摘要:

Cerebral gliomas have a poor survival time even after multimodal treatment, because of the unavoidable recurrence of tumor. Several trials with a combination of old and new chemotherapies have been performed, but survival time remains generally less than 12 months. Tamoxifen (TAM) has recently been shown to inhibit the growth rate of established and low-passage human glioma cell lines. Furthermore, this drug has enabled stabilization of the clinical and radiographic picture in selected patients with recurrent glioma. Here we review published data to discuss a potential role of TAM in the multimodal postoperative treatment of cerebral gliomas.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

During topotecan analysis of clinical urine samples, an additional peak eluting just after the solvent front was observed. This potential metabolite was isolated by chromatographic methods. Mass spectrometry data along with chromatographic retention data and fluorescence characteristics showed that the isolated fractions contained two compounds, i.e. topotecan-O-glucuronlde and N-desmethyl topotecan-O-glucuronide. The concentrations of the metabolites in human urine were relatively low. When topotecan was given as a 30 min infusion at a dosage of 1.5 mg/m2daily for five consecutive days every 3 weeks, the maximal metabolite concentrations in a 24 h urine sample were approximately 10% of topotecan-O-glucuronide and 3.5% of N-desmethyl topotecan-O-glucuronide with respect to the concentration of topotecan in the urine. This is the first report demonstrating that glucuronide metabolites of topotecan are present in the urine of treated patients.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

A total of 530 patients were treated in this multicenter, double-blind, double-dummy, parallel group study to compare the anti-emetic efficacy and safety of a once daily ondansetron oral regimen with a once daily i.v. dosing regimen over a 24 h period, administered to patients prior to receiving cisplatin (50 mg/m2or greater) chemotherapy. Patients were randomized to receive a single dose of ondansetron plus dexamethasone given either orally (ondansetron 24 mg and dexamethasone 12 mg, n=262) or i.v. (ondansetron 8 mg and dexamethasone 20 mg, n=268). Complete control of emesis (i.e. no emetic episodes, no rescue and no premature withdrawal) was achieved for 85% of patients (224 of 262) in the oral group and 83% (223 of 268) in the i.v. group. No nausea was reported in 70% of patients in the oral group and 68% in the i.v. group. There were no statistically significant differences between the two groups for any of the assessments of efficacy, which included time to first emetic episode, number of emetic episodes and the worst grade of nausea occurring over the 24 h study period. Once daily ondansetron oral and i.v., in combination with dexamethasone, was well tolerated in this study. In conclusion, once daily oral ondansetron 24 mg plus dexamethasone is equally effective in the control of emesis and nausea induced by highly emetogenic chemotherapy as once daily ondansetron 8 mg I.v. plus dexamethasone.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We conducted a multlcentric phase II study on advanced colorectal cancer to determine the efficacy and toxicity of oral treatment with leucovorin (LV) plus doxifluridine (5'DFUR), a novel fluoropyrimidine derivative with proven antitumor activity In different experimental models. Thirty-six outpatients with measurable disease entered the trial and received orally LV 20 mg In the morning and in the afternoon, and 2 h later 5-DFUR 500 mg/m2 every 2 days for 3 months. Thirty-four evaluable patients underwent a total of 408 weeks of treatment. The response rate was 35%, with two complete remissions and 10 partial responses. The median survival of patients who responded to treatment (responders) was 17.1 months (range 4-32), which was significantly longer (p< 0.001) than the 6.5 months (range 2-11) of the patients who did not respond (non-responders). Therefore, after 4-8 weeks of treatment, 14 patients (41%) had an improvement in their performance status and/or stabilization of pain. General toxicity was usually mild, myelo and gastrointestinal toxicity were moderate, and there was no evidence of relevant neurological toxicity. These results show that a home therapy with oral LV-5 DFUR Is a safe and effective treatment regimen for metastatic colorectal carcinoma.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We have investigated the patterns of In vitro cytotoxicity, Induced by six newly synthesized gold and tin compounds, In three human ovarian cancer cell lines (SW 626, IGROV 1 and OVCAR-3). Four gold compounds, i.e. gold(l)lupinylsulfide hydrochloride [1] (containing a naked gold atom), triethylphosphlnogold(l)lupinylsuMde hydrochlorlde [2], triphenyl- phosphlnogold(l)luplnylsulfide hydrochloride [3] and 1,2-bls(dlphenylphosphlno)ethane bis[gold(l)lupinylsulfide] dihydrochloride [4] (all containing a gold atom coordinated with different phosphlnes), were prepared. Moreover, the triethylphosphlnogold(l)(2-diethylamino)ethylsulfide hydrochloride [5] In which the simple diethylaminoethylthiol replaced the bulky lupinylthiol was synthesized. The tin compound, triethyltin(IV)lupinylsulfide hydrochloride [6], was also studied. Comparative tests with cisplatin, the most widely used antitumor agent in ovarian cancer, were carried out In biological investigations. In vitro cytotoxicity, by MTT assay, showed that compound [4] and compound [6] exhibited Interesting antiproliferative activity in all the three cell lines (mean ICgo=1.3 and 0.7 /μM, respectively) compared to cisplatin (mean 1050=4.8 /μM). In addition, the PA-1 cell line, more sensitive to cisplatin (1050=0-6 /μM), was Included as a comparison In the study. Cell count assays confirmed the cytotoxic properties of compounds [4] and [6] against the four cell lines, reporting higher growth Inhibition potency than cisplatin, with I CM values in the sub-micromolar range.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

A phase I study of a 96 h paclitaxel Infusion with filgrastim support was performed to determine the toxicity, maximum- tolerated dose (MTD) and pharmacokinetics In patients with refractory solid tumors. In this phase I trial, the Initial paclitaxel dose was 140 mg/m2/96 h followed by filgrastim (5 μg/kg/day s.c.) beginning 24 h after the paclitaxel and continued until granulocyte recovery. Cycles were repeated every 21 days. Patients with refractory solid tumors were eligible; however, only one previous chemotherapy regimen was allowed. The dose of paclitaxel was escalated by 20 mg/m2/96 h In subsequent cohorts until dose-limiting toxicity (DLT) occurred. Pharmacokinetic analysis was performed by quantitating paclitaxel concentrations at baseline, 24, 48, 72 and 96 h after the start of the paclitaxel Infusion. Twenty-one patients were entered Into this trial of which 19 were evaluable. A total of 52 treatment cycles were administered. DLT was seen In two of four patients at 200 mg/m2/96 h, and consisted of diarrhea, mucositis and granulocytopenic Infection. The MTD of the 96 h paclitaxel Infusion was 180 mg/m2with filgrastim support. Mucosal and granulocyte toxicity were correlated with steady-state paclitaxel concentrations (C,.) greater than 0.100 μmol/l. In the presence of liver function test 1.5 times or lower than normal, metastatic liver disease did not alter paclitaxel Cu. Objective responses were observed in non-small cell lung cancer, small cell lung cancer and melanoma. The recommended phase II dose of paclitaxel infused over 96 h with filgrastim support is 180 mg/m2. Paclitaxel C,. correlate with mucosal and granulocyte toxicity. In the presence of normal enzymatic function, metastatic liver disease does not affect paclitaxel clearance.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

A 19-year-old woman with refractory juvenile granulosa cell tumors had persistent disease after PVB (cisplatin, vinblastine and bleomycin) and multiple high doses of ICE (Ifosfamide, carboplatin and etoposide) with peripheral stem cell support. She achieved stable disease for 4 months with low dose Intensity gemcitabine of 500 mg/m2/week. The planned dose had been 1250 mg/m2/week. The dose Intensity was limited by myelosuppression especially thrombocytopenia. The use of thrombopoietic, In addition to erythropoietic and myelopoietic, agents may permit higher dose intensity of gemcitabine after bone marrow ablative therapy with resulting greater anti-tumor activity.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Recent preclinal and clinical data indicate that the main mechanisms of 5-fluorouracil (5-FU) cytotoxicity depend on the mode of administration. To gather further insight into the major causes of acquired 5-FU resistance, drug-sensitive human gastric (M2), colon (HT29) and breast (MCF7) cancer cell lines were repeatedly exposed to a fixed concentration of 5-FU given either for 1 or 24 h. Although equieffective doses (ICso) of 5-FU were used, resistance to a 1 h exposure of 5-FU developed faster In all models than to a 24 h exposure. Cell lines with acquired resistance to a 1 h application of 5-FU were only partly cross-resistant to a 24 h exposure, whereas lines with resistance to protracted application of 5-FU displayed significant cross-resistance to the 1 h schedule. Resistance to methotrexate was only seen in cell lines with acquired resistance to 24 h of 5-FU. All 5-FU-resistant cell lines showed reduced incorporation of 5-FU into cellular RNA. Furthermore, elevations of thymidylate synthase were seen in all cell lines with resistance to 24 h of 5-FU but also in one cell line with resistance to a bolus schedule. No alterations In folylpolyglutamate synthase developed in the resistant cell lines. These data support the concept that the main mechanisms of 5-FU cytotoxicity depend on the mode of application. Incorporation of fluorouridine triphosphate into RNA appears to be the most important mechanism of action for 5-FU bolus schedules, whereas inhibition of thymidylate synthase becomes more important as the infusion time Is prolonged. These data could have Implications on the interaction of 5-FU given at different schedules with various other cytostatic agents.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Mitoguazone (methylglyoxal bisguanyihydrazone, methyl- GAG or MGBG) is a synthetic polycarbonyl derivative with activity in patients with Hodgkin's and non-Hodgkin's lymphoma, head and neck cancer, prostate cancer, and esophageal cancer. Mitoguazone has also recently been documented to have activity in patients with AIDS-related lymphoma. Among anticancer drugs, mitoguazone has a unique mechanism of action via interference with the polyamine biosynthetic pathway. Polyamlnes stabilize DNA structure by non-covalent cross-bridging between phosphate groups on opposite strands. In addition, mitoguazone causes uncoupling of oxidative phosphorylation. In this study, the ability of mitoguazone to induce apoptosis by inhibiting the polyamine pathway was assessed in three Burkitt's lymphoma cell lines (Raji, Ramos and Daudi) and one prostate carcinoma cell line (MPC 3). Additional evaluations were performed in two human breast cancer cell lines (MCF7 with wild-type p53 and VM4K with mutated p53) to determine whether the p53 tumor suppressor gene was required for efficient apoptosis induction. The present study demonstrated that mitoguazone Induces apoptosis In all the different human cancer cell lines tested In a concentration- and time-dependent way, and triggers a p53-independent programmed cell death in the human breast cancer MCF7 cell line.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

To evaluate potential synergistic interactions between topoisomerase I (Topo I) inhibitors, i.e. camptothecin (CPT) and topotecan (TPT), and chemotherapeutic agents known to be active in treatment of brain tumors, in vitro studies were conducted with human glioma and medulloblastoma cell lines. Tumor cells were exposed to CPT or TPT alone or in combination with cisplatin, 4-hydroperoxycyclophosphamide (4-HC), BCNU or etoposide (VP-16). Cytotoxicity was assessed by colony formation assays. Drug interactions were evaluated by means of a novel analytical model which permits statistical evaluation over a range of dose combination. Experimental results were corroborated by published models of drug interaction. Our findings indicate that in vitro cytotoxic interactions in brain tumor cells between Topo I inhibitors and alkylating agents or etoposide depend on drug dose, dose schedule and tumor cell line. Treatment of DAOY medulloblastoma cells with CPT and either cisplatin, 4-HC or VP-16 produced significant synergistic cytotoxicity over a wide range of dose combinations. When VP-16 was administered after CPT, synergy was reduced to a narrow range of dose combinations. For U251 glioma cells, incubation with CPT and cisplatin or 4HC also produced synergistic cytotoxicity over a broad range of dose combinations. By contrast, antagonistic interactions were observed after administration of CPT with BCNU or VP-16. Treatment of U251 cells with CPT and cisplatin produced synergistic or antagonistic cytotoxicity depending on the dose combination used. These findings support a role for pharmacokinetic analysis in multiagent phase II trials involving Topo I inhibitors and have Important implications for clinical trial design strategies.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID