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Cell Death & Disease Sep 2020BRCA2 is crucial for repairing DNA double-strand breaks with high fidelity, and loss of BRCA2 increases the risks of developing breast and ovarian cancers. Herein, we...
BRCA2 is crucial for repairing DNA double-strand breaks with high fidelity, and loss of BRCA2 increases the risks of developing breast and ovarian cancers. Herein, we show that BRCA2 is inactively mutated in 10% of gastric and 7% of colorectal adenocarcinomas, and that this inactivation is significantly correlated with microsatellite instability. Villin-driven Brca2 depletion promotes mouse gastrointestinal tumor formation when genome instability is increased. Whole-genome screening data showed that these BRCA2 monoallelic and biallelic mutant tumors were selectively inhibited by mitomycin C. Mechanistically, mitomycin C provoked double-strand breaks in cancer cells that often recruit wild-type BRCA2 for repair; the failure to repair double-strand breaks caused cell-cycle arrest at the S phase and p53-mediated cell apoptosis of BRCA2 monoallelic and biallelic mutant tumor cells. Our study unveils the role of BRCA2 loss in the development of gastrointestinal tumors and provides a potential therapeutic strategy to eliminate BRCA2 monoallelic and biallelic mutant tumors through mitomycin C.
Topics: Animals; BRCA2 Protein; Gastrointestinal Neoplasms; Humans; Mice; Mitomycin
PubMed: 32980867
DOI: 10.1038/s41419-020-03013-8 -
Indian Journal of Ophthalmology Apr 2020To determine the safety and efficacy of mitomycin C (MMC) injection versus sponge during trabeculectomy.
PURPOSE
To determine the safety and efficacy of mitomycin C (MMC) injection versus sponge during trabeculectomy.
METHODS
It is a prospective analysis of patients who underwent trabeculectomy with MMC and followed up for 1 year, divided into two groups, namely, group 1- injection (n = 21), group 2-> sponge (n = 21). The same concentration of MMC was used for both groups. Inclusion criteria were trabeculectomies with MMC for intraocular pressure (IOP) control in eyes with glaucoma (primary + secondary) with a follow-up of 1 year.
RESULTS
Mean preoperative IOP in group 1 was 29.00 ± 11.92 mmHg and group 2 was 25.87 ± 11.09 mmHg, which reduced to 12.19 ± 4.03 and 15.56 ± 10.72 mmHg at final visit with P value of 0.0002 and 0.001, respectively. Mean preoperative number of antiglaucoma medications was 2.4 ± 0.87 in group 1 and 2.3 ± 0.96 in group 2, which reduced to 0.38 ± 0.5 and 0.91 ± 0.85 with P value of 0.001 and 0.0003, respectively. The complete success rate was 52.4% in the injection group and 26.1% in the sponge group at end of 1 year. Overall, success rate (complete + qualified) was 90.5% and 87% in group 1 and group 2 at final visit. All major complications were encountered in sponge group. 1 (11.1%) patient developed choroidal detachment and one had malignant glaucoma which got resolved by medical management. 33.3% cases had encapsulated bleb which received bleb needling. 44.4% cases underwent Argon laser suture lysis postoperatively.
CONCLUSION
The MMC injection may be as safe and as effective as conventional sponge application with comparable estimated complete treatment success.
Topics: Follow-Up Studies; Humans; Intraocular Pressure; Mitomycin; Prospective Studies; Trabeculectomy; Treatment Outcome
PubMed: 32174581
DOI: 10.4103/ijo.IJO_963_19 -
Viruses Oct 2022In this work, we describe a novel temperate bacteriophage, phage B13. -infecting phages are widespread and abundant, though often overlooked including because of their...
In this work, we describe a novel temperate bacteriophage, phage B13. -infecting phages are widespread and abundant, though often overlooked including because of their temperate lifestyle. B13 was isolated from its bacterial host via mitomycin C induction. Its host range was determined, and its pH and thermal stability were evaluated. The whole genome of B13 was sequenced and annotated. The genome is 36,864 bp long and contains 53 genes. The tail genes of B13 suggest that the phage has a siphovirus morphotype. It was found both in vitro and in silico that the phage uses the 3'-cos DNA packaging strategy, and the phage genome termini were located. Comparative analyses revealed that B13 has no close relatives and should therefore be assigned to a new viral genus, for which we propose the name .
Topics: Bacillus Phages; Mitomycin; Genome, Viral; Bacillus cereus; Phylogeny
PubMed: 36298855
DOI: 10.3390/v14102300 -
The Journal of Biological Chemistry Jan 1984Under anaerobic conditions and with proper electron donors, NADPH-cytochrome P-450 reductase (EC 1.6.2.4) and xanthine oxidase (EC 1.2.3.2) similarly reductively...
Under anaerobic conditions and with proper electron donors, NADPH-cytochrome P-450 reductase (EC 1.6.2.4) and xanthine oxidase (EC 1.2.3.2) similarly reductively metabolized mitomycin C. Reversed phase high performance liquid chromatography was used to separate, detect, and isolate several metabolites. Three metabolites were identified by mass spectrometry and thin layer chromatography as 1,2-cis- and trans-2,7-diamino-1-hydroxymitosene and 2,7-diaminomitosene. Three metabolites were phosphate-dependent, and two of them were identified to be 1,2-cis- and trans-2,7-diaminomitosene 1-phosphate. The amounts of the five identified metabolites generated during the reduction of mitomycin C varied with pH and nucleophile concentration. At pH 6.5, 2,7-diaminomitosene was essentially the only metabolite formed, whereas from pH 6.8 to 8.0, trans- and cis-2,7-diamino-1-hydroxymitosene increased in quantity as 2,7-diaminomitosene decreased. The disappearance of mitomycin C and the production of metabolites were enzyme and mitomycin C concentration-dependent. Substrate saturation was not reached for either enzyme up to 5 mM mitomycin C. Electron paramagnetic resonance studies demonstrated the formation of mitomycin C radical anion as an intermediate during enzymatic activation. Our results indicate that either enzyme catalyzed the initial activation of mitomycin C to a radical anion intermediate. Subsequent spontaneous reactions, including the elimination of methanol and the opening of the aziridine ring, generate one active center at C-1 which facilitates nucleophilic attack. Simultaneous generation of two reactive centers was not observed. All five primary metabolites were metabolized further by either flavoenzyme. The secondary metabolites exhibited similar changes in their absorbance spectra and were unlike the primary metabolites, suggesting that a second alkylating center other than C-1 was generated during secondary activation. We propose that secondary activation of monofunctionally bound mitomycin C is probably a main route for the bifunctional binding of mitomycin C to macromolecules and that the cytotoxic actions of mitomycin C result from multiple metabolic activations and reactions.
Topics: Animals; Arsenates; Cattle; Chromatography, High Pressure Liquid; Electron Spin Resonance Spectroscopy; Free Radicals; Hydrogen-Ion Concentration; Kinetics; Mitomycin; Mitomycins; NADPH-Ferrihemoprotein Reductase; Phosphates; Rats; Xanthine Oxidase
PubMed: 6319393
DOI: No ID Found -
World Journal of Gastroenterology Oct 2006Pseudomyxoma peritonei (PMP) is a rare disease. It refers to a progressive disease process within the peritoneum which originates from the appendix or ovaries and is... (Review)
Review
Pseudomyxoma peritonei (PMP) is a rare disease. It refers to a progressive disease process within the peritoneum which originates from the appendix or ovaries and is characterised by the production of copious amounts of mucinous fluid resulting in a "jelly belly". If untreated the condition is fatal. The traditional approach to PMP is based on repeated surgical debulking procedures, often associated with intraperitoneal or systemic chemotherapy. The natural history of this disease has been drastically modified since the introduction of a new surgical approach defined as a peritonectomy procedure. This paper is to review the literature on this treatment strategy.
Topics: Antineoplastic Agents; Cisplatin; Combined Modality Therapy; Doxorubicin; Humans; Hyperthermia, Induced; Mitomycin; Peritoneal Neoplasms; Peritoneum; Pseudomyxoma Peritonei
PubMed: 17036382
DOI: 10.3748/wjg.v12.i38.6124 -
Environmental and Molecular Mutagenesis Jul 2010Interstrand cross-links (ICLs) are among the most cytotoxic DNA lesions to cells because they prevent the two DNA strands from separating, thereby precluding replication... (Review)
Review
Interstrand cross-links (ICLs) are among the most cytotoxic DNA lesions to cells because they prevent the two DNA strands from separating, thereby precluding replication and transcription. Even though chemotherapeutic cross-linking agents are well established in clinical use, and numerous repair proteins have been implicated in the initial events of mammalian ICL repair, the precise mechanistic details of these events remain to be elucidated. This review will summarize our current understanding of how ICL repair is initiated with an emphasis on the context (replicating, transcribed or quiescent DNA) in which the ICL is recognized, and how the chemical and physical properties of ICLs influence repair. Although most studies have focused on replication-dependent repair because of the relation to highly replicative tumor cells, replication-independent ICL repair is likely to be important in the circumvention of cross-link cytotoxicity in nondividing, terminally differentiated cells that may be challenged with exogenous or endogenous sources of ICLs. Consequently, the ICL repair pathway that should be considered "dominant" appears to depend on the cell type and the DNA context in which the ICL is encountered. The ability to define and inhibit distinct pathways of ICL repair in different cell cycle phases may help in developing methods that increase cytotoxicity to cancer cells while reducing side-effects in nondividing normal cells. This may also lead to a better understanding of pathways that protect against malignancy and aging.
