摘要:

AG957 is a tyrosine kinase antagonist which prior studies had shown inhibits p2106bcr abltyrosine kinase activity and K562 chronic myelogenous leukemia cell growth. We report here the effects of AG957 on the physical state of p210bcr abnand its signaling adapter molecules She and Grb2 in K562 cells. After exposure to AG957, the amount of tyrosine-phosphorylated native p2106bcr abl210kDa) p210bcr ablThiseffect is seen after [32p]orthophosphate and [35S]methionine labeling. Material suggesting the involvement of p210bcr ablin high molecular weight complexes also appears using anti-She, anti-Grb2 and antiphosphotyrosine antibodies. AG957 also actsin vitroto shift native p2106bcr ablin anti-p210bcr ablor anti-Grb2 immunoprecipitates to higher molecular weight forms under conditions where the drug can also act as an antagonist of p210bcr ablm autokinase activity. Incubation with dithiothreitol inhibits the appearance of - 210 kDa forms of p210bcr Bbl in theIn vitroreaction. These results lead to the hypothesis that AG957 does not act simply as a reversible tyrosine kinase antagonist, but can alter the normal amounts and physical associations of molecules important in tyrosine kinase signaling. These effects likely reflect covalent cross-links induced by the drug.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Cremophor EL (CreEL), a polyethylene castor oil used as a vehicle for cyclosporin A and taxol, reverses P-glycoprotein- mediated drug resistance. The vehicle in an i.v. dosage form of PSC 833, [3´-keto-Bmt1]-[Val2]-cyclosporin, contains CreEL and has been presumed to have the potentiation of the reversal activity of PSC 833. To examine this possibility, we compared reversal activities of CreEL and PSC 833 against multidrug resistance (MDR) in vitro and in vivo. Both CreEL and PSC 833 inhibited P-glycoprotein-mediated efflux of [3H]vincristine from adriamycin-resistant myelogenous leukemia K562. The sensitization of multidrugresistant cell lines to anticancer drugs by CreEL and PSC 833 was selective to MDR-related agents, suggesting a specific interference of the P-glycoprotein function by the two MDR modulators. The concentration-dependent activity of the modulators demonstrated that CreEL is at least 100 times less potent than PSC 833. The in vivo reversal effects of CreEL alone and PSC 833 in the vehicle were investigated in multidrug-resistant tumor-bearing mouse models. In vincristine-resistant P388 leukemia-bearing mice, neither i.v. nor i.p. administration of CreEL even at 1440mg/kg enhanced the antitumor activity of adriamycin. The in vivo negligible activity of CreEL was confirmed in an HCT-15- bearing athymic mouse model. In contrast, PSC 833 significantly enhanced the antitumor activity of adriamycin in the in vivo models. The reversal activity of CreEL restricted to in vitro leads us to conclude that the vehicle containing CreEL did not potentiate the activity of PSC 833 in the tumor-bearing mouse models

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

A decrease in the intracellular drug concentration in resistant cells as compared to sensitive cells is one of the characteristics of the MDR phenotype. P-glycoprotein (Pgp) is thought to be responsible for an active efflux of some lipophilic drugs such as anthracyclines. Anthracyclines such as daunomycin are highly effective anticancer agents but induce a well-described, while incompletely explained, cardiac toxicity. In this study, we investigated the MDR phenotype in rat myocardium in terms of gene expression, detection of Pgp and indirect evaluation of Pgp function. A clear mdr1a gene specific expression in rat cultured myocardial cells and cardiac tissue was detected by RTPCR. The incorporation of [3H]daunomycin in myocardial cell cultures was studied with and without reversing agents. Daunomycin was found to have a high accumulation in cardiac cells illustrated by a C1/Ce ratio of 2890. This high accumulation was moderately but significantly (p 0.05) increased in the presence of a MDR reversing agent such as verapamil, PSC 833 or S9788. These results suggest that blockade of the Pgp in humans may result in an increased toxicity of several Pgp substrates in normal tissues like the myocardium.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The expression of heat shock proteins hsp27, hsp60, hsp70, hsp90α and hsp90β in extracts of three cell lines (LoVo DxR,KBChR8-5 and S180 DxR) expressing the MDR (multidrug resistance) positive phenotype as well as in the sensitive parental lines has been investigated. We present evidence that heat shock protein hsp90β is associated with the P-glycoprotein (Pgp or P170) one of the most prominent components of the drug resistance machinery. In the doxorubicin-resistant cell line LoVo DxR, but not in the sensitive parental line, hsp90β is expressed constitutively as shown by Northern blotting. The expression of hsp90β in the sensitive LoVo cell line, however, can be induced by exposure of the doxorubicin-sensitive parental cell line to different stress factors (dexamethasone, doxorubicin, heat treatment or cadmium chloride). We were able to demonstrate that hsp90β can be co-precipitated along with Pgp and vice versa. In native agarose gels both proteins migrated together as one single band as shown by Western blot analysis. This intracellular protein protein interaction may present a mechanism for the modulation of Pgp function possibly by a stabilization of the protein which seems to be attributed to hsp90β (in the human colon carcinoma cell line and in the murine cell line S180). Antisense experiments with oligonucleotides directed against hsp90β and Pgp, respectively, showed a synergistic effect of the selected hsp90β antisense oligonucleotide in combination with the previously described Pgp antisense oligonucleotide in reducing the doxorubicin resistance. The hsp90β antisense oligonucleotide when applied in addition to the Pgp antisense oligonucleotide increased the doxorubicin sensitivity of the resistant human colon carcinoma cell line 2-fold. On the contrary, the hsp90βantisense oligonucleotide alone in contrast to the Pgp antisense oligonucleotide alone did not cause a reduction of the chemoresistance. Moreover, Pgp half-life was reduced in the presence of both antisense oligonucleotides as compared with an incubation with an anti-Pgp antisense oligonucleotide alone

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The measurement of monoethylglycinexylidide (MEGX test) is considered a sensitive method for the evaluation of hepatic metabolic capacity. The multidrug chemotherapy CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2) is widely used in breast cancer patients but very few clinical studies have investigated its possible liver toxicity. We have prospectively evaluated the possible acute liver toxicity after a cycle (i.e. two courses) of CMF by means of the measurement of standard liver function tests and of MEGX, i.e. the main lidocaine (Lid) metabolite after the i.v. injection of Lid. Consecutive patients (n=15), aged 43 68 years, were radically operated on because of Mo primary breast cancer and candidates for adjuvant CMF because of nodal axillary involvement (pN1) were studied. Tests were performed before the first (given at day 1) and 48 h after the second course (given at day 8) of an i.v. CMF regimen to be repeated every 28 days. Full blood count, serum ALT, AST, γ-GT, alkaline phosphatase and albumin were measured with standard methods. To investigate the appearance of MEGX, blood samples were taken before, and 5, 10, 15, 20, 25, 30 and 60 min after i.v. Lid injection. MEGX serum concentration was measured by means of a fluorescent polarization immunoassay. We found no significant variation between pre- and post-CMF standard liver function tests with the exception of ALT levels, which, however, decreased (mean 48%, p 0.05). The MEGX serum concentration was significantly increased over the sampling time period and the 42% mean rise was statistically significant (p · 0.001). Moreover, the post-CMF increase of circulating MEGX was steeper than the basal pre-CMF values. The slopes relating to the curves of MEGX formation over the first 20 min were 3.30 and 2.24, respectively (p 0.001). In conclusion, no hepatic acute toxicity was observed during the CMF chemotherapy. Further studies are required to understand the meaning of the unexpected MEGX rise.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We have reported earlier that camptothecin (CPT) incorporated into multilamelar liposomes of appropriate lipid composition displayed effective anti-tumor activity with minimal host toxicity in a nude mouse model xenographed with the human breast carcinoma Clouser nut 1. To investigate this observation further, we have determined the differential effects of CPT on the Clouser tumor cells as well as normal vascular (BVEC) endothelial cells in culture. We report here that Clouser cells are 200-fold more sensitive to CPT (IC50=4.0 nM) than the normal endothelial cells (IC501µM) as assayed by MTT; however, CPT demonstrates a potent anti-proliferative activity on both cell lines at low drug concentrations as measured by [3H]thymidine uptake. At higher concentrations (25.0 nM), however, the Clouser cells maintained a higher percentage of cells capable of incorporating [3H]thymidine. No significant differences in the levels of topoisomerase I protein and in vitro enzymatic activity were seen; although, the Clouser cells showed a 2-fold greater incidence of cleavable complex formation by CPT in vivo. Based on the data presented here, we propose that the selective cytotoxic activity of CPT towards tumor cells may be a function of the tumor cells' reduced ability to prevent cleavable complex formation. We also propose that the antitumor effect of CPT may be enhanced in vivo by its anti-proliferative effect on vascular endothelial cells which are normally solicited to promote tumor growth.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The aim of this study was to evaluate whether radiolabeled iodoerythronitroimidazole (IETNIM) could predict the radiosensitization effect on tumors. Tumor-bearing mice were irradiated at a dose of 25, 31 and 37 Gy after the injection of IETNIM. They were also exposed to 37 Gy radiation at 35, 70, 140 and 240 min after the i.p. injection of IETNIM. After the irradiation, tumor growth assays were conducted and the effect of IETNIM as a radiosensitizer was estimated as enhancement factor (EF). Tumor uptake was measured at 35, 70, 140 and 240 min after i.p. injection of [131I]IETNIM, which were the same intervals used in the radiosensitization study. EF of IETNIM in mice treated with 25, 30 and 37 Gy irradiation was 0.72, 0.98 and 1.28, respectively. EF of IETNIM in mice irradiated at 35, 70, 140 and 240 min after the injection was 1.50, 1.69, 1.46 and 1.08, which corresponded to the tumor uptake and blood clearance of [131I]IETNIM. [131I]IETNIM may be a suitable radiopharmaceutical to predict the radiosensitization effect of misonidazole analogs on tumors.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The effects of 3-hydroxy-4-methoxycinnamic acid (3H4MCA) and 3,4-dimethoxycinnamic acid (3.4DMCA) on body weight, organ weight, and the contents of putrescine, spermidine and spermine in 15 different tissues were examined in rats that had been given these compounds for 5 days. In 3H4MCA-treated rats, the weight of the spleen was significantly increased, while none of the other organs showed any significant changes. A diet containing either 3H4MCA or 3.4DMCA should not be taken by patients bearing cancers in the seminal vesicles, spleen or liver, and a diet containing 3.4DMCA should not be taken by patients bearing cancers in the testis, kidney, muscle, small intestine or brain (cortex) because of the significant increases in polyamines, which are associated with a risk of cancer growth, in these tissues. However, a diet containing 3H4MCA is recommended for the management of cancers in the skeletal muscle (femoral), tongue, small intestine (jejunum), stomach, lung and brain based on reductions in polyamines which stimulate tumor growth. A diet containing 3.4DMCA is also recommended for cancer in the prostate, thymus and stomach for the same reason. In addition, a synergic therapeutic effect for the treatment of cancers in these tissues may be anticipated by a combination of such a diet with anti-cancer drugs which reduce polyamine levels. The metastasis of cancers in these tissues may also be inhibited by the reduction of polyamines by these acids. The ratio of spermidine to spermine was significantly higher in the lung of 3H4MCA-treated rats, and lower in the seminal vesicle, thymus, kidney, heart, tongue, stomach and lung of 3,4DMCA-treated rats, than in control rats. The present experiment indicated that cancer patients should pay careful attention to endogenous polyamines in tissues bearing tumors induced by chemicals in ingesta and anti-cancer drugs, in addition to exogenous polyamines.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Certain series of 2-thiohydantoin derivatives, carrying various substituents at position 5 such as 5-bromo-2-thienylmethylene, 5-(2-carboxyphenylthio)-2-thienylmethylene and 2-methylene-4H-thieno[2,3-b][1]benzothiopyran-4-one, were evaluated for their antitumor activity. Compound 5-(5- bromo-2-thienylmethylene)-3-morpholinomethyl-2-(2,3,4,6- tetra-O-acetyl--D-glucopyranosylthio)hydantoin proved to possess a broad spectrum antitumor activity against a wide range of different human cell lines of nine tumor subpanels causing both cytostatic and cytotoxic effects, resulting in full panel median growth inhibition (GI50) and total growth inhibition (TGI), with a median lethal concentration (LC50) at 15.1, 41.7 and 83.2βM, respectively. On the other hand, compound 5-(5-bromo-2-thienylmethylene)-2-thiohydantoin and compound 5-(5-bromo-2-thienylmethylene)-3-phenyl-2- (2,3,4,6-tetra-O-acetyl-bb-D-galactopyranosyl-thio)hydantoin showed potential selectivity against leukemia cell lines. Further derivatization of these compounds, deduced from the obtained tentative structure activity relationships, may lead to more potent agents

