Bactericidal and cytotoxic effect of combination of norfloxacin and 5-fluorouracil

Using the agar dilution technique, we examined the in vitro antibacterial activity of 5-fluorouracil and norfloxacin alone and in association against several bacterial strains. When administered in association, the two drugs did not antagonize each other in tests carried out on strains both sensitive and resistant to penicillins, cephalosporins, aminoglycosides, tetracyclines; furthermore their respective antibacterial properties remained largely unimpaired. The cytotoxic activity and the antitumoral effect of a combination of 5-fluorouracil and norfloxacin was determined in cultured tumor cells, and in mice bearing Ehrlich ascites carcinoma. No significant interference with the cytotoxic activity and antitumoral activity of 5-fluorouracil was observed.     

Antibacterial and cytotoxic effect of ceftazidime-mitoxantrone association

Microbial infections are a major problem in tumor-bearing and in immunocompromised patients. In such conditions it is of paramount importance to know the possible interactions between anti-tumor and antimicrobial drugs. In the present work we investigated the relationship between Ceftazidime and Mitoxantrone. Ceftazidime and Mitoxantrone were tested alone and in combination for antibacterial activity against different strains of Gram- and Gram+ bacteria. The cytotoxic effect of combination Mitoxantrone-Ceftazidime was determined in cultured P388 leukemia cells. No interference with the antibacterial activity of Ceftazidime or with the cytotoxic activity of Mitoxantrone was observed.     

Effect of adriamycin on CFUGM at plasma concentrations found following therapeutic infusions

The effect of adriamycin on human and mouse CFUGM was examined at concentrations and times suggested by plasma clearance data derived from the results of a number of published studies. Our results suggest that the high concentrations of drug present in the plasma for short periods of time following infusion are only weakly cytotoxic towards the CFUGM when incubated for similar times. In contrast, there was a considerably greater cytotoxic effect when the drug was examined at low concentrations for periods similar to those described for the terminal phase of adriamycin clearance. The principal metabolite, adriamycinol, was poorly cytotoxic.     

Adriamycin and DT-diaphorase

It has been suggested that DT-diaphorase (EC 1.6.99.2) can oppose the cytotoxic effect of the antineoplastic drug adriamycin. In this study, adriamycin was tested as a substrate for purified DT-diaphorase from rat liver. Purified DT-diaphorase was unable to use adriamycin as substrate. Also, the drug did not have any significant inhibitory effect on the enzyme.     

Evaluation of ciprofloxacin's activity against recent clinical isolates

The in vitro antibacterial activity of ciprofloxacin, a new quinoline carboxylic acid, was tested against 1671 recently clinically isolated bacterial strains, by measuring the minimum inhibitory concentrations (MIC). Comparisons were made with other quinolones: nalidixic acid, norfloxacin, and other drugs: piperacillin, cefoxitin, cefotetan, ceftazidime, tobramycin, rifampin, tetracycline, chloramphenicol. Ciprofloxacin was very active against the tested species and was the most active drug against all the bacterial strains, with a geometric mean, a MIC50 and MIC90 of 0.27, 0.12 and 2 micrograms/ml, respectively.     

Cytotoxicity of a transferrin-adriamycin conjugate to anthracycline-resistant cells.

Conjugates of adriamycin coupled to transferrin by glutaraldehyde are cytotoxic to human promyelocytic (HL-60) and erythroleukemic (K562) cells. Growth inhibition of adriamycin-sensitive cells, as evaluated by thymidine incorporation and the MTT-assay, was higher for conjugates than for free adriamycin. The cytotoxicity toward adriamycin-resistant K562 and HL-60 cells was 3-fold and more than 10-fold higher, respectively, for the transferrin-adriamycin conjugate than for the free drug. The effect of the conjugate was dependent on its adriamycin content, i.e., on its conjugation number.     

Evaluation of pefloxacin activity against recent clinical isolates

The in-vitro antibacterial activity of pefloxacin, a new quinolone carboxylic acid, was tested against 1140 bacterial strains, recently clinically isolated, by measuring the minimum inhibitory concentrations. Comparisons were made with other quinolones (enoxacin, norfloxacin, flumekin, oxolinic acid, pipemidic acid) and other drugs (piperacillin, cefotaxime, ceftazidime, gentamicin, tobramycin, amikacin) widely used for the treatment of bacterial infections. Pefloxacin was very active against the tested species and was the most active drug against all the bacterial strains, with a geometric mean of MICs, a MIC 50 and MIC 90 of 0.27, 0.12 and 4 microg/ml respectively.     

