The activity of ketoconazole against Candida albicans in Sabouraud glucose medium was markedly influenced by pH. Minimum inhibitory concentrations of this imidazole against both a standard strain and clinical isolates ranged from 40 μg/ml at pH 3 to 0.02 μg/ml at pH 7, a greater than 1,000-fold difference.
The effect of adriamycin on HeLa S-3 cells grown in monolayers was studied. Adriamycin is a newantitumor antibiotic of the anthracycline group isolated from cultures of Streptomyces peucetius var. caesiusly. Its chemical structure is very close to that of daunomycin from which it differs only in having a hydroxyl group substituted for a hydrogen atom of the acetyl radical. The effect of adriamycin on several experimental tumor systems has recently been reported from our laboratory2). The present studies were undertaken to show the cytological effects of adriamycin on HeLa S-3 cells in vitro. Furthermore, studies were made of its action on the biosynthesis of macromolecules by HeLa S-3 cells. Thymidine-6-3H with specific activity of 5.0 Ci/mmole, uridine-5-3H with specific activity of 15Ci/mmole and leucine-4,5-3H with specific activity of 32 Ci/mmole were purchased from Daiichi Pure Chemicals Co., Ltd. Materials and Methods ChemicalsTissue culture procedures : Clone S-3 of HeLa cells was used in these experiments.This clone was cultured in Rouxbottles containing 50 ml of growth mediumwhich consisted of YLE basal medium (Earle's balanced salt solution containing 0.1 % yeastolate, 0.5% lactalbumin hydrolysate and 0.ll % sodium bicarbonate) supplemented with 10 % calf serum. For observation of the effect of adriamycin on the growth of cells, a fully grown culture was treated with 0.1 % trypsin solution, and the released cells were suspended in the above mediumto approximately 2X105cells per ml. Oneml of the suspension was inoculated into each culture tube and incubated at 37°C for 24 hours in a slanted position. All experiments on asynchronous populations were performed on cells in the logarithmic phase of growth. Adriamycin at desired concentration was added on 0 day. Three tubes
A series of compounds, which are analogues of 2,2'-dithiobis(benzamide), were synthesized and tested for in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv including resistant strains against streptomycin, kanamycin, or isonicotinic acid hydrazide. MICs of these compounds against atypical mycobacteria, Mycobacterium kansasii and Mycobacterium intracellulare were also examined. Structure-activity relationships were found in a series of (acyloxy)alkyl ester derivatives depending upon the length of alkyl carbon chain. The MIC of the most potent compound, 2,2'-dithiobis[N-[3-(decanoyloxy)propyl]benzamide] [56] was superior or at least equivalent to streptomycin, kanamycin, and ethanbutol. All the compounds showed no cross-resistance between the current antitubercular agents.
Dihydropyrimidine dehydrogenase (DPD) and pyrimidine nucleoside phosphorylase (PyNPase) are the first and rate-limiting enzymes that regulate 5-fluorouracil (5-FU) metabolism, and tumoral DPD activity appears to be a promising predictor of 5-FU sensitivity. However, the regulatory mechanisms determining these enzyme activities have not been fully understood. We investigated the biological effects of epidermal growth factor (EGF) and transforming growth factor (TGF)-α α α α Key words: Dihydropyrimidine dehydrogenase -Pyrimidine nucleoside phosphorylase -Growth factor -5-Fluorouracil sensitivity -Cervical cancer 5-Fluorouracil (5-FU) has been widely used in the treatment of a variety of neoplastic diseases, particularly cancers of the breast and digestive organs, and is given either alone or in combination with other cytostatics. We have demonstrated that 5-FU-based chemotherapy is also useful for the treatment of uterine cervical cancer.1, 2) Two main modes of action have been proposed for 5-FU through its active metabolites, 5-fluoro-dUMP (FdUMP) and 5-fluoro-UTP. FdUMP suppresses thymidylate synthetase (TS) by forming a covalent ternary complex with 5,10-methylenetetrahydrofolate, which inhibits DNA synthesis.3) 5-Fluoro-UTP is incorporated into cellular RNA, resulting in RNA dysfunction. 4) 5-FU is initially anabolized by pyrimidine nucleoside phosphorylase (PyNPase) in both pathways. Thymidine phosphorylase (ThdPase) converts 5-FU to 5-fluorodeoxyuridine (FUdR), a precursor of FdUMP. Uridine phosphorylase (UrdPase) converts 5-FU to 5-fluorouridine (FUR), a precursor of 5-fluoro-UMP, which is finally metabolized to 5-fluoro-UTP. The former enzyme is identical to platelet-derived endothelial cell growth factor (PD-ECGF) 5) and is closely associated with tumor angiogenesis.5, 6) 5-FU is initially catabolized to 5-fluorodihydrouracil (DHFU) by dihydropyrimidine dehydrogenase (DPD), mainly in the liver, then dihydropyrimidinase and β-ureido-propionase catalyze the formation of 2-fluoro-β-alanine. Several recent studies 7-10) concerned with 5-FU antitumor effects have demonstrated that tumoral DPD activity may influence 5-FU sensitivity. Thus, DPD and PyNPase are considered to be the first and rate-limiting enzymes in the chain of reactions that regulate 5-FU metabolism.Determination of tumoral DPD has become of clinical interest because elevated intratumoral DPD can influence the tumor response to 5-FU therapy as a result of increased inactivation. Etienne et al. 8) evaluated DPD activity in tumor biopsy specimens from head and neck cancer patients before administration of 5-FU and found that the tumoral/non-tumoral DPD activity ratio was higher in the non-responding patients than in those with a partial or complete response. Moreover, certain biochemical modulations to enhance the antitumor activity of 5-FU by inhibiting intratumoral DPD activity have been attempted. 11,12) The underlying differences in tumoral DPD activity result in a variable 5-FU degradation prior to 5-FU
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