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Patients with hepatocellular carcinoma (HCC) are highly compromised by failing liver function. To retain good compliance in the administration of uracil and ftorafur (UFT) in such patients, an intermittent schedule for oral administration of UFT was expected to have the same effect as daily continuous use without affecting liver function. A pharmacological pilot study was carried out to confirm the efficacy of this schedule. Sixteen patients with HCC who underwent hepatectomy were given UFT 200 mg b.i.d. for five consecutive days. Blood samples were drawn before the last administration of UFT and at the operation (2 days after the last administration of UFT), and the tumor and adjacent liver tissue were collected. The concentration of ftorafur (FT), 5-fluorouracil (FUra) and uracil (Ura) in serum and liver tissue were measured. Oral administration of UFT 200 mg b.i.d. resulted in a trough level of FT, FUra and Ura in serum of 9.4 g/ml, 13.3ng/ml and 64.2 ng/ml, respectively. At the operation, FT and FUra in serum had decreased significantly. However, FUra in tissue was still higher than that in serum, in contrast to the results for FT and Ura. There was no difference in the concentration of FUra between the tumors and adjacent liver tissues. No side effect was noted in any of the patients. These results indicated that an intermittent schedule for the administration of oral UFT is not only tolerable but also effective because a sufficient concentration of FUra in the liver tissue is reached and maintained.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID