摘要:

Vesnarinone has been shown to be a unique anti-proliferating, differentiation-inducing and apoptosis inducing drug against several human malignancies, including leukemia and several solid tumors. Furthermore, vesnarinone potentiates the effect of conventional cytotoxic chemotherapy or radiation therapy. Combination of differentiation-inducing therapy by vesnarinone with conventional chemotherapy or radiation therapy might be second- or third-line therapy in patients with advanced cancer. Analysis of the molecular mechanisms of the tumor differentiation therapy by vesnarinone might provide selective and targeted molecules for novel tumor dormancy therapy.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Esophageal and gastric cancer have a poor prognosis, and chemotherapy is rarely of long-term benefit. This may be related in part to heterogeneity of chemosensitivity and to constitutive resistance to individual cytotoxic drugs. This study aimed to demonstrate the degree of heterogeneity of chemosensitivity between tumors. We have examined the heterogeneity of chemosensitivity in esophageal and gastric cancer specimens (n=85) using anex vivoATP-based chemosensitivity assay (ATP-TCA). A variety of chemotherapeutic agents were tested. Sixty-four specimens were endoscopic biopsy samples; the remainder were from resection specimens. Cells were obtained from 62 specimens (73%). Eight assays were infected due to contamination/infection of the biopsy material, giving an evaluability rate of 87%. Analysis of the data showed considerable heterogeneity of chemosensitivity. The most active single agents identified by the assay were mitomycin C (56% sensitivity) and 5-fluorouracil (5-FU; 42% sensitivity). Exposure of tumor cells to combinations of drugs showed ECF (epirubicin, cisplatin, 5-FU) and mitomycin C+5-FU to be moderately active regimens. Other experimental drug combinations showed greater activity. There is a marked heterogeneity of chemosensitivity in esophageal and gastric cancers. The degree of heterogeneity observed suggests that the ATP-TCA could be used to individualize chemotherapy by selecting agents for particular patients. This approach provides the rationale for a trial of ATP-TCA-directed therapy to determine whether individualization of chemotherapy might improve patient response and survival.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

E7070 is a novel sulfonamide anticancer agent that arrests the G1/S phase of the cell cycle. Preclinical and phase I studies have demonstrated non-linear pharmacokinetics (PK) of the drug. A population PK analysis revealed that the human plasma concentration–time data were best described by a three-compartment model with non-linear distribution. We have studied thein vitrointeraction of14C-radiolabeled E7070 with red blood cells (RBC) and its binding to plasma proteins in the concentration range where non-linearity in disposition was observed in humans to get more insight into the behavior of the drug. After the addition of E7070 to whole blood at 37°C, the drug is taken up or binds to RBC in a concentration-dependent manner. The addition of sodium azide, however, did not result in a decrease of drug uptake by RBC, indicating passive diffusion processes. A non-linear increase in drug uptake was observed at incubation concentrations above 4 μg/ml E7070 in whole blood. This non-linearity was confirmed by lower partition coefficients between RBC and plasma at higher incubation concentrations (from 2.37 at 4 μg/ml to 0.31 at 200 μg/ml). The plasma protein binding of E7070 was high (98–99%) and linear in the concentration range studied (20–200 μg/ml). In conclusion, E7070 in whole blood is preferentially bound to RBC and exhibits high plasma protein binding. The non-linear distribution of E7070 in humans can be caused, in part at least, by saturable binding of E7070 to RBC.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

