摘要:

P-glycoprotein (P-gp) is a 170 kDa transmembrane glycoprotein which plays a significant role in modulating pleomorphic or multiple drug resistance (MDR) in a wide variety of human cancers like renal and colorectal carcinoma. However, its role in modulating drug resistance in other types of cancer is less well defined. The purpose of this review is to critically examine the evidence that P-gp plays an important role in producing drug resistance in astrocytic gliomas. Malignant astrocytoma is clinically resistant to most types of cytotoxic drugs, including those associated with the MDR phenotype and the cross-resistance patterns of short-term cultures derived from malignant glioma are consistent with this phenotype. Consequently, it might be expected that this tumor would express high levels of P-gp. However, immuno-histochemical findings from a number of previous studies have provided conflicting data about the expression of P-gp in these tumors, although P-gp has been consistently detected in normal brain in the endothelial cells in cerebral blood vessels and is thought to contribute to the blood-brain barrier phenomena. In order to determine if P-gp contributes to drug resistance in malignant astrocytoma, we undertook a study of P-gp expression in a panel of short-term cultures derived from these tumors in which we determined thein vitrochemosensitivity. However, immunocytochemical studies with a panel of antibodies which recognize both internal and external epitopes of the P-gp molecule have consistently failed to show the characteristic membrane staining associated with MDR in any of the cultures, including those markedly cross-resistant to vincristine and doxorubicin. One antibody, JSB-1, showed heterogeneous granular cytoplasmic staining which was unrelated to a particular pattern of drug resistance. This is probably because this antibody cross-reacts with a widely distributed cytoplasmic antigen, pyruvate carboxylase, which is present in abundance in normal astrocytes. The unexpectedly poor specificities of many of the antibodies thought to be specific for P-gp is reviewed in the context of malignant astrocytoma. In conclusion, the role of P-gp In producing drug resistance in malignant astrocytoma is questionable and further studies might more profitably concentrate on the mechanisms of resistance to DNA-damaging agents like the nitrosoureas, methylating agents or platinum-based drugs.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Advanced soft tissue sarcomas (ASTS) refractory to therapy with doxorubicin and/or ifosfamide are highly resistant to therapy with other cytotoxic agents. The efficacy and safety of raltitrexed (‘Tomudex’) was assessed in patients with ASTS refractory to one or two doxorubicin- and/or ifosfamide-containing regimens in eight centers of the EORTC STBSG group. Raltitrexed was given at 3 mg/m2as a 15 min i.v. infusion once every 3 weeks. Among the 23 patients [mean age 54 (range 25–73) years] included, 22 patients (15 males and seven females) were eligible and evaluable for response to therapy and 21 were evaluable for toxicity. Patients had previously received chemotherapy in metastatic phase (n=16), as adjuvant treatment (n=5) or both (n=1). The primary tumor was located in the trunk (n=11), in the limbs (n=8) or in the head and neck (n=3). Most patients (n=13) received two courses of raltitrexed (range 1–8). The best response was stable disease in five (23%) patients, while disease progression was noted in 17 patients (77%); the median time to disease progression was 6 weeks. The treatment was well tolerated with only one patient experiencing grade 4 neutropenia and thrombocytopenia, one patient experiencing grade 3 nausea, one lethargy, one headache, and one asthenia. Only one patient experienced febrile neutropenia. Raltitrexed as monotherapy is not an effective treatment for patients with ASTS who failed conventional chemotherapy with doxorubicin and ifosfamide.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Aplidine is a novel marine-derived antitumor agent isolated from the Mediterranean tunicateAplidium albicans. The compound is pharmaceutically formulated as a lyophilized product containing 500 μg active substance per dosage unit. Prior to i.v. administration it is reconstituted with a solution composed of Cremophor EL, ethanol absolute and Water for Injection (15/15/70% v/v/v) with further dilution in 0.9% w/v sodium chloride for infusion (normal saline). The aim of this study was to investigate the compatibility of aplidine infusion solutions with polyvinyl chloride (PVC)-containing and PVC-free administration sets, and to determine the stability of aplidine after reconstitution and further dilution in infusion solutions. Furthermore,in vitrobiocompatibility studies to estimate the hemolytic and precipitation potential of aplidine infusion solutions upon i.v. administration were conducted. In this study we show that sorption of aplidine to PVC and to a lesser extent to PVC-free administration set materials occurs. Also, most probably due to the presence of Cremophor EL in the infusion solution, significant leaching of diethylhexyl phtalate (DEHP) from the PVC administration set occurs. After reconstitution and dilution the drug is stable for at least 24 and 48 h, respectively, in glass containers when stored at room temperature (20–25 C) and amblent light conditions. We found that aplidine should be administered in infusion concentrations equal or above 28.8 μg/ml using a PVC-free administration set consisting of a glass container and PVC-free Infusion tubing. After reconstitution it must be diluted further with normal saline within 24 h after preparation and subsequently administered to the patient within 48 h. Additionally, results from the biocompatibility studies show that neither hemolysis nor precipitation of aplidine is expected upon i.v. administration.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Intoplicine (RP 60475) was selected for a phase I evaluation because it inhibits topoisomerase I and II, and has exhibited antitumor activity against a variety of preclinical solid tumor models. Intoplicine is a 7H-benzo[e]pyrido[4,3-b]indole that inhibits DNA nicking and closing reactions by stabilizing the cleavable complex, a translent Intermediate in the religation reaction involving topoisomerase I and II and DNA. Twenty-eight patients with refractory advanced malignancies who met standard phase I eligibility criteria were enrolled in a dose-escalation study of intoplicine, ranging from 7 to 420 mg/m2/day administered as a continuous 72 h i.v. infusion. Fifty-three courses were administered and evaluated. Myelosuppression (four patients, grade 3; two patients, grade 4) and hepatic toxicity (one patient, grade 3) were dose limiting at 336 mg/m2/day. No objective antitumor responses were observed. The pharmacokinetic parameters of intoplicine were investigated in 11 patients at dose levels of 112 (n=1), 224 (n=3), 336 (n=6) and 420 (n=1) mg/m2/day. Both the area under the plasma concentration versus time curves and the maximum plasma concentrations increased linearly within the dose range studied. Intoplicine content measured in whole blood exceeded that found in plasma by 3− to 7-fold, indicating that red blood cells may serve as a drug reservoir. Preclinical cytotoxic concentrations were not achieved at the dose levels studied.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Antiestrogen tamoxifen (Tam) is the most prescribed drug for the treatment of estrogen receptor (ER)-positive breast cancers. It is also used in long-term clinical trials with encouraging preliminary results as a chemopreventive agent for breast cancer. The effect of Tam on ER-negative cancers, however, is unclear. Here we reported that paclitaxel and 4-hydroxytamoxifen (4-HT) have a synergistic cytotoxic effect on the ER-negative colon cancer cell line HCT15, which is refractory to paclitaxel alone. Our results showed that 4-HT at submicromolar concentrations effectively enhanced the antiproliferative effect of paclitaxel. In addition, at 1/10 of the paclitaxel concentrations used for HCT15, 4-HT and paclitaxel also showed synergistic effect on NCI H460, an ER-negative lung cancer cell line. For both cell lines, the effective concentration for paclitaxel to inhibit cell growth was 1 log lower in the combination treatment than the concentration used in the single treatment. Cell cycle analysis showed that the combination of paclitaxel and 4-HT increased the G/M population and resulted in the increase of apoptosis in both cell lines. Enhanced early release of cytochromecfrom mitochondria may be the apoptotic pathway activated in the combination treatment in HCT15 cells.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

