial radiotherapy are also candidates for this therapy. If systemic chemotherapy is considered for tumor progression outside the brain, radiotherapy of brain metastases might be omitted or delayed pending the effect of chemotherapy. The use of corticosteroids in patients with brain metastases treated with chemotherapy might influence the efficacy of the chemotherapy.

Adult↗
PubMed1995

Dose-finding and sequencing study of paclitaxel and carboplatin in non-small cell lung cancer.

A dose-finding study was set up to identify the optimal dose of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin for phase II studies in patients with advanced chemotherapy-naive non-small cell lung cancer (NSCLC). The influence of drug sequence on the toxicity and pharmacokinetics of both agents was also assessed. To develop an ambulatory regimen for palliation of advanced NSCLC, paclitaxel was infused over 3 hours with standard premedication and carboplatin over 30 minutes. Cycles were repeated every 4 weeks. At each dose level, at least six patients were randomized to receive either paclitaxel followed by carboplatin or the reverse sequence. In the second and following cycles the alternate sequence was administered. The pharmacokinetics of both paclitaxel and carboplatin were compared in the first two cycles in at least two patients per dose level. Sixty-two patients have been entered in this study. Paclitaxel was increased from 100 mg/m2 in 25 mg/m2 increments up to a maximum of 225 mg/m2 combined with a fixed carboplatin dose (300 mg/m2). Thereafter, the drug doses were increased to a maximum of 400 mg/m2 carboplatin and 250 mg/m2 paclitaxel. In 243 cycles, the most frequent side effects were neutropenia, alopecia, and mild emesis. Only one patient developed a major hypersensitivity reaction to paclitaxel. Bone pain, myalgia, and peripheral neurotoxicity occurred more frequently at paclitaxel doses above 200 mg/m2. No significant differences in toxicity or in the pharmacokinetics of either drug were observed between the two drug sequences. The pharmacokinetics of paclitaxel were nonlinear and consistent with saturation. At the highest paclitaxel dose (250 mg/m2 with carboplatin 350 mg/m2) a toxic death due to severe leukopenia, thrombocytopenia, and hemorrhage occurred. Safe doses for phase II trials in untreated NSCLC are 200 mg/m2 paclitaxel with 300 mg/m2 carboplatin. Of 50 evaluable patients, five of the six major responses were observed at paclitaxel doses of 175 mg/m2 and above, which suggests a dose-response relationship for paclitaxel in NSCLC.

Adult↗
PubMed1995

Topoisomerase II alpha gene expression in childhood acute lymphoblastic leukemia.

Previously, we showed that in vitro resistance to daunorubicin (DNR) at initial diagnosis was related to a poor long-term clinical outcome in childhood acute lymphoblastic leukemia (ALL), and that cells of relapsed ALL were in vitro more resistant to DNR than cells of untreated ALL. Topoisomerase II (Topo II) is an intracellular target for anthracyclines and epipodophyllotoxins. Decreased levels and/or activity of Topo II have been associated with multidrug resistance in cell lines. We investigated Topo II alpha gene expression in fresh leukemic samples from 19 children with untreated and 14 children with relapsed ALL using a sensitive RNase protection assay. The in vitro cytotoxicity of the Topo II inhibitors DNA and teniposide (VM26) was measured using the MTT assay, and the cell cycle distribution of leukemic samples was analyzed by DNA flow cytometry. Results showed that (1) relapsed ALL samples were more resistant to DNR, but not to VM26 compared to untreated samples; (2) large interpatient variations existed in both Topo II alpha gene expression and in vitro cytotoxicity results; (3) Topo II alpha gene expression was detectable in 29/33 childhood ALL samples with a median expression of 5% the level of a relatively chemosensitive human small cell lung cancer cell line; (4) Topo II alpha gene expression did not differ between untreated and relapsed ALL; (5) Topo II alpha gene expression was positively correlated with the percentage of ALL cells in S- and G2M-phase, but not with the in vitro cytotoxicity of the drugs tested. In conclusion, resistance to DNR in childhood ALL can not be explained by decreased levels of Topo II alpha gene expression, but additional Topo II activity studies in fresh leukemia samples may need further exploration.

Antigens, Neoplasm↗
PubMed1994

Amyloid fibrils in Gerstmann-Sträussler-Scheinker disease (Indiana and Swedish kindreds) express only PrP peptides encoded by the mutant allele.

Gerstmann-Sträussler-Scheinker (GSS) disease is a cerebral amyloidosis linked to mutations of the PRNP gene. We previously reported that the amyloid protein in the Indiana kindred of GSS is an internal fragment of prion protein (PrP). To investigate whether this fragment originates only from mutant or from both mutant and wild-type PrP, we have characterized amyloid proteins purified from patients of the Indiana and Swedish GSS families. These patients were heterozygous for the Met-Val polymorphism at PRNP codon 129 and carried a mutation at PRNP codon 198 (Phe-->Ser) and codon 217 (Gln-->Arg), respectively. The smallest amyloid subunit was a 7 kDa peptide spanning residues approximately 81 to approximately 150 in the Indiana patient and approximately 81 to approximately 146 in the Swedish patient. In both patients, only Val was present at position 129. Since Val-129 was in coupling phase with Ser-198 and Arg-217, our findings indicate that only the mutant PrP is involved in amyloid formation in both kindreds.

Amino Acid Sequence↗
PubMed1994

Antiproliferative activity of the topoisomerase I inhibitors topotecan and camptothecin, on sub- and postconfluent tumor cell cultures.

We have assessed the antiproliferative effects of a 24-hr exposure to the topoisomerase I inhibitors, topotecan and camptothecin, on two colon and one ovarian human tumor cell lines, cultured as subconfluent and as multilayered postconfluent cultures. Chemosensitivity was measured by the sulforhodamine B assay. In general, postconfluent cultures were less sensitive to these agents, yielding GI50S (drug concentrations inhibiting growth by 50%) from 1.2 to more than 6000 times higher than those of subconfluent cultures. Both compounds displayed similar effects on subconfluent cells, inducing complete growth inhibition at concentrations ranging from 0.03 to 0.5 microM. Topotecan, however, was more potent than camptothecin in two out of the three cell lines tested as multilayered postconfluent cultures. Topoisomerase I mRNA expression on postconfluent cultures was 50% lower than on subconfluent cultures in the three cell lines studied. However, we did not detect any reproducible differences in topoisomerase I protein expression and in relaxation activity of supercoiled DNA between the two types of cultures. From accumulation experiments it appeared that the peak concentration of the lactone form of topotecan as well as the area under the concentration-time curve (AUC) were 2-fold higher in the monolayer than in the multilayer cultures. Therefore, the differences in the activity of topoisomerase I inhibitors under our experimental conditions were likely due to a decreased rate of proliferation of postconfluent cells, associated with a reduction in drug uptake.

Camptothecin↗
PubMed1994

Chemosensitivity to the indoloquinone EO9 is correlated with DT-diaphorase activity and its gene expression.

EO9, a new bioreductive indoloquinone alkylating agent, requires activation by a two-electron reduction, which can be catalysed by the NAD(P)H:quinone oxidoreductase DT-diaphorase (DTD) (EC 1.6.99.2). Seven human and four murine tumor cell lines from different histological origins were evaluated for their DTD enzyme activity (evaluated using dichlorophenolindophenol and EO9 as substrates), DTD gene expression and chemosensitivity to EO9. In general the cell lines could be divided into two groups: leukemic cells which were relatively resistant to EO9 (IC50 > or = 0.5 microM) and had no measurable DTD activity, and solid tumor cells, which were more sensitive to the drug (IC50 < 0.06 nM) and contained a high DTD activity (> 90 nmol/min/mg). The expression of the DTD gene was measured by semiquantitative PCR in the human cell lines and an excellent correlation between gene expression and enzyme activity was observed (r2 = 0.94). A higher DTD gene expression also correlated with higher chemosensitivity to EO9. Protection of chemosensitivity to EO9 by dicoumarol, a strong and specific inhibitor of DTD activity, was dependent on duration of exposure and concentration of dicoumarol. Inhibition was best observed by short exposure to dicoumarol and EO9 together, demonstrating that bioactivation of EO9 by DTD is essential. In conclusion, DTD activity and expression appear to predict sensitivity to EO9 in a variety of cell lines. Evaluation of activity or expression in patients' tumor samples might predict the response to EO9.

Alkylating Agents↗
PubMed1994

Familial Gerstmann-Sträussler-Scheinker disease with neurofibrillary tangles.

Patients affected with Gerstmann-Sträussler-Scheinker disease from two families, one from Indiana and one of Swedish origin, have been studied. The patients are clinically characterized by cerebellar ataxia, extrapyramidal signs, and dementia. Accumulation of amyloid deposits and neurofibrillary tangles are the most conspicuous neuropathologic features. In the patients from the Indiana family, the amyloid contains an 11-kDa peptide, an amyloidogenic degradation product of the prion protein. The neurofibrillary tangles are composed of paired helical filaments and immunoreact with antibody to A68, an abnormally phosphorylated form of the microtubule-associated protein tau. In these families, the disease is caused by a point mutation in the PRNP gene. In the Indiana family, the mutation is at codon 198, and in the Swedish family at codon 217.

Aged↗
PubMed1994

In vitro sequence-dependent synergistic effect of suramin and camptothecin.

