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Molecules (Basel, Switzerland) Nov 2021Mitomycin has a unique chemical structure and contains densely assembled functionalities with extraordinary antitumor activity. The previously proposed mitomycin C...
Mitomycin has a unique chemical structure and contains densely assembled functionalities with extraordinary antitumor activity. The previously proposed mitomycin C biosynthetic pathway has caused great attention to decipher the enzymatic mechanisms for assembling the pharmaceutically unprecedented chemical scaffold. Herein, we focused on the determination of acyl carrier protein (ACP)-dependent modification steps and identification of the protein-protein interactions between MmcB (ACP) with the partners in the early-stage biosynthesis of mitomycin C. Based on the initial genetic manipulation consisting of gene disruption and complementation experiments, genes , , and were identified as the essential functional genes in the mitomycin C biosynthesis, respectively. Further integration of biochemical analysis elucidated that MitE catalyzed CoA ligation of 3-amino-5-hydroxy-bezonic acid (AHBA), MmcB-tethered AHBA triggered the biosynthesis of mitomycin C, and both MitB and MitF were MmcB-dependent tailoring enzymes involved in the assembly of mitosane. Aiming at understanding the poorly characterized protein-protein interactions, the pull-down assay was carried out by monitoring MmcB individually with MitB and MitF. The observed results displayed the clear interactions between MmcB and MitB and MitF. The surface plasmon resonance (SPR) biosensor analysis further confirmed the protein-protein interactions of MmcB with MitB and MitF, respectively. Taken together, the current genetic and biochemical analysis will facilitate the investigations of the unusual enzymatic mechanisms for the structurally unique compound assembly and inspire attempts to modify the chemical scaffold of mitomycin family antibiotics.
Topics: Acyl Carrier Protein; Amino Acid Sequence; Aminobenzoates; Anti-Bacterial Agents; China; Escherichia coli; Escherichia coli Proteins; Hydroxybenzoates; Mitomycin; Mitomycins; Protein Interaction Mapping; Protein Interaction Maps; Streptomyces
PubMed: 34833880
DOI: 10.3390/molecules26226791 -
Genetika Oct 1986The mutagenic effect of mitomycin C (MC) has been shown in the S phase of Crepic capillaris cells. The repair ability of MC-induced DNA lesions proves exceedingly high,...
The mutagenic effect of mitomycin C (MC) has been shown in the S phase of Crepic capillaris cells. The repair ability of MC-induced DNA lesions proves exceedingly high, due to post-replicative and excision repair processes. In the experiments with MC-pretreatment of Crepic capillaris cells, nonmutagenic concentration of 1 microgram/ml provides inducible repair system--"adaptive response", which considerably decreases the levels of mutagenesis induced by MC at concentrations of 10, 20 and 40 micrograms/ml. Under adaptive response, the action of methyltransferase is possible.
Topics: Chromosome Aberrations; DNA Repair; Mitomycin; Mitomycins; Mutagenicity Tests; Mutagens; Plants
PubMed: 3098630
DOI: No ID Found -
Cancer Research Jul 1993The penetration of mitomycin C (MMC) in bladder tissue was studied in patients who received intravesical chemotherapy at the time of radical cystectomy. An intravesical...
The penetration of mitomycin C (MMC) in bladder tissue was studied in patients who received intravesical chemotherapy at the time of radical cystectomy. An intravesical dose of MMC (20 mg/40 ml) was instilled and maintained in the bladder for 60 to 120 min at which time the solution was drained. Within 10 to 60 min after draining the drug solution, the bladder vasculature was ligated, and the bladder was removed. Tissues were sectioned serially in layers parallel to the urothelium and analyzed for MMC concentration. Of the 24 patients evaluated, 17 patients had a low final MMC concentration in urine (< 66 micrograms/ml) or had the MMC solution drained more than 30 min before ligation of the blood vessels. Among these 17 patients, the concentration in the urothelium was measurable in only 4 patients, while the concentrations in deeper tissues were not measurable. In the remaining 7 patients where the urine concentration was > 120 micrograms/ml and where the vasculature was ligated within 30 min after the MMC solution was drained, the bladder wall contained significant MMC concentrations. The drug penetration was studied in the latter 7 patients, using sections of bladder wall that were grossly normal and non-tumor bearing. Concentrations in the bladder wall declined semilogarithmically with tissue depth from the urothelium to the deep muscle and reached a plateau at about 2000 microns depth. The median MMC concentrations were 5.6 micrograms/g in the urothelium and lamina propria interface, 2.7 micrograms/g in the lamina propria, and 0.9 microgram/g in the muscularis. The distance over which the MMC concentration decreased by one-half was about 500 microns. The concentration ratio between the urine and urothelium/lamina propria interface was about 35-fold. The mean plasma concentrations were 0.003, 0.1, and 0.4% of the mean concentration in urine, urothelium, and the averaged bladder tissue concentrations, respectively. Paired superficial tumor and normal tissues were obtained from 5 bladders. In 4 of 5 cases, the concentration in tumors was higher than in normal tissues, while the reverse was seen in the remaining tumor. In one sessile bladder tumor a complete concentration-depth profile could be obtained. While the concentrations in the tumor tissue were 2-3-fold higher than that in the adjacent normal tissue, the rate of concentration declined with respect to tissue depth and hence the distance over which the MMC concentration decreased by one-half was similar in both tumors.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Administration, Intravesical; Aged; Animals; Combined Modality Therapy; Cryopreservation; Cystectomy; Dogs; Female; Humans; Male; Middle Aged; Mitomycin; Time Factors; Tissue Preservation; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 8324743
DOI: No ID Found -
Cancer Chemotherapy and Pharmacology 1988It has been suggested that quinone reductase [NAD(P)H: (quinone-acceptor)oxidoreductase], also known as DT-diaphorase, protects hypoxic cells against mitomycin C...
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.
Topics: 2,6-Dichloroindophenol; Alkylation; Chromatography, High Pressure Liquid; Humans; Kidney; Mitomycin; Mitomycins; NAD(P)H Dehydrogenase (Quinone); Quinone Reductases
PubMed: 3136941
DOI: 10.1007/BF00257309 -
Biochemistry Apr 1988Mitomycin C, an antitumor antibiotic, is known to require reductive activation in order to function as an alkylating agent. In this work reduction has been carried out...
Mitomycin C, an antitumor antibiotic, is known to require reductive activation in order to function as an alkylating agent. In this work reduction has been carried out by using radiolytically produced formate radicals that reduce mitomycin C to its semiquinone in a clean rapid one-electron reaction. The ultimate products of the reduction are cis- and trans-2,7-diamino-1-hydroxymitosene (B1 and B2) and 2,7-diaminomitosene (C). The yields of these compounds were found to be the same when the rate of reduction was varied by 11 orders of magnitude. At pH 7, one mitosene molecule is formed for every two formate radicals, while at pH 9.1, about eight mitosene molecules are formed per formate radical. The ratio of (B1 + B2)/C is less than 0.4 at pH 5.7, 1.0 at pH 7, and greater than 3.5 at pH 9.1. Observations have been made of changes in optical absorption due to the formation of the semiquinone and hydroquinone of both mitomycin C itself and 2,7-diamino-1-hydroxymitosene (B). The direct conversion of the semiquinone form of mitomycin C into the semiquinone of B proceeds slowly, if at all. The semiquinone form of B will rapidly reduce mitomycin C (k = 7.2 X 10(8) M-1 s-1). The hydroquinone of mitomycin C undergoes changes resulting in the formation of B and C. The yields of B and C depend on pH.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Chromatography, High Pressure Liquid; Kinetics; Mitomycin; Mitomycins; Oxidation-Reduction; Pharmaceutical Preparations; Prodrugs; Spectrophotometry
PubMed: 3132971
DOI: 10.1021/bi00407a051 -
Progress in Clinical and Biological... 1984
Clinical Trial Review
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Mitomycin; Mitomycins; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms
PubMed: 6438638
DOI: No ID Found -
Cornea Jul 2009
Topics: Humans; Mitomycin; Myopia; Photorefractive Keratectomy
PubMed: 19512890
DOI: 10.1097/ICO.0b013e31819c16a8 -
Intravesical radiofrequency induced hyperthermia enhances mitomycin C accumulation in tumour tissue.International Journal of Hyperthermia :... Nov 2018Non-muscle invasive bladder cancer (NMIBC) is a highly recurrent disease with potential progression to muscle invasive disease despite the standard bladder instillations...
