共查询到20条相似文献,搜索用时 31 毫秒
1.
《Journal of liposome research》2013,23(2):199-228
AbstractWe have previously demonstrated that liposomal doxorubicin (DXR), targeted against the CD 19 receptor of human B lymphoma (Namalwa) cells resulted in selective affinity of SIL[anti-CD19] for CD19+ Namalwa cells in vitro and significantly increased therapeutic efficacy in mice compared to non-targeted liposomal DXR or to free drug (1). In this study we have examined the cellular trafficking of DXR in Namalwa cells for free drug compared to non-targeted liposomal drug (DXR-SL) or immunoliposomal drug targeted via the monoclonal antibody anti-CD19 (DXR-SIL[anti-CD19]). Liposomes were sterically stabilized with lipid derivatives of polyethylene glycol (PEG) and anti-CD 19 was attached to the PEG terminus. Time-dependent studies using flow cytometry revealed that free DXR accumulated rapidly in cells. Drug from DXR-SIL[anti-CD19] accumulated less rapidly in Namalwa cells than free drug but the cellular levels of DXR were several-fold higher than for drug presented in non-targeted DXR-SL. Internalization of SIL[anti-CD 19] into a low pH compartment could be demonstrated using a pH-sensitive probe, HPTS, encapsulated in liposomes. The endocytosis and intracellular fate of DXR-loaded liposomes were also studied by confocal microscopy, subcellular fractionation, and HPLC. At early times (1 h), DXR from targeted preparations appeared mainly at the cell surface with some DXR sequestered within vesicular structures, likely endosomes, in cells. DXR from non-targeted preparations (I)XR-SL) was only found on the cell surface after a one hour incubation. After two hours, drug from the targeted DXR formulation was mostly found within vesicular structures, whereas drug from the non-targeted formulation was still present only at the surface of the cells. The intracellular levels of DXR from DXR-S1L[anti-CD 19) continued to increase with longer incubation periods, and this endocytotic event could be abolished by metabolic inhibitors. Namalwa cells incubated with DXR-SIL[anti-CD 19] for 48 hours appear to demonstrate nuclear accumulation of DXR. This suggests that lysosomal processing of targeted liposomes allows trafficking of DXR from the lysosomal apparatus to its nuclear site of action. The cytotoxicity of DXR-SIL[anti-CD19] was 5-fold higher than that observed for non-targeted controls. The use of the cationic exchange resin, Dowex, to absorb DXR released from liposomes outside the cells demonstrated that a substantial portion of the cytotoxicity of DXR-SL, but not DXR-SIL, was due to uptake of released drug into cells. The targeted formulations were shown to be selectively apoptotic to CD 19 ' cells compared to CD 19 cells. 相似文献
2.
Arnold RD Slack JE Straubinger RM 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2004,808(2):141-152
The anthracycline Doxorubicin (DXR) is used widely for the treatment of human malignancies, and drug delivery technologies are under investigation to enhance antitumor selectivity and effectiveness. A liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method was developed to identify and quantify DXR and key metabolites in small-volume biological samples. The assay was linear over the therapeutically relevant concentration range (0.125-10,000 nM); in brain tissue, the lower limit of quantification was 0.247 nM and the sensitivity was 1.4 pg. The ability to quantify DXR and detect metabolite formation may provide insight into the toxicity and bioavailability of drug incorporated into carriers such as liposomes. 相似文献
3.
Yamamoto E Hyodo K Ohnishi N Suzuki T Ishihara H Kikuchi H Asakawa N 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2011,879(30):3620-3625
A method for the simultaneous measurement of liposome-encapsulated and released drugs in mouse plasma by on-line solid phase extraction (SPE)-SPE-HPLC with direct plasma injection was developed using a doxorubicin (DXR)-containing liposome formulation as the model drug. During SPE, the released DXR was extracted on the 1st restricted-access media (RAM) SPE column, whereas the liposomes were eluted. The eluted liposomes were collapsed on-line, and the released DXR was delivered to the 2nd RAM SPE column for extraction. The retained DXR on the SPE columns was analyzed via HPLC-fluorescent detector by switching the valves. The method was validated and applied to the pharmacokinetic study of DXR in mice after intravenous injection of DXR-containing liposomes. 相似文献
4.
Antunes LM de Barros E Lima Bueno R da Luz Dias F de Lourdes Pires Bianchi M 《Mutation research》2007,626(1-2):155-161
Acetylsalicylic acid (ASA) is a non-steroidal anti-inflammatory drug (NSAID) with many pharmacological properties, such as anti-inflammatory, antipyretic and analgesic. Many studies have suggested the possible efficiency of ASA and other NSAIDs in preventing cancer. ASA could also have antimutagenic and antioxidant properties. The aim of this study was to investigate the possible clastogenic and anticlastogenic effects of different concentrations of ASA on doxorubicin-induced chromosomal aberrations in human lymphocytes. Human blood samples were obtained from six healthy, non-smoking volunteers; and the chromosomal aberration assay was carried out using conventional techniques. The parameters analyzed were mitotic index, total number of chromosomal aberrations and percentage of aberrant metaphases. The concentrations of ASA (25, 50 or 100 microg/mL) tested in combination with DXR (0.2 microg/mL) were established on the basis of the results of the mitotic index. The treatment with ASA alone was neither cytotoxic nor clastogenic (p>0.01). In lymphocyte cultures treated with different combinations of ASA and DXR, a significant decrease in the total number of chromosome aberrations was observed compared with DXR alone (p<0.01). This protective effect of ASA on DXR-induced chromosomal damage was obtained for all combinations, and it was most evident when ASA was at 25.0 microg/mL. In our experiments, ASA may have acted as an antioxidant and inhibited the chromosomal damage induced by the free radicals generated by DXR. The identification of compounds that could counteract the free radicals produced by doxorubicin could be of possible benefits against the potential harmful effects of anthracyclines. The results of this study show that there is a relevant need for more investigations in order to elucidate the mechanisms underlying the anticlastogenic effect of ASA. 相似文献
5.
《Journal of liposome research》2013,23(1):143-165
AbstractLong-circulating liposomes containing amphipathic polyethyleneglycol (PEG) or ganglioside GM1 (GM1) have been tested for their utility as enhanced delivery system of doxorubicin (DXR) in vivo. DXR was entrapped into liposomes by pH gradient method.The long-circulating LUV (200 nm in size) composed of DSPC/CH (1:1, m/m) and either 6 mol% of DSPE-PEG1000 or GM1 entrapped DXR with >95% in trapping efficiency. DXR-long-circulating LUVs were administered to leukemic (LI210) mice via the tail vein at a dose of 5mg DXR/kg. The high blood concentration was kept for long time, and significantly increased survival time was observed as compared with free DXR and DXR-LUV. The data indicated that DXR was slowly released from long-circulating LUV during that stayed in bloodstream for long time. Administration of DXR-long-circulating SUV (100 nm) to the colon 26 bearing mice produced the increased DXR level in tumor compared with bear SUV or free drug did, respectively, and resulted in effective tumor growth retardation and increased survival time. DXR was delivered to tumor by accumulation of SUVs themselves.Long-circulating thermosensitive liposomes (TSL) were prepared from DPPC /DSPC (9:1, m/m) and 3-6 mol% of PEG1000 or GM1. DXR was entrapped with >95% in trapping efficiency. Accumulation of DXR into tumor tissue by local hyperthermia after injection of DXR-long-circulating TSL to colon 26 bearing mice was significantly higher man that of DXR-bare TSL or free DXR, and resulted in effective tumor growth retardation and increased survival time. It was suggested that the entrapped DXR was efficiently released from long-circulating TSL by hyperthermia at the tumor site and entered the tumor tissue by simple diffusion. 相似文献
6.
《Journal of liposome research》2013,23(1):455-479
AbstractThe amphipathic anthracycline base doxorubicin (DXR) was accumulated in the aqueous phase of the liposomes where it reached a level as high as 100-fold its concentration in the remote loading medium. Most of the intraliposomal DXR was present in an aggregated state. Efficient (>90%) and stable loading into the liposomes' and ligandoliposomes' aqueous phase was obtained by using gradients of ammonium sulfate in which the ammonium sulfate concentration in the liposomes was higher than its concentration in the extraliposomal medium [(NH4)2SO4)lip. ? [(NH4)2SO4)med.]. The “remote” loading is a result of the DXR exchange with ammonia from (NH4)2SO4. Both the ammonium and sulfate contribute to high level and stability of the loading. The ammonium sulfate gradient method differs from most other chemical approaches used for remote loading of liposomes since it neither requires to prepare the liposomes in acidic pH, nor to alkalinize the extraliposomal aqueous phase. Although most of the intraliposomal DXR is present in an aggregated gel-like state, the drug is bioavailable. This approach permits the preparation of DXR-loaded liposomes of a broad spectrum of types, sizes, and composition, including sterically-stabilized liposomes, immunoliposomes, and sterically-stabilized immunoliposomes. Due to the long shelf stability (>6 mo), no “bedside” remote loading is required immediately before patient treatment, and the formulation is ready for injection. The stable encapsulation of the doxorubicin in an aggregated form also permits freezing and lyophilization of the liposomes with only minimal drug release. The loading by ammonium sulfate gradient approach meets all pharmaceutical requirements; it has brought the clinical use of DXR-loaded sterically-stabilized liposomes to reality. 相似文献
7.
Curcumin ameliorates doxorubicin‐induced cardiotoxicity by abrogation of inflammation,apoptosis, oxidative DNA damage,and protein oxidation in rats
下载免费PDF全文
![点击此处可从《Journal of biochemical and molecular toxicology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Fulya Benzer Fatih Mehmet Kandemir Mustafa Ozkaraca Sefa Kucukler Cuneyt Caglayan 《Journal of biochemical and molecular toxicology》2018,32(2)
Doxorubicin (DXR) is a highly effective drug for chemotherapy. However, cardiotoxicity reduces its clinical utility in humans. The present study aimed to assess the ameliorative effect of curcumin against DXR‐induced cardiotoxicity in rats. Rats were subjected to oral treatment of curcumin (100 and 200 mg/kg body weight) for 7 days. Cardiotoxicity was induced by single intraperitoneal injection of DXR (40 mg/kg body weight) on the 5th day and the rats sacrificed on 8th day. Curcumin ameliorated DXR‐induced lipid peroxidation, glutathione depletion, decrease in antioxidant (superoxide dismutase, catalase, and glutathione peroxidase) enzyme activities, and cardiac toxicity markers (CK‐MB, LDH, and cTn‐I). Curcumin also attenuated activities of Caspase‐3, cyclooxygenase‐2, inducible nitric oxide synthase, and levels of nuclear factor kappa‐B, tumor necrosis factor‐α, and interleukin‐1β, and cardiac tissue damages that were induced by DXR. Moreover, curcumin decreased the expression of 8‐OHdG and 3,3′‐dityrosine. This study demonstrated that curcumin has a multi‐cardioprotective effect due to its antioxidant, anti‐inflammatory, and antiapoptotic properties. 相似文献
8.
The pharmacokinetics (PK), biodistribution (BD), and therapeutic activity of pegylated liposomal doxorubicin formulations with different drug release rates were studied in an orthotopic 4T1 murine mammary carcinoma model. The focus of these experiments was to study the effects of different release rates on the accumulation of liposomal lipid and doxorubicin (DXR) into the tumor and cutaneous tissues of mice (skin and paws). These tissues were chosen because the clinical formulation of pegylated liposomal doxorubicin (Caelyx)/Doxi) causes mucocutaneous reactions such as palmar-plantar erythrodysesthesia (PPE). Liposomes with different doxorubicin (DXR) leakage rates were prepared by altering liposome fluidity through changing the fatty acyl chain length and/or degree of saturation of the phosphatidylcholine component of the liposome. Liposomes with fast, intermediate, and slow rates of drug release were studied. The plasma PK of the liposomal lipid was similar for all formulations, while the plasma PK of the DXR component was dependent on the liposome formulation. Liposomal lipid accumulated to similar levels in tumor and cutaneous tissues for all three formulations tested, while the liposomes with the slowest rates of DXR release produced the highest DXR concentrations in both cutaneous tissues and in tumor. Liposomes with the fastest drug release rates resulted in low DXR concentrations in cutaneous tissues and tumor. The formulation with intermediate release rates produced unexpected toxicity that was not related to the lipid content of the formulation. The liposomes with the slowest rate of drug leakage had the best therapeutic activity of the formulations tested. 相似文献
9.
Dutra ES Dias CD de Araújo BC Castro AJ Nepomuceno JC 《Genetics and molecular biology》2009,32(1):133-137
The consumption of organic tomatoes (ORTs) reduces the risk of harmful effects to humans and the environment caused by exposure to toxic agrochemicals. In this study, we used the somatic mutation and recombination test (SMART) of wing spots in Drosophila melanogaster to evaluate the genotoxicity of ORT and the effect of cotreatment with ORT on the genotoxicity of Doxorubicin® (DXR, a cancer chemotherapeutic agent) that is mediated by free radical formation. Standard (ST) cross larvae were treated chronically with solutions containing 25%, 50% or 100% of an aqueous extract of ORT, in the absence and presence of DXR (0.125 mg/mL), and the number of mutant spots on the wings of emergent flies was counted. ORT alone was not genotoxic but enhanced the toxicity of DXR when administered concomitantly with DXR. The ORT-enhanced frequency of spots induced by DXR may have resulted from the interaction of ORT with the enzymatic systems that catalyze the metabolic detoxification of this drug. 相似文献
10.
《Journal of liposome research》2013,23(2):195-210
AbstractPrevious results suggested that drug formation in macrophages is an important aspect of the mode of action of doxorubicin (DXR)-containing liposomes. Intracellular degradation of DXR-liposomes may result in the liberation of DXR molecules that subsequently are released from the macrophages. We investigated whether the rate of intracellular degradation of DXR-liposomes phagocytosed by rat liver macrophages (Kupffer's cells) in monolayer culture is dependent on the type of DXR-liposomes internalized and whether differences in degradation rate of DXR-liposomes are reflected in different DXR release profiles. Two DXR-liposome types that were previously shown to differ markedly both in antitumor activity and degradation rate in vivo were selected for this investigation: a liposome composed of egg-phosphatidylcholine (PC), phosphatidylserine (PS), and cholesterol (chol), and a liposome composed of distearoylphosphatidylcholine (DSPC), dipalmitoyl-phosphatidylglycerol (DPPG), and chol. To monitor the rate of intracellular degradation of DXR-liposomes, cholesterol-1-[14Cjoleate was used as marker of the liposomal lipid phase. DXR was monitored with the use of a high-performance liquid chromatography (HPLC) method capable of detecting not only intact DXR but also major metabolites.Comparable amounts of both types of DXR-liposomes were taken up by in vitro cultured Kupffer's cells. Liposome-associated cholesteryloleate was metabolized by the cells in a liposome-type-dependent pattern. During the first 30 min after start of the incubation, degradation of cholesteryloleate occurred at a similar rate for both types of DXR-liposomes. During continued incubation, however, PC/PS/chol DXR-liposomes were degraded at a considerably higher rate than DSPC/DPPG/ chol DXR-liposomes. the difference in susceptibility to lysosomal degradation of the two liposome preparations was also demonstrated by incubating the DXR-liposomes with lysosomal fractions isolated from rat liver homogenates: PC/PS/chol DXR-liposomes were much more sensitive to lysosomal esterase than DSPC/DPPG/chol DXR-liposomes. DXR either free or in liposomal form was chemically stable for up to 26 hr during incubation with the lysosomal fractions. Following uptake of DXR-liposomes by the cells, DXR was released from the cells into the medium. the release of DXR from cells that internalized DSPC/DPPG/chol DXR-liposomes was significantly delayed compared to the release of DXR from cells that internalized PC/PS/chol DXR-liposomes. Correlation of the relatively slow intracellular degradation of the DSPC/DPPG/chol DXR-liposomes with the delayed release of DXR from the cells suggests that by varying the type of DXR-liposomes, the rate of intracellular degradation can be manipulated, which, in turn, determines the rate of extracellular DXR release and thereby the therapeutic availability of the drug. 相似文献
11.
Tokarska-Schlattner M Zaugg M da Silva R Lucchinetti E Schaub MC Wallimann T Schlattner U 《American journal of physiology. Heart and circulatory physiology》2005,289(1):H37-H47
Doxorubicin (DXR) is a widely used and efficient anticancer drug. However, its application is limited by the risk of severe cardiotoxicity. Impairment of cardiac high-energy phosphate homeostasis is an important manifestation of both acute and chronic DXR cardiotoxic action. Using the Langendorff model of the perfused rat heart, we characterized the acute effects of 1-h perfusion with 2 or 20 microM DXR on two key kinases in cardiac energy metabolism, creatine kinase (CK) and AMP-activated protein kinase (AMPK), and related them to functional responses of the perfused heart and structural integrity of the contractile apparatus as well as drug accumulation in cardiomyocytes. DXR-induced changes in CK were dependent on the isoenzyme, with a shift in protein levels of cytosolic isoenzymes from muscle-type CK to brain-type CK, and a destabilization of octamers of the mitochondrial isoenzyme (sarcometric mitochondrial CK) accompanied by drug accumulation in mitochondria. Interestingly, DXR rapidly reduced the protein level and phosphorylation of AMPK as well as phosphorylation of its target, acetyl-CoA-carboxylase. AMPK was strongly affected already at 2 microM DXR, even before substantial cardiac dysfunction occurred. Impairment of CK isoenzymes was mostly moderate but became significant at 20 microM DXR. Only at 2 microM DXR did upregulation of brain-type CK compensate for inactivation of other isoenzymes. These results suggest that an impairment of kinase systems regulating cellular energy homeostasis is involved in the development of DXR cardiotoxicity. 相似文献
12.
Morelli D. Ménard S. Pozzi B. Balsari A. Colnaghi M. I. 《Cell biochemistry and biophysics》1994,24(1-3):119-126
Even though the first monoclonal antibodies (MAbs) directed against tumor cells were produced 15 yr ago, the therapeutic application
of immunoconjugates is still at the beginning. This is principally because of the enormous work that is required for the development
of completely new therapeutic tools. An alternative could be to only use MAbs to improve conventional treatment such as chemotherapy.
To this aim, a MAb directed against doxorubicin (DXR) was produced. DXR is an anthracycline antibiotic of which the clinical
usefulness in cancer chemotherapy is limited by serious side effects, such as cardiomyopathy, bone marrow depression, and
gastrointestinal tract mocositis. This toxicity was found to be reduced by treatment with the antidrug MAb, as shown by reduction
in body weight loss and mortality of experimental mice. To improve the DXR therapeutic index, a bifunctional hybrid MAb (DOXER2),
capable of simultaneously recognizing DXR and the epidermal growth factor (EGF) receptor, was produced. This reagent was found
in vitro to increase the drug toxicity on the epidermoid carcinoma cell line A431, which overexpresses the EGF-R and, at the
same time, to reduce DXR cytotoxicity on EGF-R negative cells. The effect of DOXER2 on the DXR biodistribution in vivo was
also investigated. In mice previously injected ip with the DOXER2, the uptake of the drug, in comparison to the control group,
was found to be reduced in the intestine and in myocardial tissue, and significantly increased in the tumor. The alteration
in the drug distribution induced in mice by administration of the DOXER2 could prevent the drug from reaching critical toxic
concentrations at sites such as the intestine and heart, which are the main targets of early anthracycline toxic effects.
In conclusion, the data so far obtained show that this bifunctional MAb appears to be able to deliver the drug selectively
to a tumor that overexpresses the EGF-R maintaining the capability to reduce DXR cytotoxicity on normal cells. 相似文献
13.
Xiaoru Wang Xiaorong Tian Yuanjie Wu Xiaofang Shen Songbai Yang 《Preparative biochemistry & biotechnology》2013,43(6):514-521
AbstractDoxorubicin (DXR), which is produced by Streptomyces peucetius, is an important anthracycline-type antibiotic used for the treatment of various cancers. However, due to the low DXR productivity of wild-type S. peucetius, it is difficult to produce DXR by one-step fermentation. In this study, a DXR-resistance screening method was developed to screen for DXR high-producing mutants. Then, S. peucetius SIPI-11 was treated several times with UV and ARTP (atmospheric and room temperature plasma) to induce mutations. Treated strains were screened by spreading on a DXR-containing plate, isolating a mutant (S. peucetius 33-24) with enhanced DXR yield (570?mg/L vs. 119?mg/L for the original strain). The components of the fermentation medium, including the carbon and nitrogen sources, were optimized to further enhance DXR yield (to 850?mg/L). The pH of the fermentation medium and culture temperature were also optimized for effective DXR production. Finally, DXR production by S. peucetius 33-24 was investigated in flask culture and a fermenter. The yield of DXR was as high as 1100?mg/L in a 5-L fermenter, which is the highest DXR productivity reported thus far, suggesting that S. peucetius 33-24 has the potential to produce DXR by direct fermentation. 相似文献
14.
The influence of physical characteristics of liposomes containing doxorubicin on their pharmacological behavior 总被引:1,自引:0,他引:1
We have investigated the behavior of two populations of doxorubicin (DXR)-containing phospholipid vesicles with regard to various physical and pharmacological parameters. DXR-containing liposomes were prepared by ultrasonic irradiation, the lipid composition being phosphatidylglycerol (or phosphatidylserine), phosphatidylcholine and cholesterol. The vesicles were fractionated into oligolamellar vesicles (OLV) and small unilamellar vesicles (SUV) by preparative differential ultracentrifugation (150,000 x g for 1 h). Unentrapped DXR was removed by gel exclusion chromatography. OLV and SUV liposomes differed in size (mean diameters, 247 +/- 113 nm and 61 +/- 16 nm, respectively) and number of lamellae (two for OLV, one for SUV). Drug entrapment per unit of lipid was three to 5-fold higher in OLV than in SUV. In both liposome populations more than 95% of the entrapped drug was membrane-associated. Physical studies on these two vesicle populations revealed higher motional restriction and greater susceptibility to iodide-mediated fluorescence collisional quenching of DXR in the small vesicles. OLV showed superior stability in the presence of plasma as determined by the fraction of DXR retained by the vesicles. It was also found that the tissue distribution of DXR in SUV follows a pattern different from that of DXR in OLV and resembling that of soluble DXR. In accordance with these differences in patterns of tissue distribution, animal studies demonstrated that DXR in OLV is significantly less toxic than DXR in SUV and more effective in a tumor model with predominant involvement of the liver. These results indicate that vesicle size and/or number of lamellae play an important role in optimizing liposome-mediated delivery of DXR, and that oligolamellar liposomes are distinctively superior to small unilamellar liposomes when fluid phase formulations (Tm less than 37 degrees C) with bilayer-associated DXR are considered. 相似文献
15.
Jenna Kropp Elon C. Roti Roti Ashley Ringelstetter Hasan Khatib David H. Abbott Sana M. Salih 《PloS one》2015,10(11)
Advances in cancer treatment utilizing multiple chemotherapies have dramatically increased cancer survivorship. Female cancer survivors treated with doxorubicin (DXR) chemotherapy often suffer from an acute impairment of ovarian function, which can persist as long-term, permanent ovarian insufficiency. Dexrazoxane (Dexra) pretreatment reduces DXR-induced insult in the heart, and protects in vitro cultured murine and non-human primate ovaries, demonstrating a drug-based shield to prevent DXR insult. The present study tested the ability of Dexra pretreatment to mitigate acute DXR chemotherapy ovarian toxicity in mice through the first 24 hours post-treatment, and improve subsequent long-term fertility throughout the reproductive lifespan. Adolescent CD-1 mice were treated with Dexra 1 hour prior to DXR treatment in a 1:1 mg or 10:1 mg Dexra:DXR ratio. During the acute injury period (2–24 hours post-injection), Dexra pretreatment at a 1:1 mg ratio decreased the extent of double strand DNA breaks, diminished γH2FAX activation, and reduced subsequent follicular cellular demise caused by DXR. In fertility and fecundity studies, dams pretreated with either Dexra:DXR dose ratio exhibited litter sizes larger than DXR-treated dams, and mice treated with a 1:1 mg Dexra:DXR ratio delivered pups with birth weights greater than DXR-treated females. While DXR significantly increased the “infertility index” (quantifying the percentage of dams failing to achieve pregnancy) through 6 gestations following treatment, Dexra pretreatment significantly reduced the infertility index following DXR treatment, improving fecundity. Low dose Dexra not only protected the ovaries, but also bestowed a considerable survival advantage following exposure to DXR chemotherapy. Mouse survivorship increased from 25% post-DXR treatment to over 80% with Dexra pretreatment. These data demonstrate that Dexra provides acute ovarian protection from DXR toxicity, improving reproductive health in a mouse model, suggesting this clinically available drug may provide ovarian protection for cancer patients. 相似文献
16.
Guobin Cai Lisheng Deng Jian Xue Silvia N.J. Moreno Boris Striepen Yongcheng Song 《Bioorganic & medicinal chemistry letters》2013,23(7):2158-2161
The apicomplexan parasite Toxoplasma gondii, the causative agent of toxoplasmosis, is an important human pathogen. 1-Deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate isoprene biosynthesis pathway is essential to the organism and therefore a target for developing anti-toxoplasmosis drugs. In order to find potent inhibitors, we expressed and purified recombinant T. gondii DXR (TgDXR). Biochemical properties of this enzyme were characterized and an enzyme activity/inhibition assay was developed. A collection of 11 compounds with a broad structural diversity were tested against TgDXR and several potent inhibitors were identified with Ki values as low as 48 nM. Analysis of the results as well as those of Escherichia coli and Plasmodium falciparum DXR enzymes revealed a different structure–activity relationship profile for the inhibition of TgDXR. 相似文献
17.
A fiber optic spectrometer setup was designed for white light excitation fluorescence ‘WLEF’ based measurements. Using this setup, two different analytical methods, a self referencing ratio‐metric and a difference WLEF methods, were developed for the quantification of doxorubicin (DXR) in biofluids. It was seen that Acetonitrile (ACN) acts as an efficient and transparent extracting medium for DXR. The figures of merit and the percent recoveries of DXR in blood serum, even in presence of external fluorophores and in urine samples are comparable with existing analytical methods. The compact spectrometer is expected to be useful for easy quantification of fluorescent pharmaceuticals in biofluids. (© 2014 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim) 相似文献
18.
The methylerythritol phosphate (MEP) pathway of Plasmodium falciparum (P. falciparum) has become an attractive target for anti-malarial drug discovery. This study describes a kinetic model of this pathway, its use in validating 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) as drug target from the systemic perspective, and additional target identification, using metabolic control analysis and in silico inhibition studies. In addition to DXR, 1-deoxy-d-xylulose 5-phosphate synthase (DXS) can be targeted because it is the first enzyme of the pathway and has the highest flux control coefficient followed by that of DXR. In silico inhibition of both enzymes caused large decrement in the pathway flux. An added advantage of targeting DXS is its influence on vitamin B1 and B6 biosynthesis. Two more potential targets, 2-C-methyl-d-erythritol 2,4-cyclodiphosphate synthase and 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate synthase, were also identified. Their inhibition caused large accumulation of their substrates causing instability of the system. 相似文献
19.
《Journal of liposome research》2013,23(2):1063-1073
AbstractA fluorometric method is presented that allows a continuous monitoring in 50% (v/v) human serum of the release of liposome-entrapped doxorubicin (DXR).This method exploits the intrinsic fluorescence of DXR and uses DNA as a fluorescence quencher of the released drug. It is much more simple and rapid than the commonly used methods. It is shown that this method can be applied to the study of the stability of liposomal-DXR encapsulated using either an ammonium sulfate gradient or a pH gradient. Small unilamellar vesicles (SUVs) made from egg yolk phosphatidylcholines (EPC) were much less stable, either in phosphate buffer saline or in human serum, than SUVs made from a 1/1 mixture of EPC and cholesterol (Choi). SUVs made from EPC/Chol loaded with DXR using an ammonium sulfate gradient were found to be more stable than those loaded using a pH gradient. 相似文献
20.
Muriel Almeida Xavier Marcelo Tempesta de Oliveira Adrivanio Baranoski Mário Sérgio Mantovani 《Saudi Journal of Biological Sciences》2018,25(8):1568-1576
There is a lack of consensus on whether the role of folate in cancer cells is protective or harmful. The use of folates in combination with cancer-targeting therapeutic regimens requires detailed information to ensure their safe and proper use. Therefore, we evaluated the effects of folic acid (FA) in combination with the chemotherapeutic compounds doxorubicin (DXR), camptothecin (CPT) and methyl methanesulfonate (MMS) on the growth of MCF-7 cells. The data generated from the RTCA assays demonstrated that FA did not affect proliferation in MCF-7 cells treated with DXR and CPT; however, FA reduced the efficacy of MMS treatment. RTCA data also confirmed that DXR and CPT exert their cytotoxic effects in a time-dependent manner and that CPT induced a significantly greater decrease in MCF-7 cell proliferation compared with DXR. The MTT assay failed to detect a reduction in cell proliferation in cells treated with MMS. We quantified the mRNA expression levels of genes associated with cellular stress response, cell cycle and apoptosis pathways using RT-qPCR. The addition of FA to DXR or CPT promoted a similar shift in the gene expression profile of MCF-7 cells compared with cells treated with DXR or CPT without FA; however, this shift did not alter the bioactivity of these drugs. Rather, it indicated that these drugs promoted cell death by alternative mechanisms. In contrast, the addition of FA to MMS reduced the efficacy of the drug without changing the gene expression profile. None of the genes encoding folate receptors that were analyzed were differentially expressed in cells treated with or without FA. In conclusion, supplementation with 450 μM FA was not cytotoxic to MCF-7 cells. However, the addition of FA to anti-cancer drugs must be performed cautiously as the properties of FA might lead to a reduction in drug efficacy. 相似文献