Suramin, a hexasulphonated naphthylurea with activity in prostatic cancer, possesses a wide variety of antitumour mechanisms of action, one of which is the inhibition of topoisomerase II. In this in vitro study, suramin was combined with the topoisomerase I inhibitor, camptothecin. Several suramin concentrations (0.2-3000 microM) were combined with camptothecin (0.4 pM-20 microM) in MCF-7 and PC3 human cancer cell line cultures. In addition, we studied the topoisomerase II and I gene expression by northern blot analysis, and the cell cycle distribution by flow cytometry, after exposure to suramin. While there was only an additive effect when suramin and camptothecin were added simultaneously, a remarkable synergism was obtained when camptothecin was added after a 3-day exposure to suramin. Topoisomerase II and I gene expression and the number of cells in S phase were significantly reduced after exposure to suramin. In conclusion, interaction of suramin with camptothecin is schedule-dependent and can be synergistic. These findings might help in identifying optimal combinations of suramin or other topoisomerase II inhibitors, with topoisomerase I inhibitors.

Camptothecin↗
PubMed1994

Clinical and pharmacologic study of multidrug resistance reversal with vinblastine and bepridil.

PURPOSE: To achieve an adequate plasma concentration of bepridil, a calcium channel blocker, which reverts multidrug resistance (MDR) in vitro, when administered in combination with vinblastine in patients with advanced colorectal cancer, a tumor characterized by high MDR1 gene expression. To study the pharmacokinetics of both drugs, tolerability and antitumor activity in relation to the MDR1 expression in tumor tissue. PATIENTS AND METHODS: Sixteen colorectal cancer patients entered the study. Bepridil was administered by central venous catheter as 5-mg/kg bolus over 30 minutes, followed by 12 mg/kg for 12 hours and 5 mg/kg for 24 hours. Vinblastine 5 mg/m2 was administered as an intravenous (i.v.) bolus 24.5 hours after the start of bepridil. MDR1/P-glycoprotein (Pgp) expression was assessed in 14 tumor samples by immunohistochemistry and RNase protection assay. RESULTS: The bepridil plasma level was greater than 2 mumol/L at the time of vinblastine administration in all patients investigated. At the dose used in the study, bepridil produced a QTc-prolongation more than 50 ms, which prevented further dose escalation. However, cardiac toxicity was asymptomatic in all treated patients, and other side effects were mild. MDR1/Pgp expression was positive in nine of 14 cases. Of fifteen patients assessable for response, one complete remission of 8 months' duration and 14 progressions were observed. The responding patient attained complete remission again when re-treated on progression with vinblastine alone. CONCLUSION: Bepridil plasma concentrations needed in vitro to modulate MDR could be achieved in this study with tolerable toxicity; however, despite most tumors being MDR1/Pgp-positive, no response was obtained that could be attributed to the drug combination. Mechanisms of drug resistance other than MDR are probably implicated in drug resistance of colorectal cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Cerebrospinal fluid levels of amyloid beta-protein precursor are low in Gerstmann-Sträussler-Scheinker disease, Indiana kindred.

We studied levels of amyloid beta-protein precursor (beta PP) in CSF from four patients affected with Gerstmann-Sträussler-Scheinker disease and one asymptomatic gene-carrier from an Indiana kindred. Levels of beta PP were decreased in all affected patients with the lowest levels occurring in the clinically most severely affected patients. Correlation of neuropathology with CSF data in three patients suggested that low beta PP in CSF may be associated with beta PP accumulation in neurites surrounding cortical and cerebellar amyloid deposits.

Aged↗
PubMed1994

A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy.

Three hundred twenty-eight patients with limited stage small cell lung cancer were enrolled in a trial to evaluate surgical treatment for such patients responding to chemotherapy. Cyclophosphamide, doxorubicin, and vincristine were administered every 21 days for five cycles. Patients achieving at least partial response who had confirmation of pure small cell histologic features by pathology review and who were fit enough for thoracotomy were randomized to undergo or not to undergo pulmonary resection. All randomized patients received radiotherapy to the chest and brain. Two hundred seventeen (66%) of the patients achieved objective response (90 complete response; 127 partial response). One hundred forty-six patients were randomized (66% of responders, 44% of all patients): 70 to surgery and 76 to no surgery. Results of surgery were 83% resection rate, 19% pathologic complete remission rate, and 9% with residual non-small cell histologic features only, for a total of 28% eradication of small cell lung cancer. The survival curves for the two arms are not different (log rank p = 0.78). Median survivals were 12 months for all enrolled patients and 16 months for those who were randomized. Actuarial 2-year survival is 20%. The results of this trial do not support the addition of pulmonary resection to the multimodality treatment of small cell lung cancer.

Adult↗
PubMed1994

DNA topoisomerases and topoisomerase inhibitors.