INTRODUCTION
Non-muscle invasive bladder cancer (NMIBC) is a highly recurrent disease with potential progression to muscle invasive disease despite the standard bladder instillations with mitomycin C (MMC) or Bacille Calmette-Guérin immunotherapy. Therefore, alternatives such as radiofrequency-induced chemohyperthermia (RF-CHT) with MMC are being investigated. The mechanism explaining the efficacy of RF-CHT is only partly understood. We examined whether RF-CHT results in higher MMC tissue concentrations as compared to cold MMC instillation.
PATIENTS AND METHODS
Prior to a planned transurethral resection of bladder tumour (TURBT), patients with stage Ta NMIBC were allocated to either (1) cold MMC instillation or (2) RF-CHT. After MMC instillation, three biopsies were taken of both normal and tumour tissue. Biopsies were snap-frozen and MMC tissue concentrations were analysed using ultra-performance liquid chromatography.
RESULTS
Eleven patients were included of which six received RF-CHT. Ten patients had TaG2-LG/HG papillary tumours at pathology. One patient in the RF-CHT group appeared to be free of malignancy and was excluded from the analysis as no tumour biopsies were available. The median MMC concentration in tumour tissue was higher in the RF-CHT group (median 665.00 ng/g vs. 63.75 ng/g, U = 51.0, p = 0.018). Moreover, in both techniques the MMC concentration was lower in normal tissue compared to tumour tissue. Tissue MMC concentration measurements varied substantially within, and between, different patients from the same group.
CONCLUSION
Intravesical RF-CHT results in higher tumour MMC concentrations vs. cold MMC instillation which contributes to its superior efficacy.
Topics: Aged; Female; Humans; Hyperthermia, Induced; Male; Middle Aged; Mitomycin; Urinary Bladder Neoplasms
PubMed: 29191126
DOI: 10.1080/02656736.2017.1406618 -
Revue de Pneumologie Clinique 1995Mitomycin C is an antibiotic used for its alkylizing effect in the treatment of broncogenic cancer. Haematologic, renal or pulmonary complications are sometimes severe.... (Review)
Review
Mitomycin C is an antibiotic used for its alkylizing effect in the treatment of broncogenic cancer. Haematologic, renal or pulmonary complications are sometimes severe. We report a case in a patient with poorly differentiated epidermoid bronchogenic carcinoma who developed clinical and radiological signs of bilateral infiltrating pneumonia due to mitomycine. This observation emphasizes the importance of bronchoalveolar lavage which implicated the immunological toxicity of mitomycine and explained the efficacity of corticosteroid treatment. Pulmonary lesions due to mitomycine were discussed.
Topics: Adult; Bronchoalveolar Lavage Fluid; Humans; Lung Diseases, Interstitial; Male; Mitomycin
PubMed: 7740265
DOI: No ID Found -
Genetics Apr 1965
Topics: Animals; Cell Division; Chromosomes; Crossing Over, Genetic; DNA; Drosophila; Drosophila melanogaster; Mitomycin; Mitomycins; Pharmacology; Research
PubMed: 14330699
DOI: 10.1093/genetics/51.4.635