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891.
Edward R. Block Anne E. Jennings John E. Bennett 《Antimicrobial agents and chemotherapy》1973,3(6):649-656
Isolates of Cryptococcus neoformans from six patients were obtained before and after unsuccessful therapy with 5-fluorocytosine (5-FC). Post-therapy isolates exhibited massive and stable 5-FC resistance. The frequency of drug-resistant mutants in susceptible isolates of C. neoformans was <0.001% (70.4 +/- 17.9 per 10(7) cryptococci), whereas mutant frequencies in resistant isolates approached 100%. Non-drug-induced, spontaneously appearing 5-FC resistant mutants were documented in four susceptible isolates of C. neoformans by use of the statistical method of fluctuation analysis. Mutation rates on these same four isolates ranged from 1.2 x 10(-7) to 4.8 x 10(-7). Total intracellular uptake and incorporation of cytosine-5-(3)H (CyH(3)) and 5-fluorocytosine-2-(14)C (5-FC(14)) into a trichloroacetic acid-insoluble fraction were markedly reduced in six isolates with in vivo-acquired resistance when compared with susceptible pretreatment strains from the same patients. Five of these six isolates also had acquired massive resistance to 5-fluorouracil (5-FU), suggesting that a mutation in the uridine-5'-monophosphate pyrophosphorylase was responsible for drug resistance. The sixth isolate, which remained susceptible to 5-FU, appeared to have a defect in a cytosine-specific permease accounting for 5-FC resistance. A single isolate with in vitro-acquired 5-FC and 5-FU resistance had no reduction in uptake or incorporation of CyH(3) or 5-FC(14). The mechanism of resistance in this isolate is discussed. 相似文献
892.
The ability of a range of trypanocidal drugs, including a number known to be active inTrypanosoma cruzi infections were tested againstTrypanosoma musculi infections in the mouse. The ability of these drugs, particularly in their ability to eliminate the cryptic phase ofT. musculi infections remaining in the kidneys, was investigated and their activity against this phase ofT. musculi largely paralleled their known activity againstT. cruzi infections. It is suggested that this could be used as a preliminary screening test for potentialT. cruzi-active drugs. 相似文献
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896.
Paclitaxel induces the phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1 through a Cdk1-dependent mechanism 总被引:3,自引:0,他引:3
Initial chemotherapeutic treatment triggers a stress-related response, which can lead to an increase in the expression of survival proteins. In this study we examine whether paclitaxel (PTX) alters the expression and/or phosphorylation of the translation initiation proteins, eukaryotic initiation factor 4E (eIF-4E) and 4E-binding protein (4E-BP1), a suppressor of eIF-4E in the dephosphorylated state. We found that PTX induced the hyperphosphorylation of 4E-BP1 in the breast cancer cell line, MDA MB 231, which reduced its association with eIF-4E, but did not alter the expression and phosphorylation of eIF-4E. The hyperphosphorylation of 4E-BP1 correlated with G2/M accumulation and with an increase in the phosphorylation of cdk1 substrates. Cotreatment with a histone deacetylase inhibitor (an indirect inhibitor of cdk activity), purvalanol A and roscovitine (direct cdk inhibitors), and the reduction of cyclin B expression using RNA interference decreased the hyperphosphorylation of 4E-BP1 in PTX treated cells. The hyperphosphorylation of 4E-BP1 by PTX increased the association of eIF-4E with eIF-4G, whereas cotreatment with purvalanol A inhibited the association of eIF-4E with eIF-4G in PTX treated cells. Taken together, our data suggest that PTX-increases the functional level of eIF-4E by promoting the hyperphosphorylation and release of 4E-BP1 through a cdk1-dependent mechanism. 相似文献
897.
Grau E Oltra S Orellana C Hernández-Martí M Castel V Martínez F 《Oncology research》2005,15(7-8):393-398
Neuroblastoma and pheochromocytoma have the same embryonal origin. They originate from neural crest cells, and they usually affect suprarenal glands. The SDHB gene encodes the B subunit of succinate dehydrogenase, a protein implicated in the electron transport chain and Krebs cycle. Some mutations have been described in this gene in pheochromocytoma, and this gene could be an appropriate candidate for its study in neuroblastoma given its localization in 1p35-36. The aim of this study was to analyze neuroblastoma tumors in order to assess a possible implication of this gene in neuroblastoma development. We studied 28 neuroblastoma tumor samples from different stages. Mutation research in genomic DNA was carried out after individual amplification of each of the eight SDHB exons by SSCP analysis and sequencing of those samples with migration pattern variants. No variant was found except for three polymorphisms in four neuroblastoma samples. The first polymorphism was a synonymous A-->C change in the third position of codon 6 (exon 1). The other two polymorphisms were a TTC insert at the 5' flanking intron sequence of exon 5 in a stretch of seven TTC repeats. Upon the basis of posterior microsatellite instability and hypermethylation promoter studies, which were not significant, we can conclude that the SDHB gene, a positional candidate gene, is unlikely to be related to either initiation or tumoral progression in neuroblastoma. 相似文献
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900.
Inhibition of experimental colon cancer metastasis by the GABA-receptor agonist nembutal 总被引:2,自引:0,他引:2
Thaker PH Yokoi K Jennings NB Li Y Rebhun RB Rousseau DL Fan D Sood AK 《Cancer biology & therapy》2005,4(7):753-758
Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter, and GABA receptors have been recently detected on epithelial colon cancer cells. Nembutal (pentobarbital) is a barbiturate with GABA-agonistic effects. We demonstrate that GABA receptors are present on colon cancer cell lines (KM12SM, HT29, RKO). Nembutal (0.1-500 microg/ml) continuous exposure resulted in an IC50 level of 58 microg/ml for the KM12SM cells and 120 microg/ml for the HT29 cells. Nembutal reduced cellular cAMP concentration in colon cancer cells and resulted in a dose and time dependent decrease in MMP-2 and MMP-9 levels. In the KM12SM intracecal injected mice, 9 of 10 mice in the metaphane group developed a primary tumor (mean weight = 2.16 g +/- 0.76) compared to 7 of 10 mice in the nembutal group (mean weight = 0.41 g +/- 0.21, p = 0.03). In the KM12SM intrasplenic injected mice, the tumor weight in the spleen was 85% smaller in the nembutal group compared to the metaphane group (p = 0.008). In the HT29 injected mice, the metaphane group and nembutal group had similar tumor incidence, but combined tumor weight (primary tumor and liver metastases) was significantly higher in the metaphane group (1.61+/- 0.45 g) versus 0.07 +/- 0.05 g; p = 0.008. The incidence of liver metastases in the nembutal group was zero compared to eight out of nine in the metaphane group. To the best of our knowledge, this is the first evidence that nembutal is a potent inhibitor of primary colon cancer and metastasis. These findings may have therapeutic implications for the treatment of colon and other cancers. 相似文献