褪黑素对阿霉素抗ER~+乳腺癌细胞MCF-7作用的影响及其机制

目的:探讨生理浓度(10~(-9)mol/L)褪黑素和药理浓度(10~(-5)mol/L)褪黑素对阿霉素抑制ER~+乳腺癌细胞MCF-7作用影响及其机制.方法:1)应用四甲基偶氮唑蓝(MTT)法检测经不同浓度褪黑素孵育后阿霉素对MCF-7的抑制率和IC_(50)变化.2)应用流式细胞学方法观察不同浓度褪黑素、阿霉素以及两药联用时对MCF-7凋亡的影响.3)应用Western blotting法检测不同浓度褪黑素、阿霉素单药和两药联用对MCF-7细胞p53和bcl-2蛋白表达的影响.结果:1)阿霉素对MCF-7乳腺癌细胞具有明显的抑制作用,且成剂量时间依赖性.IC_(50)值为0.62±0.07μg/ml,经生理浓度和药理浓度褪黑素孵育后IC_(50)值分别降为0.59±0.09μg/ml和0.42±0.02μg/ml,前者与孵育前相比未见统计学差异(P>0.05),后者相比差异显著(P<0.01).2)流式细胞学检测结果显示:阿霉素对MCF-7细胞具有凋亡促进作用,随浓度增高凋亡率未见增加(P>0.05).生理浓度褪黑素联合阿霉素与相应浓度的阿霉素单药相比,凋亡率未见明显增加(P>0.05).药理浓度褪黑素联合阿霉素与相应浓度阿霉素单药比较,凋亡率明显增加(P<0.05),联合组随着阿霉素浓度增加凋亡率并未见明显变化(P>0.05).3)MCF-7乳腺癌细胞株中呈p53蛋白低表达、bcl-2蛋白高表达.生理浓度褪黑素即可显著增高MCF-7细胞p53蛋白并降低bcl-2蛋白表达,并有剂量依赖性(P<0.01).药理浓度褪黑素联合不同浓度阿霉素对两个蛋白表达未见显著性差异(P>0.05);阿霉素对两种蛋白表达未见明显影响(P>0.05).结论:1)生理浓度褪黑素(10~(-9)mol/L)对阿霉素的抗癌作用未见明显影响,药理浓度(10~(-5)mol/L)以上褪黑素表现出对阿霉素明显的增敏作用.2)阿霉素较低浓度时,凋亡促进作用可能是褪黑素对其增敏机制的一部分,随着阿霉素浓度的提高,褪黑素的细胞毒增敏机制可能占主要地位.3)生理浓度褪黑素能提高ER~+乳腺癌细胞p53蛋白表达并降低bcl-2蛋白表达,并具有剂量依赖性.涉及p53和bcl-2的凋亡通路可能是褪黑素对阿霉素增敏机制的一部分.     

Structure-activity relationship between anthracycline-induced differentiation and inhibition of glycoprotein synthesis in Friend erythroleukemia cells

The effect of adriamycin, daunomycin, N,N-dimethyladriamycin, N,N-dimethyldaunomycin, pyrromycin, marcellomycin, and aclacinomycin A on erythroid differentiation and glycoprotein synthesis in Friend erythroleukemia cells, clone F4-6 was investigated. Whereas N-dimethylated natural anthracyclines, pyrromycin, marcellomycin, and aclacinomycin A stimulated erythroid differentiation (induction of hemoglobin synthesis), this was not seen with adriamycin, daunomycin and their N-dimethylated derivatives. The incorporation of 3H-mannose in glycoprotein was inhibited by the N-alkylated natural anthracyclines at a concentration at which they induced erythroid differentiation. N,N-Dimethyladriamycin and N,N-dimethyldaunomycin only inhibited 3H-mannose incorporation into glycoprotein at cytotoxic concentrations. However, adriamycin and daunomycin did not inhibit glycoprotein synthesis, even at high cytotoxic concentrations. Aclacinomycin A decreased the incorporation of 3H-mannose into proteins earlier than the incorporation into dolichol-linked oligosaccharide intermediates. Tunicamycin, a specific inhibitor of glycoprotein synthesis, failed to stimulate differentiation in Friend erythroleukemia cells. These results indicate a structure-specific induction of the differentiation and inhibition of glycoprotein synthesis in Friend cells by N-alkylated anthracyclines. The inhibition of glycoprotein synthesis may be involved in the induction of differentiation by N-alkylated anthracyclines, but it cannot be the only target for the differentiation-inducing effect of these substances.     

Caffeine Enhancement of the Effect of Anticancer Agents on Human Sarcoma Cells

It is necessary to find modifiers which enhance the effects of known anticancer agents in order to improve both survival rate and local curability of patients with high-grade sarcomas. In this study, the effect of anticancer agents combined with caffeine was examined on cultured sarcoma cells and fresh human sarcoma specimens, utilizing the human tumor clonogenic assay technique. The combination of cisplatin and caffeine showed a synergistic inhibition of the growth of two strains of cultured sarcoma cells tested, and 14 of 18 fresh human sarcoma specimens (77.8%). This synergistic effect of caffeine was also observed with cyclophosphamide (44.8%), mitomycin C (44.8%) and adriamycin (27.8%). The combination of vincristine or methotrexate with caffeine, however, did not exhibit a synergistic effect. Caffeine, therefore, enhanced the effect of four cytotoxic DNA damaging agents. No antag- onistic effects were seen in our series. This study suggests that caffeine may be useful in enhancing the tumoricidal effect of anticancer drugs, especially DNA-damaging agents, and possibly may aid in overcoming natural drug resistance.     

Intracellular uptake, retention and cytotoxic effect of adriamycin combined with hyperthermia in vitro

The intracellular uptake, retention and cytotoxic effect of adriamycin (ADR) were investigated by a flow cytometry technique with NIH 3T3 cells. The intracellular uptake and cytotoxic effect of ADR increased as a function of exposure time and external drug concentration at 37 degrees. A good correlation was found between eventual survival and intracellular ADR uptake. The intracellular uptake and cytotoxic effect of ADR increased with increasing temperature and were shown to be functions of both incubation time and temperature. The intracellular uptake and cytotoxic effect of ADR were increased even at 39 degrees and 41 degrees, temperatures which had no effect on the viability of cells. The combination of hyperthermia (43 degrees) and ADR showed a synergistic effect. It was found that the cytotoxic effects of ADR in combination with various levels of hyperthermia were stronger than those which would be predicted from the intracellular ADR uptake at 37 degrees. The degree of enhancement was temperature-dependent. Since the efflux of intracellular ADR was the same with or without hyperthermia, the increased intracellular ADR uptake caused by elevated temperature was considered to result from an increase in influx.     

Evaluation of Ciprofloxacin’s Activity against Recent Clinical Isolates

Summary

The in vitro antibacterial activity of ciprofloxacin, a new quinoline carboxylic acid, was tested against 1671 recendy clinically isolated bacterial strains, by measuring the minimum inhibitory concentrations (MIC). Comparisons were made with other quinolones: nalidixic acid, norfloxacin, and other drugs: piperacillin, cefoxitin, cefotetan, ceftazidime, tobramycin, rifampin, tetracycline, chloramphenicol.

Ciprofloxacin was very active against the tested species and was the most active drug against all the bacterial strains, with a geometric mean, a MIC₅₀ and MIC₉₀ of 0.27, 0.12 and 2 μg/ml, respectively.     

Effect of a calcium influx blocker, verapamil, on the sensitivity of human bladder cancer cells to adriamycin and mitomycin C

We have investigated the effect of verapamil on the cytotoxicity of adriamycin and mitomycin C with human bladder cancer cell lines T-24 and JTC-30. The concentration of verapamil was 10 M, and adriamycin and mitomycin C were used at the concentrations ranging from 10(-2) micrograms/ml to 10 micrograms/ml. The efficacy of drugs were evaluated using cytotoxicity and colony forming assays. Judging from the results of these assays, no significant difference was observed between the drugs in combination with verapamil and drugs alone. The results indicate verapamil has no enhancement for the cytotoxic activity of the anticancer drugs when cell lines T-24 and JTC-30 are used.     

The effect of the non-ionic surfactant brij 30 on the cytotoxicity of adriamycin in monolayer,spheroid and clonogenic culture systems

The effects of a non-ionic polyoxyethylated lauryl ether surfactant (Brij 30) on monolayer uptake and spheroid penetration of adriamycin have been studied. Co-incubation of adriamycin with Brij 30 increases intracellular adriamycin levels by 2–3-fold. Although, in the concentrations used, Brij 30 alone is not cytotoxic, adriamycin and Brij 30 mixtures are significantly more cytotoxic (monlayer id₉₀ = 0.6 μg/ml; disaggregated spheroid id₃₀ = 1.9 μg/ml) and induce significantly longer spheroid growth delay than adriamycin alone (monolayer id₉₀ = 2.1 μg/ml; disaggregated spheroid id₅₀ = 3.3 μg/ml). Adriamycin is equally cytotoxic to mouse normal granulocytes and chronic myeloid leukaemic (M1 cell line) cells in agar clonogenic cultures. The addition of Brij 30 appears to enhance preferentially the activity of adriamycin against these tumour cells relative to the normal granulocytes.     

Correlation between EGF receptor expression and peplomycin cytotoxicity in squamous cell carcinoma cell lines.

The relationship between sensitivity to anti-cancer agents and EGF receptor expression on squamous cell carcinoma (SCC) cells was investigated. The cytotoxicity of peplomycin (PEP) was correlated with the number of the EGF receptors expressed on the cancer cells, but no correlations were found between the cytotoxicity of adriamycin and cisplatin and EGF receptors. Addition of TNFalpha increased the number of EGF receptors in the SCC cell lines 1.5- to 2-fold. The cytotoxic effect of combined administration of PEP and TNFalpha was correlated with the number of EGF receptors, and produced a 2- to 5-fold increase in IC50 compared with administration of PEP alone. These observations suggest that EGF receptor expression is closely associated with the cytotoxic effect of PEP on SCC cells.     

Potentiation of the cytotoxic effects of various anticancer drugs by interferon on human neoplastic cells (HeLa) in culture

Potentiation of the cytotoxic effects of various anticancer agents by interferon on human malignant cells was examined in culture. The human neoplastic cells used were HeLa cells derived from uterine cervical cancer. The interferon was produced in human diploid fibroblasts treated with Poly I:C. Anticancer drugs examined were as follows; antibiotics (aclacinomycin, actinomycin D, adriamycin, cycloheximide, mitomycin C, peplomycin, puromycin), antimetabolites (cytosine arabinoside, 5-fluorouracil, 6-mercaptopurine, methotrexate), alkylating agents (ACNU, melphalan), and others (cisplatin, hydroxyurea, vincristine). The cytotoxic effects were determined by colony formation. Our results demonstrated that interferon potentiated significantly the cytotoxic effects of peplomycin, aclacinomycin, cisplatin, 5-fluorouracil, and adriamycin on HeLa cells. The present results indicate that a combined administration of interferon and these drugs may be effective in the treatment of human cancers.     

Apparent ineffectiveness of adriamycin for growth of androgen-dependent Shionogi carcinoma 115 in the mouse

Although adriamycin (1 mg/kg) and 5-fluorouracil (25 mg/kg) were equally effective in inhibiting the growth of Ehrlich carcinoma, both ascites and solid forms, in the mouse, the growth of Shionogi carcinoma 115 in the male DS mouse was relatively resistant to the treatment with adriamycin as compared to 5-fluorouracil. However, direct cytotoxic activity of adriamycin in cultured Shionogi carcinoma 115 (SC 115) cells was about 1000-fold molar potent when compared with 5-fluorouracil. The apparent ineffectiveness of adriamycin against SC 115 in the DS mouse seems to be, at least in part, due to the depression of host defence mechanisms.     

补骨脂素逆转人乳腺癌细胞多药耐药性的研究

目的研究中药补骨脂素对人乳腺癌细胞多耐药性的逆转作用.方法用MTT法测定药物的细胞毒性和IC50用流式细胞仪测定耐药细胞P170糖蛋白表达,并选异搏定作阳性对照,观察具有钙拮抗作用的补骨脂素对MCF-7/ADR多药耐药性的逆转作用.结果补骨脂素在非细胞毒性剂量下能使MCF-7/ADR对阿霉素的浓度升高,但对细胞表面的糖蛋白P-170却没有影响.结论补骨脂素具有逆转人乳腺癌MCF-7/ADR多药耐药性的作用.     

Quinolone prophylaxis in neutropenic patients - efficacy versus resistance

To assess the efficacy of quinolones in the prophylaxis of infections in neutropenic patients with acute non-lymphocytic leukemia, and to evaluate the emergence of quinolone resistance in two University Hospitals in Brazil, we retrospectively compared 101 consecutive episodes of neutropenia managed with quinolone prophylaxis between 1989 and November 1993, and 26 previous episodes without prophylaxis, and reviewed the results of in vitro sensitivity of Gram-negative strains to quinolones in the same period. Prophylaxis with quinolones resulted in less episodes of bacteremias (21% vs. 69%, p=10(-7)), including Gram-negative bacteremias (6% vs. 38%, p=10(-5)), with no statistically significant difference in the death rate (18% vs. 31%, p=0.14, 95% confidence interval -6-32). The resistance of Gramnegative strains to quinolones rose from 7% to 18% between 1990 and 1993 (p=10(-5)). The resistance against ceftazidime and amikacin, the agents used in the empirical antibiotic therapy, increased in the same proportion as the quinolones. Given the limited benefit of quinolones as prophylaxis and the increasing number of quinolone-resistant Gram-negative strains observed in our hospitals, the use of quinolones as prophylaxis must be seriously questioned. A stricter control of the use of quinolones in these hospitals might decrease resistance.