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  • 21
    Electronic Resource
    Electronic Resource
    Mitomycin C is not metabolized by but is an inhibitor of human kidney NAD(P)H:(quinone-acceptor)oxidoreductase (1988)
    Springer
    Cancer chemotherapy and pharmacology 22 (1988), S. 126-130 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary It has been suggested that quinone reductase [NAD(P)H:(quinone-acceptor)oxidoreductase], also known as DT-diaphorase, protects hypoxic cells against mitomycin C cytotoxicity by metabolizing mitomycin C to less toxic metabolites. This hypothesis is based on an increase in mitomycin C's cytotoxicity in the presence of the potent quinone reductase inhibitor dicumarol. It has been suggested that under aerobic conditions the metabolism of mitomycin C by quinone reductase leads to the formation of cytotoxic metabolites. In the present study, mitomycin C was found not to be a substrate for partially purified quinone reductase from human kidney. Mitomycin C did not cause the oxidation of NADPH by quinone reductase and there was no utilization of mitomycin C and no appearance of its metabolites. Quinone reductase did not catalyze the formation of alkylating metabolites from mitomycin C, determined by the lack of formation of 4-(p-nitrobenzyl)pyridine conjugates. However, mitomycin C was a weak competitive inhibitor of quinone reductase with dichloroindophenol as the substrate, with Ki=0.32 mM. Therefore, the alteration of mitomycin C's cytotoxicity by dicumarol in tumor cell lines appears to involve a mechanism other than the direct inhibition of mitomycin C reduction by quinone reductase.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00257309
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  • 22
    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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  • 23
    Electronic Resource
    Electronic Resource
    Increased intracellular Ca2+ signaling caused by the antitumor agent helenalin and its analogues (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 344-350 
    Details
    ISSN: 1432-0843
    Keywords: Key words: Intracellular Ca2+– Helenalin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. The antitumor sesquiterpene lactone helenalin, which is found in species of the plant genus Helenium, caused a marked potentiation of the increases in intracellular free Ca2+ concentration ([Ca2+]i) produced by mitogens such as vasopressin, bradykinin, and platelet-derived growth factor in Swiss mouse 3T3 fibroblasts. Removing external Ca2+ partly attenuated the increased [Ca2+]i responses caused by helenalin. The increased [Ca2+]i responses occurred at concentrations of helenalin that inhibited cell proliferation. At higher concentrations, helenalin inhibited the [Ca2+]i responses. No change in resting [Ca2+]i was caused by helenalin even at high concentrations. Other helenalin analogues also increased the [Ca2+]i response. Helenalin did not inhibit protein kinase C (PKC) and PKC appeared to play a minor role in the effects of helenalin on [Ca2+]i responses in intact cells. Studies with saponin-permeabilized HT-29 human colon carcinosarcoma cells indicated that helenalin caused an increased accumulation of Ca2+ into nonmitochondrial stores and that the potentiating effect of helenalin on mitogen-stimulated [Ca2+]i responses was due in part to an increase in the inositol-(1,4,5)-trisphosphate-mediated release of Ca2+ from these stores.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050152
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  • 24
    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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  • 25
    Electronic Resource
    Electronic Resource
    Anticancer drug pharmacodynamics (1985)
    Springer
    Cancer chemotherapy and pharmacology 14 (1985), S. 177-183 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A considerable amount of information is available on the pharmacokinetics of anticancer drugs, but much less is known of their pharmacodynamics, that is of the relationship between therapeutic or toxic response and drug concentration. Drug dosage regimens which are to achieve defined therapeutic objectives can only be designed when both the pharmacokinetic and the pharmacodynamic characteristics of a drug are known. There are a few reports in the literature of relationships in man between toxic response and pharmacokinetic parameters of anticancer drugs; and an even smaller number of reports of relationships between therapeutic response and pharmacokinetic parameters. It is suggested that the lack of pharmacodynamic information is currently limiting the application of pharmacokinetic information to cancer therapy. Ways of improving knowledge of the pharmacodynamics of anticancer drugs are suggested.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00258112
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  • 26
    Electronic Resource
    Electronic Resource
    Effects of advanced leukemia on hepatic drug-metabolizing activity in the mouse (1986)
    Springer
    Cancer chemotherapy and pharmacology 16 (1986), S. 43-49 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mice that had received 106 P388 leukemia cells IV 8 days previously exhibited a decrease in the components of the hepatic microsomal mixed function oxidase, with a 58% decrease in cytochrome P-450, and up to a 60% decrease in hepatic microsomal metabolism of biphenyl. Liver weight was increased by 49% due to infiltration of the liver with leukemic cells. Changes in liver drug-metabolizing activity and liver weight were not seen 6 days after administration of P388 leukemia. There was a small increase in serum liver enzyme but no increase in total serum bilirubin in tumor-bearing mice. In vivo total-body plasma clearance of cyclophosphamide, a drug metabolized by hepatic cytochrome P-450, was decreased to 53 ml/min/kg in mice that had received P388 cells 8 days earlier, as against 97.2 ml/min/kg in control mice. Cytochrome P-450-independent metabolism of [14C]5-fluorouracil, measured by means of [14C]CO2in the breath over 3 h, was decreased to 21% of the dose administered by 8 days after tumor cell administration, compared with 31% of the dose in control mice. P388 leukemia cells growing in the ascitic form in the intraperitoneal cavity of mice did not release an inhibitor of 5-fluorouracil metabolism into the ascitic fluid. Total-body plasma clearance of indocyanine green was decreased to 11 ml/min/kg by 8 days after P388 cell administration, compared with 36 ml/min/kg in control mice. The decrease in indocyanine green clearance might reflect a decrease in hepatic blood flow in the tumor-bearing mice. A possible explanation for the decrease in hepatic drug metabolism caused by P388 leukemia is that the hepatocytes are deprived of oxygen and nutrients by the tumor in the liver, coupled with or caused by a physical obstruction of hepatic blood flow.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00255284
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  • 27
    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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  • 28
    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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  • 29
    Electronic Resource
    Electronic Resource
    Increased intracellular Ca2+ signaling caused by the antitumor agent helenalin and its analogues (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 344-350 
    Details
    ISSN: 1432-0843
    Keywords: Intracellular Ca2+ ; Helenalin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The antitumor sesquiterpene lactone helenalin, which is found in species of the plant genusHelenium, cause a marked potentiation of the increases in intracellular free Ca2+ concentration ([Ca2+]i) produced by mitogens such as vasopressin, bradykinin, and platelet-derived growth factor in Swiss mouse 3T3 fibroblasts. Removing external Ca2+ partly attenuated the increased [Ca2+]i response. caused by helenalin. The increased [Ca2+]i responses occurred at concentrations of helenalin that inhibited cell proliferation. At higher concentrations, helenalin inhibited the [Ca2+]i responses. No change in resting [Ca2+]i was caused by helenalin even at high concentrations. Other helenalin analogues also increased the [Ca2+]i response. Helenalin did not inhibit protein kinase C (PKC) and PKC appeared to play a minor role in the effects of helenalin on [Ca2+]i responses in intact cells. Studies with saponin-permeabilized HT-29 human colon carcinosarcoma cells indicated that helenalin caused an increased accumulation of Ca2+ into nonmitochondrial stores and that the potentiating effect of helenalin on mitogen-stimulated [Ca2+]i responses was due in part to an increase in the inositol-(1,4,5)-trisphosphate-mediated release of Ca2+ from these stores.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686043
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  • 30
    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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