DNA topoisomerases are ubiquitous nuclear enzymes, essential for several steps of DNA metabolism. They have recently been shown to be specific targets of a number of anticancer agents. In this review are discussed the most recent discoveries in the physiology and the molecular biology of DNA topoisomerases, and the mechanism of interaction with drugs. In addition, alterations of DNA topoisomerases are also described, as potential responsible of drug resistance.

Antineoplastic Agents↗
PubMed1994

Preliminary results of two dose-finding studies of paclitaxel (Taxol) and carboplatin in non-small cell lung and ovarian cancers: a European Cancer Centre effort.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given as a 24-hour infusion, and carboplatin have activity in advanced non-small cell lung cancer (NSCLC) and ovarian cancer. Two dose-finding studies were initiated to identify the optimal doses for the paclitaxel/carboplatin combination when paclitaxel is given in a 3-hour infusion. The fact that the pharmacologic interaction between paclitaxel and cisplatin increases the toxicity of paclitaxel when cisplatin is given before it also prompted an investigation of the influence of drug sequence on toxicity and pharmacokinetics in the NSCLC trial. Thirty-three patients with advanced NSCLC and 11 with advanced ovarian cancer previously untreated by chemotherapy have been enrolled to date. In the NSCLC trial escalating doses of paclitaxel were given in combination with a fixed carboplatin dose of 300 mg/m2, while both drugs were escalated in the ovarian cancer study. In both studies paclitaxel was infused over 3 hours and carboplatin over 30 minutes, and cycles were repeated every 4 weeks. The most frequent side effect has been neutropenia, although this did not result in any infectious episodes. Alopecia and mild emesis also have been frequently encountered. Mild skin reactions have been reported in a few patients. Bone pain and myalgia occur more frequently at the highest paclitaxel doses. No difference in toxicity has been observed thus far between the two drug sequences in the NSCLC study. Both studies are still accruing patients as the maximum tolerated doses of paclitaxel in combination with carboplatin have not yet been reached (carboplatin 300 mg/m2 with paclitaxel 175 mg/m2 in the NSCLC study; carboplatin 400 mg/m2 with paclitaxel 150 mg/m2 in the ovarian cancer study). An investigation of maximum tolerated doses with granulocyte colony-stimulating factor support is planned thereafter.

Adolescent↗
PubMed1994

Bioanalysis, pharmacokinetics, and pharmacodynamics of the novel anticancer drug paclitaxel (Taxol).

Several high-performance liquid chromatographic assays have been reported for the analysis of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in biologic matrices. The recently developed method of using solid-phase extraction as a sample pretreatment is preferred, as it is the most sensitive assay and is also capable of detecting metabolites in the plasma of treated patients. The pharmacokinetics of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), administered in different doses and schedules, has been studied using this method. After cessation of the infusion, a three-phasic decay of plasma concentrations has been found. There are indications for nonlinear pharmacokinetics when paclitaxel is administered as a short infusion and at higher doses. Different metabolic products of paclitaxel have been detected in the plasma of treated patients. Three hydroxylated metabolites have been identified so far. Pharmacokinetics have been related with pharmacodynamics. Neuropathy, mucositis, and leukopenia correlate with pharmacokinetic parameters such as area under the plasma concentration time curve and steady-state paclitaxel levels. The hematologic toxicity of paclitaxel also has been modelled with a sigmoidal maximum effect equation with the time spent above the biologically active threshold concentration of 0.1 mumol/L as a pharmacokinetic parameters.

Animals↗
PubMed1993

Synthetic peptides homologous to prion protein residues 106-147 form amyloid-like fibrils in vitro.

Gerstmann-Sträussler-Scheinker disease (GSS) is a prion-related encephalopathy pathologically characterized by massive deposition of prion protein (PrP) amyloid in the central nervous system. The major component of amyloid fibrils isolated from patients of the Indiana kindred of GSS (GSS-Ik) is an 11-kDa fragment of PrP spanning residues 58 to approximately 150. These patients carry a missense mutation of the PRNP gene, causing a Phe-->Ser substitution at codon 198. We investigated fibrillogenesis in vitro by using synthetic peptides homologous to consecutive segments of GSS-Ik amyloid protein (residues 57-64, 89-106, 106-126, and 127-147) as well as peptides from the PrP region with the GSS-Ik mutation (residues 191-205 and 181-205, both wild type and mutant). Peptide PrP-(106-126) formed straight fibrils similar to those extracted from GSS brains, whereas peptide PrP-(127-147) formed twisted fibrils resembling scrapie-associated fibrils isolated from subjects with transmissible spongiform encephalopathies. Congo red staining and x-ray fibril diffraction showed that both straight and twisted fibrils had tinctorial and conformational properties of native amyloid. Conversely, the other peptides did not form amyloid-like fibrils under similar conditions. These findings suggest that the sequence spanning residues 106-147 of PrP is central to amyloid fibril formation in GSS and related encephalopathies.

Amino Acid Sequence↗