This study was designed to examine the effect of rutin and cinchonine on the uptake and metabolism of idarubicin (IDA) in the isolated perfused rat lung. IDA (2 mg) was infused for 2 min into the truncus pulmonalis in the presence of P-glycoprotein (P-gp) modulators cinchonine (1 μM) or rutin (6 μM). (Rutin is also known as an aldo–keto reductase inhibitor.) Venous outflow samples were collected up to 60 min, and the concentration of IDA and its primary metabolite idarubicinol (IDOL) were measured by high-performance liquid chromatography) with fluorescence detection. Thereafter, the tissue concentrations of IDA and IDOL were determined in the lung (n= 5 in each group). The estimated mean transit times for IDA in the treatment groups (MTTcinchonine= 21.8±3.5 min; MTTrutin= 20.1±5.0 min) were significantly higher than in the control group (11.6±2.1 min). Both cinchonine and rutin significantly enhanced the lung tissue concentrations of IDA (1.7- and 2.4-fold), as well as of IDOL (2.1- and 2.4-fold). Cinchonine and rutin also increased the outflow recovery of IDOL 2.6- and 2.7-fold, respectively. The results suggest that uptake kinetics of IDA into the rat lung is partly controlled by a P-gp efflux pump and its inhibition enhances the accumulation of IDA.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Our aim was to assess the pharmacokinetics of a low-dose schedule of paclitaxel in combination with radiation therapy in patients with brain tumors. Eighteen patients received 20–50 mg/m2paclitaxel as a 1-h infusion 18–24 h before radiation with 2 Gy on 5 consecutive days. In total, 156 plasma samples from 13 patients and 38 urine samples from nine patients were collected and analyzed by a validated capillary electrophoresis method. Data analysis was done using NONMEM with a two-compartmental model and proportional error model. No signs of non-linearity in the pharmacokinetic parameters were observed in this dosing range. The median cumulative urinary excretion was 2.4% (range 0.86–7.72%) of the given dose. Plasma clearance was found to be 6.71 l/h±70% and central volume of distribution was 3.64 l±79% (population mean ± interindividual variability, respectively). At the time of the radiation, i.e. 24 h after administration with the lowest dose of 20 mg/m2, the mean concentration of paclitaxel was 0.038 mg/l (0.045 μM) in plasma. We conclude that even with the lowest dose of 20 mg/m2paclitaxel, plasma concentrations at the time of radiation are achieved which are radiosensitizingin vitro.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Venlafaxine (Effexor; Wyeth Lederlé) has previously shown therapeutic effects for the management of chronic and neuropathic pains. We report here the efficacy of venlafaxine upon acute neurosensory symptoms secondary to oxaliplatin toxicity. A dose of 50 mg of venlafaxine was given orally at the beginning of the oxaliplatin infusion. Patients did not experience any or very low paresthesias, even in the cold. As the results were very dramatic and reproducible, we propose that venlafaxine may be of use in the daily management of oxaliplatin-related neurosensory toxicity.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We have investigated whether variability in the apoptotic pathway may account for the differential susceptibility to apoptosis-induction by 9-nitrocamptothecin (9-NC) in cell subpopulations derived from the human ovarian cancer cell line, SKOV-3. Quantitative differences in the apoptotic fractions of cells were assessed by flow cytometry, whereas major regulatory and executing components of the apoptotic machinery were investigated by Western blot analysis using specific antibodies. The results indicate that indeed the apoptotic pathway was activated by 9-NC in some, but not all, cells of the SKOV-3 cell line, suggesting that 9-NC alone may partially be effective for treatment of patients with ovarian cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The aim of this study was to assess the efficacy and toxicity of a combination of dacarbazine (D) and fotemustine (F) administered to a homogenous group of patients with recurrent or progressive glioblastoma multiforme (GBM). Thirty-one patients with computed tomography or magnetic resonance imaging scan evidence of recurrent or progressive GBM after first-line chemotherapy with nitrosoureas as well as radiation therapy were given a combination of D (200 mg/m2) and F (100 mg/m2). At 30 min after termination of D administration, F was given over 60 min. Treatment was performed in an outpatient setting every 21 days. A total of 140 cycles (range 1–12 cycles; median 4 cycles) was administered. One partial response (3%) lasting for 11 weeks was observed. Sixteen (52%) patients reached stable disease lasting between 7 and 94 weeks. Median survival from start of the D/F combination was 45 (range 10–150) weeks. Median time to progression was 17 (3–101) weeks for all patients. Major toxicity was myelosuppression resulting in exclusion from study in seven (23%) patients [due to thrombocytopenia common toxicity criteria (CTC) grade 2 persisting longer than 3 weeks in three patients, due to thrombocytopenia CTC grade ≥3 in three and due to leukopenia CTC grade 3 in one patient]. No other toxicity than alopecia occurred. We conclude that the D/F combination is a well-tolerated second-line regimen and can be administered in a complete outpatient setting. D/F shows efficacy even in nitrosourea-pretreated patients and justifies further investigation.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Cisplatin induces mainly a peripheral sensory neuropathy, but occasionally may also induce an encephalopathy with or without seizures. We describe the clinical signs and symptoms of cisplatin encephalopathy. The clinical events in three patients that developed seizures and encephalopathy with focal signs are described. Two patients completely recovered, one patient developed a focal status epilepticus, refractory to antiepileptic treatment, and died due to ongoing seizures. Post-mortem examination of the central nervous system in this patient showed an ischemic lesion in the left temporal area and mild gliosis of the white matter. One patient was rechallenged with cisplatin after which he developed a second episode of encephalopathy. We conclude that physicians using cisplatin chemotherapy should be aware of this rare complication.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID