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  • 11
    Electronic Resource
    Electronic Resource
    Cell signalling and cancer treatment (1998)
    Springer
    Journal of cancer research and clinical oncology 124 (1998), S. 462-469 
    Details
    ISSN: 1432-1335
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004320050200
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  • 12
    Electronic Resource
    Electronic Resource
    Disposition and metabolism in mice of the potential antitumor and anti-human immunodeficiency virus-1 agent, 2-chloro-2′,3′-dideoxyadenosine (1991)
    Springer
    Cancer chemotherapy and pharmacology 27 (1991), S. 285-289 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A high-performance liquid chromatographic (HPLC) procedure was developed to examine the preclinical pharmacology and pharmacokinetics of 2-chloro-2′,3′-dideoxyadenosine (ClddAd). The HPLC assay for ClddAd in human plasma was linear from 0.25 to 500 μg ClddAd/ml. Coefficients of variation for the measurement of ClddAd in human plasma were 9.7%, 4.1%, and 2.7% at 2.5, 25, and 250 μg/ml, respectively. Binding of ClddAd to human and mouse plasma proteins was determined by filtration to be 26,9% and 34.4%, respectively. ClddAd concentrations decreased by 〈5% when ClddAd was stored for 126 h at 37° C in 0.9% NaCl or 0.1m NaH2PO4 (pH 7.4) or when ClddAd was stored for 24 h at 37° C in citrate-buffered human blood or plasma. Estimates of the lethal dose for 50% (LD50) and 10% (LD10) of male CD2F1 mice that received a single i.v. dose of ClddAd were 27 and 24 mg/kg, respectively. Elimination of a 24-mg/kg i.v. bolus dose of ClddAd from mouse plasma was biphasic, with half-lives of 0.73 and 14.7 min. The apparent volume of distribution of ClddAd was 215 ml/kg and total body clearance was 20 ml min−1 kg−1. No ClddAd metabolites were detected in mouse plasma after in vivo exposure or in human whole blood or plasma after in vitro incubation. ClddAd was detected in the urine of mice within 2 min after exposure, and the total urinary excretion of unchanged ClddAd for 24 h after exposure to 24 mg/kg was 3.4% of the delivered dose. At least two possible ClddAd metabolites were detected in mouse urine; they did not co-elute with 2-chloro-2′,3′-dideoxy-inosine, 2-chloroadenine, or 2-chlorohypoxanthine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685113
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  • 13
    Electronic Resource
    Electronic Resource
    Inhibition of growth factor binding and intracellular Ca2+ signalling by dextran sulfates of different sizes and degrees of sulfation (1992)
    Springer
    Cancer chemotherapy and pharmacology 30 (1992), S. 483-486 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ability of dextran sulfates of varying molecular sizes (5–500 kDa) and degrees of sulfate substitution (0.3–1.9) to inhibit the binding of platelet-derived growth factor (PDGF) to intact Swiss 3T3 fibroblasts and to inhibit inositol(1,4,5)trisphosphate-dependent release of Ca2+ in permeabilized Swiss 3T3 cells was examined in the present study. Significant correlations were found between increased molecular size of the dextran sulfates and inhibition of both PDGF binding (r=0.77) and Ca2+ release (r=0.72). The degree of sulfate substitution did not correlate with inhibition of either activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685602
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  • 14
    Electronic Resource
    Electronic Resource
    Reversible inhibition of human thioredoxin reductase activity by cytotoxic alkyl 2-imidazolyl disulfide analogues (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 434-438 
    Details
    ISSN: 1432-0843
    Keywords: Key words: Thioredoxin  –  Thioredoxin reductase  –  Disulphides  –  Growth inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. The thioredoxin/thioredoxin reductase system is important for several aspects of the regulation of cellular proliferation by both intracellular and extracellular mechanisms. The effects of n-butyl 2-imidazolyl disulfide (III-2), 1-methylpropyl 2-imidazolyl disulfide (IV-2), and n-decyl 2-imidazolyl disulfide (VII-2) on purified human placental thioredoxin reductase activity were examined. The analogues were competitive inhibitors with DTNB for reduction by thioredoxin reductase, with K i values for III-2, IV-2, and VII-2 being 3.3, 13.0, and 8.6 μM, respectively. The inhibition was noncompetitive with reduced nicotinamide adenine dinucleotide phosphate (NADPH). None of the analogues was a suicide substrate inhibitor of the flavoenzyme. III-2 and VII-2 were metabolized by thioredoxin reductase at about half the rate of DTNB, whereas IV-2 was not detectably metabolized. The second order rate constants for the reactions of III-2 and IV-2 with reduced GSH were 931 and 91 M  – 1 s – 1, respectively. The lower reactivity of IV-2 with reduced GSH and the lack of the analogue’s metabolism by thioredoxin reductase may be due to the more sterically hindered structure of this analogue. The 50% inhibitory concentrations (IC50 values) for the inhibition of serum-dependent cellular proliferation of Swiss 3T3 murine fibroblasts by III-2, IV-2, and VII-2 were 2.0, 3.5, and 4.0 μM, respectively. IV-2 was considerably more potent as an inhibitor of the thioredoxin-dependent cellular proliferation of Swiss 3T3 fibroblasts, showing an IC50 value of 60 nM. Thus, inhibition of cellular proliferation by alkyl 2-imidazolyl disulfide analogues may involve interaction with thioredoxin, thioredoxin reductase, or an alternative target that is redox-regulated by thioredoxin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685570
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  • 15
    Electronic Resource
    Electronic Resource
    Increased toxicity of the antitumor drug cyclophosphamide in mice in the presence of the volatile anesthetic agent halothane (1986)
    Springer
    Cancer chemotherapy and pharmacology 16 (1986), S. 35-42 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Exposure of mice to 0.5% halothane in air, which is close to a maintenance concentration in man, after an IP dose of cyclophosphamide produced an increase in the lethality of cyclophosphamide. The LD50 (30 day) for cyclophosphamide without halothane was 251 mg/kg; with 2 h subsequent exposure to halothane it was 152 mg/kg; and with 20 h subsequent exposure to halothane it was 158 mg/kg. The median survival time of mice receiving cyclophosphamide at doses between 137 and 240 mg/kg was more than 30 days in the absence of halothane, 12 days with 2 h halothane, and 10.5 days with 20 h halothane exposure. Survival of mice was decreased irrespective of whether 2 h halothane exposure preceded or followed cyclophosphamide administration. Separation of cyclophosphamide administration and preexposure to halothane by breathing air for 1 h abolished the decrease in survival. Halothane exposure for 2 h after cyclophosphamide had no effect on the antitumor activity of cyclophosphamide. Total-body clearance of cyclophosphamide in mice exposed to halothane was 60 ml/min/kg, as against 188 ml/min/kg in nonexposed mice. No change was produced by halothane in the area under the plasma concentration-time curve over 2 h for 4-hydroxycyclophosphamide following cyclophosphamide administration. The reason for the increased lethality of cyclophosphamide in the presence of halothane could not be determined. There was no increase in leukopenia caused by cyclophosphamide and no increase in bladder toxicity, in liver toxicity, in renal toxicity, or in the penetration of cyclophosphamide into the brain. The study, together with reports of increased toxicity in patients receiving cancer chemotherapy in close proximity to general anesthesia, should alert physicians and others to the possibility of an interaction between volatile anesthetic agents and chemotherapeutic drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00255283
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  • 16
    Electronic Resource
    Electronic Resource
    Disposition and metabolism of the antitumor glycoside phyllanthoside in mouse and beagle dog (1986)
    Springer
    Cancer chemotherapy and pharmacology 16 (1986), S. 218-222 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Phyllanthoside is a naturally occurring glycoside with activity against IP transplantable murine tumors. Phyllanthoside administered IV, to mice at a nontoxic dose of 16 mg/kg could not be detected in blood or plasma even 30 s after administration. There was rapid formation of a less polar metabolite, which disappeared with a half-life of about 10 min. When phyllanthoside was administered as an IV bolus to beagle dogs at doses of 0.1, 0.5, and 3.0 mg/kg the mean half-life of phyllanthoside elimination from plasma was 1.3 min and total body clearance 85.8 ml min-1 kg-1. A second phase of elimination was seen but could not be accurately defined. Only trace amounts of the less polar metabolite were detected in dog plasma. Infusion of phyllanthoside to beagle dogs at doses of 0.5 and 3.0 mg/kg over 70 min gave values for an initial half-life of 0.3 and 0.6 min, a terminal half-life of 99.4 and 16.5 min, and a total body clearance of 11.2 and 49.2 ml min-1 kg-1, respectively. The highest nontoxi dose of phyllanthoside in dog was 0.1 mg/kg, while doses of 0.5 mg/kg and 3.0 mg/kg resulted in ataxia and death of the dog. There was no difference in toxicity to dog according to whether phyllanthoside was given by IV bolus or continuous infusion. Isolated hepatocytes from rat metabolized phyllanthoside at a rate of 4.4 μg/min per 106 cells to form the less polar metabolite. Coculture with isolated hepatocytes decreased the cytotoxicity of phyllanthoside to A204 human rhabdomyosarcoma cell line growing in soft agarose. It is suggested that rapid metabolism of phyllanthoside in mouse as against dog might account for the lower toxicity of phyllanthoside in mouse, and might also account for the reported poor antitumor activity of IV-administered phyllanthoside in the mouse.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00293981
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  • 17
    Electronic Resource
    Electronic Resource
    Disposition and metabolism of the antitumor agent pyrazine-2-diazohydroxide in mouse and beagle dog (1988)
    Springer
    Cancer chemotherapy and pharmacology 21 (1988), S. 269-273 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pharmacokinetics and metabolism of pyrazine-2-diazohydroxide have been studied in the beagle dog and mouse. When pyrazine-2-diazohydroxide was administered to beagle dogs at a dose of 18.6 mg/kg (428 mg/m2) by i. v. bolus, the plasma half-life (t1/2) was 7.3 min, the apparent volume of distribution (Vd) 577 ml/kg, and the total body clearance (Cl) 55 ml/min per kg. In mice given pyrazine-2-diazohydroxide by i. v. bolus at 100 mg/kg (428 mg/m2), the t1/2 was 5.8 min, the Vd 250 ml/kg, and the Cl 30 ml/min per kg. When [2-14C]pyrazine-2-diazohydroxide was infused i. v. to mice at 100 mg/kg over 8 h, the Cl for parent drug was 122 ml/min per kg. The major product formed from pyrazine-2-diazohydroxide was 2-hydroxypyrazine, which accounted for 80% of the total radioactivity in the plasma after a 6-h drug infusion. These were three other metabolites in plasma, two more polar than pyrazine-2-diazohydroxide, which accounted for 7% of the radioactivity, and one less polar, which accounted for 5% of the radioactivity. Following an i. v. bolus dose of [2-14C]pyrazine-2-diazohydroxide, 79% of the radioactivity was excreted in the urine in 24 h, 3% in the feces, and 0.4% in the expired air; 18% remained in the carcass. The liver and kidney showed the highest tissue levels of radioactivity. 2-Hydroxypyrazine accounted for 45% of the urinary radioactivity, pyrazine-2-diazohydroxide for 14%, and a glucuronide or sulfate conjugate of 2-hydroxypyrazine for 17%. Twenty-four percent of the radioactivity eluted near the void volume on high-performance liquid chromatography and was not identified.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00264190
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  • 18
    Electronic Resource
    Electronic Resource
    Preclinical pharmacologic studies of the new antitumor agent carmethizole (NSC-602668) in the mouse and beagle dog (1989)
    Springer
    Cancer chemotherapy and pharmacology 24 (1989), S. 277-283 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The chemical breakdown of carmethizole [1-methyl-2-methylthio-4,5-bis-(hydroxymethyl)imidazole-4′,5′-bis(N-methylcarbamate)hydrochloride] and its pharmacokinetics in the mouse and beagle dog were studied. Carmethizole was relatively unstable in aqueous media, having a half-life of ≤1 h in 0.9% sodium chloride, human whole blood, human plasma, and dog urine at 37°C. Its major breakdown product in 0.9% sodium chloride and pH 5.0 sodium phosphate buffer was carmethizole diol. When carmethizole was added to pH 7.0 or pH 9.0 sodium phosphate buffer, the major breakdown product was carmethizole diol-4′-monophosphate. Carmethizole reacted directly with glutathione at pH 8.0, forming a glutathione adduct of carmethizole monocarbamate. Elimination of the drug from the plasma of the beagle dog following i.v. bolus doses of 22.4 and 4.3 mg/kg was biphasic. At these doses the terminal half-life was 39 and 46 min, respectively, and the respective total body clearance was 4.6 and 7.7 ml/min per kg. The 22.4 mg/kg dose was lethal to the beagle dog by day 4. Elimination of carmethizole from the plasma of mice following an i. v. bolus dose of 115 mg/kg was monoexponential, with a half-life of 11.6 min and a total body plasma clearance of 43.6 ml/min per kg. When the drug was infused at 230 mg/kg over 8 h into mice, the total body clearance was 40.8 ml/min per kg. Following the i.v. bolus administration of carmethizole to mice, 30% of the total dose was excreted in urine over 3 h as carmethizole diol, 10%, as carmethizole diol-sulfate, 3.4%, as carmethizole 4′-monocarbamate, and 2.4%, as unchanged drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00304758
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  • 19
    Electronic Resource
    Electronic Resource
    D-3-Deoxy-3-substitutedmyo-inositol analogues as inhibitors of cell growth (1991)
    Springer
    Cancer chemotherapy and pharmacology 29 (1991), S. 95-104 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A number of unnaturald-3-deoxy-3-substitutedmyo-inositols were synthesized and their effects on the growth of wild-type NIH 3T3 cells and oncogenetransformed NIH 3T3 cells were studied. The compounds were found to exhibit a diversity of growth-inhibitory activities and showed selectivity in inhibiting the growth of some transformed cells as compared with wild-type cells. Remarkably,d-3-deoxy-3-azido-myo-inositol exhibited potent growth-inhibitory effects toward v-sis-transformed NIH 3T3 cells but had little effect on the growth of wildtype cells. The growth-inhibitory effects of themyo-inositol analogues were antagonized bymyo-inositol. Since [3H]-3-deoxy-3-fluoro-myo-inositol was shown to be taken up by cells and incorporated into cellular phospholipids, we suggest that these unnaturalmyo-inositol analogues may act as antimetabolites in the phosphatidylinositol intracellular signalling pathways. Because cells transformed by oncogenes often exhibit elevated phosphatidylinositol turnover, the inhibition of signalling pathways that mediate oncogene action could offer new opportunities for controlling the growth of cancer cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00687317
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  • 20
    Electronic Resource
    Electronic Resource
    Reversible inhibition of human thioredoxin reductase activity by cytotoxic alkyl 2-imidazolyl disulfide analogues (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 434-438 
    Details
    ISSN: 1432-0843
    Keywords: Thioredoxin ; Thioredoxin reductase ; Disulphides ; Growth inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The thioredoxin/thioredoxin reductase system is important for several aspects of the regulation of cellular proliferation by both intracellular and extracellular mechanisms. The effects ofn-butyl 2-imidazolyl disulfide (III-2), 1-methylpropyl 2-imidazolyl disulfide (IV-2), andn-decyl 2-imidazolyl disulfide (VII-2) on purified human placental thioredoxin reductase activity were examined. The analogues were competitive inhibitors with DTNB for reduction by thioredoxin reductase, withK i values for III-2, IV-2, and VII-2 being 3.3, 13.0, and 8.6 μM, respectively. The inhibition was noncompetitive with reduced nicotinamide adenine dinucleotide phosphate (NADPH). None of the analogues was a suicide substrate inhibitor of the flavoenzyme. III-2 and VII-2 were metabolized by thioredoxin reductase at about half the rate of DTNB, whereas IV-2 was not detectably metabolized. The second order rate constants for the reactions of III-2 and IV-2 with reduced GSH were 931 and 91M −1 s−1, respectively. The lower reactivity of IV-2 with reduced GSH and the lack of the analogue's metabolism by thioredoxin reductase may be due to the more sterically hindered structure of this analogue. The 50% inhibitory concentrations (IC50 values) for the inhibition of serum-dependent cellular proliferation of Swiss 3T3 murine fibroblasts by III-2, IV-2, and VII-2 were 2.0, 3.5, and 4.0 μM, respectively. IV-2 was considerably more potent as an inhibitor of the thioredoxin-dependent cellular proliferation of Swiss 3T3 fibroblasts, showing an IC50 value of 60 nM. Thus, inhibition of cellular proliferation by alkyl 2-imidazolyl disulfide analogues may involve interaction with thioredoxin, thioredoxin reductase, or an alternative target that is redox-regulated by thioredoxin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685570
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