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Alan C Sartorelli - One of the best experts on this subject based on the ideXlab platform.
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the intracellular location of nadh cytochrome b5 reductase modulates the cytotoxicity of the Mitomycins to chinese hamster ovary cells
Journal of Biological Chemistry, 1998Co-Authors: Michael F Belcourt, William F Hodnick, Sara Rockwell, Alan C SartorelliAbstract:Abstract NADH:cytochrome b 5reductase activates the Mitomycins to alkylating intermediates in vitro. To investigate the intracellular role of this enzyme in Mitomycin bioactivation, Chinese hamster ovary cell transfectants overexpressing rat NADH:cytochrome b 5 reductase were generated. An NADH:cytochrome b 5reductase-transfected clone expressed 9-fold more enzyme than did parental cells; the levels of other Mitomycin-activating oxidoreductases were unchanged. Although this enzyme activates the Mitomycins in vitro, its overexpression in living cells caused decreases in sensitivity to Mitomycin C in air and decreases in sensitivity to porfiromycin under both air and hypoxia. Mitomycin C cytotoxicity under hypoxia was similar to parental cells. Because NADH:cytochrome b 5 reductase resides predominantly in the mitochondria of these cells, this enzyme may sequester these drugs in this compartment, thereby decreasing nuclear DNA alkylations and reducing cytotoxicity. A cytosolic form of NADH:cytochrome b 5 reductase was generated. Transfectants expressing the cytosolic enzyme were restored to parental line sensitivity to both Mitomycin C and porfiromycin in air with marked increases in drug sensitivity under hypoxia. The results implicate NADH:cytochrome b 5 reductase in the differential bioactivation of the Mitomycins and indicate that the subcellular site of drug activation can have complex effects on drug cytotoxicity.
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reductive activation of Mitomycin c by nadh cytochrome b5 reductase
Cancer Research, 1993Co-Authors: William F Hodnick, Alan C SartorelliAbstract:Abstract Mitomycin C requires bioreduction in order to exert its cytotoxic action. Activation of Mitomycin C to an electrophile was equally supported by NADPH and NADH in EMT6 tumor cell sonicates under hypoxia. No alkylation was observed under aerobic conditions. Purified NADH:cytochrome b 5 reductase catalyzed the reduction of Mitomycin C with a K m of 23 µm at pH 6.6. At pH 7.6, the rate of enzymatic reduction of Mitomycin C was 61% of that at pH 6.6. NADH:cytochrome b 5 reductase catalyzed the activation of Mitomycin C to alkylating metabolites under both hypoxic and aerobic conditions, with alkylation being 1.5 times greater in hypoxia. Dicumarol at 100 µm inhibited the NADH:cytochrome b 5 reductase-catalyzed reduction of Mitomycin C by 24% and by 57% at 300 µm. The degree of inhibition of the enzyme by dicumarol was the same at both pH 6.6 and 7.6. NADH:cytochrome b 5 reductase exhibited a small but measurable NADH-oxidase activity, which was unaffected by 300 µm dicumarol. These findings demonstrate that ( a ) NADH:cytochrome b 5 reductase can metabolically activate Mitomycin C and ( b ) dicumarol is capable of inhibiting this enzymatic activity.
Wim P J Witjes - One of the best experts on this subject based on the ideXlab platform.
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results of a randomized phase iii trial of sequential intravesical therapy with Mitomycin c and bacillus calmette guerin versus Mitomycin c alone in patients with superficial bladder cancer
The Journal of Urology, 1998Co-Authors: J A Witjes, C T M Caris, N A Mungan, F M J Debruyne, Wim P J WitjesAbstract:AbstractPurpose: We study toxicity and efficacy of sequential intravesical therapy with Mitomycin C and bacillus Calmette-Guerin (BCG) in patients with intermediate or high risk superficial bladder cancer compared to the use of intravesical Mitomycin C alone.Materials and Methods: Patients with intermediate and high risk papillary superficial bladder cancer and carcinoma in situ were randomized after transurethral resection between 4 weekly instillations with 40 mg. Mitomycin C followed by 6 weekly instillations with BCG (group 1, 90 patients) or 10 weekly instillations with Mitomycin C (group 2, 92 patients).Results: The frequency of bacterial and chemical cystitis, and other local side effects was similar in both groups. Allergic reactions, including skin rash, were more frequent in the Mitomycin C only group (12 of 92 patients versus 5 of 90, p = 0.08), and other systemic side effects were more frequent in the sequential group (16 of 90 versus 8 of 92, p = 0.07). After a median followup of 32 months th...
P R Bock - One of the best experts on this subject based on the ideXlab platform.
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intravesical bacillus calmette guerin versus Mitomycin c for superficial bladder cancer a formal meta analysis of comparative studies on recurrence and toxicity
The Journal of Urology, 2003Co-Authors: Andreas Bohle, Dieter Jocham, P R BockAbstract:Purpose: We compare the therapeutic efficacy and toxicity of intravesical bacillus Calmette-Guerin (BCG) with Mitomycin C on recurrence of stages Ta and T1 bladder carcinoma.Materials and Methods: Combined published and unpublished data from comparative studies on BCG versus Mitomycin C for superficial bladder carcinoma considering possible confounding factors were analyzed. Odds ratio (OR) and its 95% CI were used as primary effect size estimate. Toxicity data were evaluated descriptively.Results: In 11 eligible clinical trials 1,421 patients were treated with BCG and 1,328 were treated with Mitomycin C. Within the overall median followup time of 26 months 38.6% of the patients in the BCG group and 46.4% of those in the Mitomycin C group had tumor recurrence. In 7 of 11 studies BCG was significantly superior to Mitomycin C, in 3 studies no significant difference was found, while in 1 study Mitomycin C was significantly superior to BCG. An overall statistically significant superiority of BCG versus mitomy...
William F Hodnick - One of the best experts on this subject based on the ideXlab platform.
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the intracellular location of nadh cytochrome b5 reductase modulates the cytotoxicity of the Mitomycins to chinese hamster ovary cells
Journal of Biological Chemistry, 1998Co-Authors: Michael F Belcourt, William F Hodnick, Sara Rockwell, Alan C SartorelliAbstract:Abstract NADH:cytochrome b 5reductase activates the Mitomycins to alkylating intermediates in vitro. To investigate the intracellular role of this enzyme in Mitomycin bioactivation, Chinese hamster ovary cell transfectants overexpressing rat NADH:cytochrome b 5 reductase were generated. An NADH:cytochrome b 5reductase-transfected clone expressed 9-fold more enzyme than did parental cells; the levels of other Mitomycin-activating oxidoreductases were unchanged. Although this enzyme activates the Mitomycins in vitro, its overexpression in living cells caused decreases in sensitivity to Mitomycin C in air and decreases in sensitivity to porfiromycin under both air and hypoxia. Mitomycin C cytotoxicity under hypoxia was similar to parental cells. Because NADH:cytochrome b 5 reductase resides predominantly in the mitochondria of these cells, this enzyme may sequester these drugs in this compartment, thereby decreasing nuclear DNA alkylations and reducing cytotoxicity. A cytosolic form of NADH:cytochrome b 5 reductase was generated. Transfectants expressing the cytosolic enzyme were restored to parental line sensitivity to both Mitomycin C and porfiromycin in air with marked increases in drug sensitivity under hypoxia. The results implicate NADH:cytochrome b 5 reductase in the differential bioactivation of the Mitomycins and indicate that the subcellular site of drug activation can have complex effects on drug cytotoxicity.
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reductive activation of Mitomycin c by nadh cytochrome b5 reductase
Cancer Research, 1993Co-Authors: William F Hodnick, Alan C SartorelliAbstract:Abstract Mitomycin C requires bioreduction in order to exert its cytotoxic action. Activation of Mitomycin C to an electrophile was equally supported by NADPH and NADH in EMT6 tumor cell sonicates under hypoxia. No alkylation was observed under aerobic conditions. Purified NADH:cytochrome b 5 reductase catalyzed the reduction of Mitomycin C with a K m of 23 µm at pH 6.6. At pH 7.6, the rate of enzymatic reduction of Mitomycin C was 61% of that at pH 6.6. NADH:cytochrome b 5 reductase catalyzed the activation of Mitomycin C to alkylating metabolites under both hypoxic and aerobic conditions, with alkylation being 1.5 times greater in hypoxia. Dicumarol at 100 µm inhibited the NADH:cytochrome b 5 reductase-catalyzed reduction of Mitomycin C by 24% and by 57% at 300 µm. The degree of inhibition of the enzyme by dicumarol was the same at both pH 6.6 and 7.6. NADH:cytochrome b 5 reductase exhibited a small but measurable NADH-oxidase activity, which was unaffected by 300 µm dicumarol. These findings demonstrate that ( a ) NADH:cytochrome b 5 reductase can metabolically activate Mitomycin C and ( b ) dicumarol is capable of inhibiting this enzymatic activity.
Steven A Madreperla - One of the best experts on this subject based on the ideXlab platform.
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topical Mitomycin c for the treatment of conjunctival and corneal epithelial dysplasia and neoplasia
American Journal of Ophthalmology, 1997Co-Authors: Matthew W Wilson, John L Hungerford, Sheena M George, Steven A MadreperlaAbstract:Purpose To evaluate the efficacy of topical Mitomycin C in treating conjunctival and corneal epithelial dysplasia and neoplasia. Methods Seven eyes of seven patients with conjunctival and corneal epithelial dysplasia and neoplasia were treated with one drop of topical Mitomycin C 0.04% four times a day for 7 days in alternate weeks. The patients' charts were reviewed retrospectively. Patients with either multiple recurrences or extensive ocular surface involvement were treated. In all eyes, the diagnosis of epithelial dysplasia or neoplasia was confirmed by histopathology before the onset of therapy. Patients were examined at least every 14 days during treatment and examined at intervals after completion of treatment. Results With topical Mitomycin C, six eyes of seven patients had complete clinical regression of their conjunctival and corneal epithelial dysplasia and neoplasia. One eye of one patient had partial clinical regression of conjunctival and corneal epithelial dysplasia. Follow-up after completion of topical Mitomycin C therapy and excision of residual disease ranged from 2 to 16 months (mean, 9 months; SD, 4.3 months) and was without clinical sign of recurrence. Topical Mitomycin C therapy was associated with transitory ocular discomfort, conjunctival injection, tearing, photophobia, and punctate epithelial keratopathy. Conclusion In this small series of eyes, topical Mitomycin C was effective as a treatment for conjunctival and corneal epithelial dysplasia and neoplasia.