As analogs of the widely used anti-tumor agents,N-(2-chloroethyl)-N-nitrosoureas,N-(2-chloroethyl)-N-nitroureas andN-(2-chloroethyl)-N-nitrocarbamates were synthesized by nitration following the reaction of the appropriate amines or alcohols with 2-chloroethyl isocyanate. All tested compounds exert cytotoxic effect with IC50values of 104to 106M and most of them show somewhat higher cytotoxicity in nitrogen than in air.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

We investigated the pharmacokinetics and therapeutic efficacy of cisplatin encapsulated in polyethyleneglycol-coated long-circulating liposomes in a formulation referred to as SPI-077, in three mouse tumor models (M-109 lung carcinoma inoculated s.c., J-6456 lymphoma inoculated i.p. and A-375 melanoma inoculated s.c.). Tumor-bearing mice were injected i.v. with single doses of SPI-077 and cisplatin. For pharmacokinetic experiments, mice were sacrificed at different timepoints post-treatment. Platinum levels were determined in plasma, spleen, liver, kidneys and tumors using flameless atomic absorption spectrophotometry. Survival times and/or tumor size were recorded for therapeutic studies. The pharmacokinetic studies revealed a prolonged circulation time and enhanced tumor uptake for SPI-077. In contrast to these results, no superior antitumor activity of SPI-077 over cisplatin could be observed in all tumor models.In vitrorelease experiments showed a negligible release (below 10%) of platinum from the liposomes. An in vitro cytotoxicity assay indicated a reduced cytotoxic activity of SPI-077 in comparison to cisplatin. We concluded that SPI-077 is being delivered to the tumor sites in a low bioavail-ability form, with extremely slow release kinetics. This explains the discrepant results of high platinum concentrations in tumors and reduced therapeutic activity after administration of SPI-077.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Previous investigations have indicated the possibility to circumvent multidrug resistance (MDR) by incorporation of an anthracycline into liposomes. We examined thein vitrocytotoxicity and cellular drug accumulation of the anthracy-clines daunorubicin and doxorubicin compared with the commercially available liposomal formulations DaunoX-ome‘’ and Caelyx‘’ in human myelogenous leukemia K562 cells. The drug-sensitive parental K562/K line was compared with the P-glykoprotein (P-gp)-expressing cell lines K562/Dnr and K562/Vcr. Two cell lines with reduced levels of topoisomerase II (K562/Nov and K562/lda) were also included. The cytotoxicity was determined by fluorometric microculture cytotoxicity assay and the cellular drug levels were determined by high performance liquid chromatograghy. There was a strong inverse correlation between P-gp levels and celluar drug accumulation (p= 0.83,p=0.04) and cytotoxicity (p=-0.95,p=0.01) of daunorubicin. Also the cytotoxicity of DaunoXome and doxorubicin was related to P-gp levels (p=-0.96,p=0.01 andp=-0.90,p=0.07, respectively). Caelyx did not show any cytotoxic effect due to impaired cellular uptake of the pegylated liposome. Regardless of the P-gp levels of the treated cells, DaunoXome showed the same cytotoxic effect despite lower intracellular accumulation (range 22–47%), compared with conventional daunorubicin.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID