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PubMed1994

Effects of ischemia-reperfusion injury on myocardial single pass extraction and retention of Cu-PTSM in perfused rat hearts: comparison with 201T1 and 14C-iodoantipyrine.

The effects of ischemia-reperfusion-induced myocardial damage on the single pass extraction and retention of 64Cu-pyruvaldehyde-di(N4-methylthiosemicabazone) (64Cu-PTSM) in perfused rat hearts were compared to these effects on that of 201T1 and 14C-iodoantipyrine. 201T1 and 14C-iodoantipyrine did not show significant changes, but in the case of 64Cu-PTSM, the single pass extraction and retention was reduced with reperfusion. These findings indicate that ischemia-reperfusion-induced myocardial damage decrease the generator-produced 62Cu-labeled 62Cu-PTSM extraction and retention, and that 62Cu-PTSM might have potential not only as a blood flow tracer but also as a functional tracer.

Animals↗
PubMed1994

Evaluation of Cu-PTSM as a tracer of tumor perfusion: comparison with labeled microspheres in spontaneous canine neoplasms.

Copper-62-labeled Cu-PTSM is a promising generator-produced PET tracer for myocardial, cerebral and renal perfusion. To evaluate whether [62Cu]Cu-PTSM could also serve as a blood flow tracer in PET studies of tumor tissue, the tumor uptake of [62Cu]Cu-PTSM was examined in dogs with spontaneously-occurring soft-tissue neoplasms. Copper-67-labeled Cu-PTSM was administered intravenously to four anesthetized dogs, followed c. 5 min later by a left ventricular injection of 85Sr-labeled microspheres (15 microns) to provide an independent measure of tumor perfusion. Forty-seven tumors (average weight = 2.5 +/- 3.7 g) were obtained and sectioned into 80 samples. The correlation of 67Cu-PTSM uptake with regional renal perfusion was also examined in data from 395 tissue samples ranging in flow from 0.02 to 9.39 mL min-1 g-1. Rates of tumor perfusion assessed with 85Sr-labeled microspheres ranged from 0.011 to 3.0 mL min-1 g-1. No correlation was found between tumor size and the rate of tumor perfusion. However, an excellent linear correlation exists between tumor perfusion calculated from [62Cu]Cu-PTSM data and tumor perfusion measured with 85Sr-microspheres (r = 0.94 for 80 samples), suggesting that [62Cu]Cu-PTSM may be useful as a radiopharmaceutical for PET studies of tumor perfusion.

Animals↗
PubMed2006

Ribonucleotide reductase inhibitors as anti-herpes agents.

Ribonucleotide reductases (RNRs) supply the 2'-deoxyribonucleotide building blocks for DNA synthesis in mammalian cells and for herpes viruses. The viral-encoded RNRs have unique protein sequences that differ from mammalian enzyme primary structures. Selective inhibition of a viral RNR might provide an approach to new anti-herpes agents with minimal effects on the mammalian host RNRs. This review summarizes efforts to develop anti-herpes agents that selectively target viral-encoded RNRs.

Antiviral Agents↗
PubMed2006

Synthesis and biological evaluation of phenolic Mannich bases of benzaldehyde and (thio)semicarbazone derivatives against the cysteine protease falcipain-2 and a chloroquine resistant strain of Plasmodium falciparum.

A targeted series of phenolic Mannich bases of benzaldehyde and (thio)semicarbazone derivatives were synthesized and evaluated in vitro against the malarial cysteine protease falcipain-2 and a chloroquine resistant strain (W2) of Plasmodium falciparum. A novel series of 4-aminoquinoline semicarbazones were the most effective inhibitors of falcipain-2 (most potent inhibitor had IC(50)=0.63microM) while a bisquinoline semicarbazone compound 8f was the most potent antimalarial compound with an IC(50) of 0.07microM against W2. Compound 8f also weakly inhibited falcipain-2, with an IC(50) of 3.16microM, although its principal antiparasitic activity did not appear to be due to inhibition of this enzyme.

Animals↗
PubMed2004

Cytotoxicity and oncostatic activity of the thiazolidinedione derivative CGP 52608 on central nervous system cancer cells.

Oncostatic activity of CGP 52608 at concentrations 1 microM or lower, and cytotoxicity at 5 and 10 microM, are showed in central nervous system cancer cell lines. Inhibition of cell growth is accompanied by arrest of the cell cycle in G0/G1 or G2/M, depending on the cells, and suggests different intracellular pathways used on each cell type. Cytotoxicity is not mediated by oxidative stress, since no intra or extracellular peroxides were found after treatment and antioxidants failed to rescue cells from apoptosis induced by CGP 52608. Its use as anticancer drug susceptible of being concomitantly administered with antioxidants must be considered provided its antitumoral effects do not rely on free radical production.

Animals↗
PubMed2004

RNA expression of human telomerase subunits TR and TERT is differentially affected by melatonin receptor agonists in the MCF-7 tumor cell line.

The RNA expression levels of human catalytic subunit (TERT) and the RNA subunit (TR) of telomerase were analysed after treatment with the agonists of the membrane receptor (S 20098) and the nuclear receptor (CGP 52608) for melatonin in the MCF-7 human breast tumor cell line. Neither membrane nor nuclear signalling affected the RNA steady-state levels of the TR subunit of telomerase. On the contrary, we observed a significant decreased in the RNA levels of TERT after treatment with CGP 52608 while S 20098 produced a significant increase in the RNA levels of TERT. These results support a cross-talk between membrane and nuclear melatonin signalling and provide new data on the hormonal regulation of telomerase function.

Acetamides↗
PubMed2006

Synthesis and oxidant properties of novel (5-bromobenzofuran-2-yl)(3-methyl-3-mesitylcyclobutyl)ketonethiosemicarbazone.

The reaction of 5-bromosalicylaldehyde with 1-mesityl-1-methyl-3-(2-chloro-1-oxoethyl)cyclobutane (1) and potassium carbonate was used to prepare (5-bromobenzofuran-2-yl)(3-methyl-3-mesitylcyclobutyl)methanone (2) for the starting reagent purposes. (5-Bromobenzofuran-2-yl)(3-methyl-3-mesitylcyclobutyl)ketonethiosemicarbazone (3) was synthesized from the reaction of the compound (2) with thiosemicarbazide. In the present study, it was aimed to examine the influence of synthetic (5-bromobenzofuran-2-yl)(3-methyl-3-mesityl cyclobutyl)ketonethiosemicarbazone on levels of vitamins (A, E, C), selenium and malondialdehyde in rats. A total of 42 rats were used and the animals were divided into two groups in the study. Only a subcutaneous injection of 250 microl of 75% ethanol was given to the control group every other day. A subcutaneous injection of this compound (25 mg kg-1, dissolved in 250 microl of 75% ethanol) was administered to the other group of rats. After the application of (5-bromobenzofuran-2-yl)(3-methyl-3-mesitylcyclobutyl)ketonethiosemicarbazone for 20 days, the serum vitamins (A, E, C) and malondialdehyde levels were determined with high performance liquid chromatography, the serum selenium level was determined by using fluorescence spectrophotometer. The serum vitamin A, E, C and selenium levels were significantly decreased compared to control group (P<0.005), whereas serum malondialdehyde levels were higher than control group levels (P<0.005). As a result, it could be suggested that this compound induced a severe stress, and also increased the amount of free radicals depending on the stress.

Animals↗
PubMed2005

In vitro antimycobacterial activity of newly synthesised S-alkylisothiosemicarbazone derivatives and synergistic interactions in combination with rifamycins against Mycobacterium avium.

The antimycobacterial activities of two new S-alkylisothiosemicarbazone derivatives (1i and 1f) against 32 Mycobacterium avium isolates were investigated. The minimum inhibitory concentrations (MICs) were significantly lower than those of rifampicin and other reference drugs. The two derivatives also showed excellent intracellular activity against M. avium residing in the macrophage-like J774 cells. Interestingly, the combination of subinhibitory concentrations of 1i and rifabutin or rifampicin induced a potent synergistic effect, as determined by the fractional inhibitory concentration indexes (FICIs) ranging between 0.103 and 0.412. Such synergistic effect resulted in a 81-fold and 139-fold reduction of the MICs of rifabutin and rifampicin, respectively. Enhancement of intracellular activity of rifabutin by the S-alkylisothiosemicarbazone derivative 1i was also observed. Results indicate that S-alkylisothiosemicarbazones can be useful in the therapy and prophylaxis of M. avium infections and can represent a template for the development of novel antimycobacterial drugs. Furthermore, as a consequence of their ability to enhance the activity of rifamycins, a reduction of drug interactions following the co-administration of protease inhibitors could be achieved by lower doses of rifampicin and rifabutin.

Animals↗
PubMed2005

Assessment of regional tumor hypoxia using 18F-fluoromisonidazole and 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) positron emission tomography: Comparative study featuring microPET imaging, Po2 probe measurement, autoradiography, and fluorescent microscopy in the R3327-AT and FaDu rat tumor models.

PURPOSE: To compare two potential positron emission tomography (PET) tracers of tumor hypoxia in an animal model. METHODS AND MATERIALS: The purported hypoxia imaging agents (18)F-fluoromisonidazole (FMISO) and (64)Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) were compared by serial microPET imaging of Fisher-Copenhagen rats bearing the R3327-AT anaplastic rat prostate tumor. Probe measurements of intratumoral Po(2) were compared with the image data. At the microscopic level, the relationship between the spatial distributions of (64)Cu (assessed by digital autoradiography) and tumor hypoxia (assessed by immunofluorescent detection of pimonidazole) was examined. (18)F-FMISO and (64)Cu-ATSM microPET images were also acquired in nude rats bearing xenografts derived from the human squamous cell carcinoma cell line, FaDu. RESULTS: In R3327-AT tumors, the intratumoral distribution of (18)F-FMISO remained relatively constant 1-4 h after injection. However, that of (64)Cu-ATSM displayed a significant temporal evolution for 0.5-20 h after injection in most tumors. In general, only when (64)Cu-ATSM was imaged at later times (16-20 h after injection) did it correspond to the distribution of (18)F-FMISO. Oxygen probe measurements were broadly consistent with (18)F-FMISO and late (64)Cu-ATSM images but not with early (64)Cu-ATSM images. At the microscopic level, a negative correlation was found between tumor hypoxia and (64)Cu distribution when assessed at early times and a positive correlation when assessed at later times. For the FaDu tumor model, the early and late (64)Cu-ATSM microPET images were similar and were in general concordance with the (18)F-FMISO scans. CONCLUSION: The difference in behavior between the R3327-AT and FaDu tumor models suggests a tumor-specific dependence of Cu-ATSM uptake and retention under hypoxic conditions.

Animals↗
PubMed2006

Application of iron-rich natural clays in Camlica, Turkey for boron sorption from water and its determination by fluorimetric-azomethine-H method.

In this study, iron-rich natural Camlica Bentonites, CB1 and CB2, were used for the sorption of boron in water samples. Boron was determined by newly progressed fluorimetric azomethine-H method. The optimum conditions found using factorial designs are pH 10, 45 degrees C, 0.250 g of clay and 20 mL of sample volume. It was found that 180 min is enough time for the equilibrium state to be reached in boron adsorption. At these conditions, boron sorption percentage was 80% for CB1 and 30% for CB2. The adsorption isotherms are well described by linear Freundlich model. Various geothermal waters in our country were also studied for boron sorption.

Adsorption↗
PubMed2005

Vanadium(V) complexes with salicylaldehyde semicarbazone derivatives bearing in vitro anti-tumor activity toward kidney tumor cells (TK-10): crystal structure of [VVO2(5-bromosalicylaldehyde semicarbazone)].

As a contribution to the development of novel vanadium complexes with pharmacologically interesting moieties, new dioxovanadium(V) semicarbazone complexes with the formula cis-VO(2)L, where L=5-bromosalicylaldehyde semicarbazone and 2-hydroxynaphtalen-1-carboxaldehyde semicarbazone have been synthesized and characterized by (1)H and (13)C NMR, Raman and FTIR spectroscopies. Results were compared with those previously reported for other three analogous complexes of this series. The five complexes were tested in three different human tumor cell lines for bioactivity as potential anti-tumor agents, showing selective cytotoxicity on TK-10 cell line. Results showed that structural modifications on the semicarbazone moiety could have a significant effect on the anti-tumor activity of the vanadium complexes. In addition, the electrochemical behavior of all the complexes was studied. No apparent correlation could be demonstrated between reduction potentials of the complexes and their anti-tumor activities. The molecular structure of the novel [V(V)O(2)(5-bromosalicylaldehyde semicarbazone)] complex was solved by X-ray diffraction methods. The vanadium atom shows a distorted square pyramidal coordination sphere. The (VO(2))(+) cation is coordinated to a nearly planar (L)(-) anion acting as a tridentate ligand through both oxygen and one nitrogen atoms.

Aldehydes↗
PubMed2006

Triapine and cytarabine is an active combination in patients with acute leukemia or myelodysplastic syndrome.

Triapine, an iron chelator and a potent inhibitor of ribonucleotide reductase, has significant anti-leukemia activity. A phase I study of Triapine in combination with ara-C was conducted in 32 patients with refractory acute leukemia and high-risk MDS. Triapine (105 mg/m2/day 6-h infusion) was followed immediately by ara-C [100 (n=4), 200 (n=6), 400 (n=7), or 800 (n=8)mg/m2/day] as an 18-h infusion for 5 consecutive days. Dose-limiting toxicities (DLTs) were observed at the 800 mg/m2 ara-C dose level (one patient each with grade 4 mucositis; grade 4 neutropenic colitis, sepsis; grade 4 neuropathy; and grade 4 hyperbilirubinemia). Therefore, the study was amended to include an ara-C dose level of 600 mg/m2/day, no DLTs occurred in seven patients treated at this dose level. Mean Triapine C(max) and AUC were 1.13 microg/mL and 251.5 minmicrog/mL. Of 31 evaluable patients, 4 (13%) (3 AML, 1 Ph+ALL) achieved a CR (1 at a dose of 800 mg/m2; 2 at 600 mg/m2; 1 at 200mg/m2). The recommended phase II regimen is Triapine 105 mg/m2/day followed by ara-C 600 mg/m2/day for 5 consecutive days every 3-6 weeks.

Acute Disease↗
PubMed2005

Basic characterization of 64Cu-ATSM as a radiotherapy agent.

64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) is a promising radiotherapy agent for the treatment of hypoxic tumors. In an attempt to elucidate the radiobiological basis of 64Cu-ATSM radiotherapy, we have investigated the cellular response patterns in vitro cell line models. Cells were incubated with 64Cu-ATSM, and the dose-response curves were obtained by performing a clonogenic survival assay. Radiation-induced damage in DNA was evaluated using the alkali comet assay and apoptotic cells were detected using Annexin V-FITC and propidium iodide staining methods. Washout rate and subcellular distribution of 64Cu in cells were investigated to further assess the effectiveness of 64Cu-ATSM therapy on a molecular basis. A direct comparison of subcellular localization of Cu-ATSM was made with the flow tracer analog Cu-pyruvladehyde-bis(N4-methylthiosemicarbazone). In this study, 64Cu-ATSM was shown to reduce the clonogenic survival rate of tumor cells in a dose-dependent manner. Under hypoxic conditions, cells took up 64Cu-ATSM and radioactive 64Cu was highly accumulated in the cells. In the 64Cu-ATSM-treated cells, DNA damage by the radiation emitted from 64Cu was detected, and inhibition of cell proliferation and induction of apoptosis was observed at 24 and 36 h after the treatment. The typical features of postmitotic apoptosis induced by radiation were observed following 64Cu-ATSM treatment. The majority of the 64Cu taken up into the cells remained in the postmitochondrial supernatant (the cellular residue after removal of the nuclei and mitochondria), which indicates that the beta- particle emitted from 64Cu may be as effective as the Auger electrons in 64Cu-ATSM therapy. These data allow us to postulate that 64Cu-ATSM will be able to attack the hypoxic tumor cells directly, as well as potentially affecting the peripheral nonhypoxic regions indirectly by the beta- particle decay of 64Cu.

Animals↗
PubMed2005

Cell line-dependent differences in uptake and retention of the hypoxia-selective nuclear imaging agent Cu-ATSM.

BACKGROUND: Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) [Cu-ATSM] is a potential marker for tumor hypoxia that has been under evaluation for clinical use. In this study, we examined the mechanisms underlying the uptake of (64)Cu in cells incubated with (64)Cu-ATSM. METHODS: The in vitro uptake of (64)Cu was determined as a function of oxygenation conditions and incubation time with (64)Cu-ATSM using four and two tumor cell lines of human origin and rodent origin, respectively. Additionally, the rate of (64)Cu efflux and Cu-ATSM metabolism was determined. RESULTS: (64)Cu accumulation is rapid during the first 0.5-1 h of incubation. It is highest in anoxic cells but is also significant in normoxic cells. After this initial period, the level of intracellular (64)Cu varies depending on the cell line and the oxygenation conditions and, in some circumstances, may decrease. During the first 0.5-1 h, the ratio of (64)Cu levels between anoxic and normoxic cells is approximately 2:10 and that between hypoxic (0.5% O(2)) and normoxic cells is approximately 1:2.5, depending on the cell line. These ratios generally decrease at longer times. The (64)Cu-ATSM compound was found to be metabolized during incubation in a manner dependent on oxygenation conditions. Within 2 h under anoxic conditions, (64)Cu-ATSM could no longer be detected, although 60-90% of the amount of (64)Cu added as (64)Cu-ATSM was present in the medium. Non-ATSM (64)Cu was taken up by the cells, albeit at a much slower rate. Efflux rates of (64)Cu were found to be cell line dependent and appeared to be inversely correlated with the final (64)Cu uptake levels under anoxic conditions. CONCLUSION: The uptake and retention of (64)Cu and their relation to oxygenation conditions were found to be cell line dependent. Given the complexities in the oxygen dependence and cell line-dependent kinetics of uptake and retention of Cu following exposure to Cu-ATSM, the clinical utility of this compound may be disease site specific.

Animals↗
PubMed2006

An improved 62Zn/62Cu generator based on a cation exchanger and its fully remote-controlled preparation for clinical use.

OBJECTIVE: The goal of this study was to develop an improved (62)Zn/(62)Cu generator based on cation exchange resin and remote preparation at high radioactivity scale for clinical use. METHODS: A natural Cu target was irradiated with proton beam in the energy range of 30-->19 MeV at a beam current of 10 muA for 1 h to obtain around 1.7 GBq of (62)Zn. The (62)Zn was isolated from the Cu target on an anion exchange column with more than 97% yield within 2.5 h from the EOB. The (62)Zn/(62)Cu generator was prepared by loading the (62)Zn(2+) on a Sep-Pak plus CM cartridge. RESULTS: The generator showed high elution efficiency ( approximately 96%) using a small volume (ca. 3 ml) of a 200-mM glycine solution with a very low breakthrough of (62)Zn (<0.1%). CONCLUSIONS: This (62)Zn/(62)Cu generator has been proven to be highly useful as a source of (62)Cu for the synthesis of (62)Cu-labeled compounds. The clinical application of [(62)Cu]Cu-ATSM produced with this generator has been already approved by the Institutional Review Board at the National Institute of Radiological Sciences.

Cation Exchange Resins↗
PubMed2006

Double-tracer autoradiography with Cu-ATSM/FDG and immunohistochemical interpretation in four different mouse implanted tumor models.

BACKGROUND: We studied the regional characteristics within tumor masses using PET tracers and immunohistochemical methods. METHODS: The intratumoral distribution of (64)Cu-diacetyl-bis(N4-methylthiosemicarbazone) ([(64)Cu]Cu-ATSM) and [(18)F] 2-fluoro-2-deoxyglucose ((18)F]FDG) in mice with tumors of four different origins (LLC1, Meth-A, B16 and colon26) was compared with the immunohistochemical staining of proliferating cells (Ki67), blood vessels (CD34 or von Willebrand factor), and apoptotic cells (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling method). RESULTS: With all cell lines, [(64)Cu]Cu-ATSM and [(18)F]FDG were distributed with different gradation in the tumor mass. The immunohistochemical study demonstrated that the high [(64)Cu]Cu-ATSM uptake regions were hypovascular and consisted of tumor cells arrested in the cell cycle, whereas the high [(18)F]FDG uptake regions were hypervascular and consisted of proliferating cells. CONCLUSION: In our study, it was revealed that one tumor mass contained two regions with different characteristics, which could be distinguished by [(64)Cu]Cu-ATSM and [(18)F]FDG. Because hypoxia and cell cycle arrest are critical factors to reduce tumor sensitivity to radiation and conventional chemotherapy, regions with such characteristics should be treated intensively as one of the primary targets. [(64)Cu]Cu-ATSM, which can delineate hypoxic and cell cycle-arrested regions in tumors, may provide valuable information for cancer treatment as well as possibly for treating such regions directly as an internal radiotherapy reagent.

Animals↗
PubMed2005

Evaluation of the acidity constants of the 4-hidroxy-5-[salicylideneamino]-2-7-naphthalenedisulfonic acid (Azomethine-H) using UV-vis spectrophotometry.

The time stability of the azomethine-H species was determined not to be better than 10 min in the absence of oxygen and light, however under phosphate buffered conditions the azomethine-H species remained stable for longer periods, as indicated by the spectrophotometric behaviour. Nevertheless, the analysis time still exceeded the stability allowance. Therefore, the determination of the acidity constants of the Azomethine-H species was studied by means of UV-vis spectrophotometry in buffered media by means of the point-by-point analysis and data processing with SQUAD to refine the resulting constants, which were: pK(a1) = 3.39, pK(a2) 7.36 and pK(a3) 8.73. The latter were associated to the corresponding acid-base equilibria of the amine and hydroxy groups constituting the molecule.

Buffers↗