Topics: Animals; Cisplatin; Codon, Initiator; Cross-Linking Reagents; DNA Repair; Humans; Mitomycin; Transcription, Genetic
PubMed: 20658650
DOI: 10.1002/em.20559 -
Arquivos Brasileiros de Oftalmologia 2005Mitomycin C is an antimetabolite agent that blocks DNA and RNA replication and protein synthesis. It has been used in several ophthalmologic areas, and recently as a... (Review)
Review
Mitomycin C is an antimetabolite agent that blocks DNA and RNA replication and protein synthesis. It has been used in several ophthalmologic areas, and recently as a modulator of corneal wound healing in excimer laser surgeries. A single application of mitomycin C during surface corneal photoablative surgery seems a safe and efficient therapeutic option for eyes with corneal opacity and/or as prophylaxis in eyes with high risk for corneal opacity development. The use of this drug in photoablative surgery should be cautious until long-term safety results have been reported. The present text presents a review about corneal wound healing with the use of mitomycin C.
Topics: Animals; Cornea; Corneal Opacity; Humans; Lasers, Excimer; Mitomycin; Myopia; Nucleic Acid Synthesis Inhibitors; Photorefractive Keratectomy; Visual Acuity; Wound Healing
PubMed: 17344997
DOI: 10.1590/s0004-27492005000600031 -
International Journal of Molecular... Jun 2022Malignant peritoneal mesothelioma is a rare tumor entity. Although cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have increased overall survival,...
Malignant peritoneal mesothelioma is a rare tumor entity. Although cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have increased overall survival, its prognosis remains poor. Established chemotherapeutics include mitomycin C (MMC) and cisplatin (CP), both characterized by severe side effects. GP-2250 is a novel antineoplastic agent, currently under clinical investigation. This in vitro study aims to investigate effects of GP-2250 including combinations with CP and MMC on malignant mesothelioma. JL-1 and MSTO-211H mesothelioma cell lines were treated with increasing doses of GP-2250, CP, MMC and combination therapies of GP-2250 + CP/MMC. Microscopic effects were documented, and a flow-cytometric apoptosis/necrosis assay was performed. Synergistic and antagonistic effects were analyzed by computing the combination index by Chou-Talalay. GP-2250 showed an antiadhesive effect on JL-1 and MSTO-211H spheroids. It had a dose-dependent cytotoxic effect on both monolayer and spheroid cultured cells, inducing apoptosis and necrosis. Combination treatments of GP-2250 with MMC and CP led to significant reductions of the effective doses of CP/MMC. Synergistic and additive effects were observed. GP-2250 showed promising antineoplastic effects on malignant mesothelioma cells in vitro especially in combination with CP/MMC. This forms the basis for further in vivo and clinical investigations in order to broaden treatment options.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cisplatin; Humans; Mesothelioma; Mesothelioma, Malignant; Mitomycin; Necrosis; Peritoneal Neoplasms
PubMed: 35806313
DOI: 10.3390/ijms23137293 -
Bioorganic Chemistry Apr 2016Mitomycin C (MC) and Decarbamoylmitomycin C (DMC) - a derivative of MC lacking the carbamate on C10 - are DNA alkylating agents. Their cytotoxicity is attributed to...
Mitomycin C (MC) and Decarbamoylmitomycin C (DMC) - a derivative of MC lacking the carbamate on C10 - are DNA alkylating agents. Their cytotoxicity is attributed to their ability to generate DNA monoadducts as well as intrastrand and interstrand cross-links (ICLs). The major monoadducts generated by MC and DMC in tumor cells have opposite stereochemistry at carbon one of the guanine-mitosene bond: trans (or alpha) for MC and cis (or beta) for DMC. We hypothesize that local disruptions of DNA structure from trans or cis adducts are responsible for the different biochemical responses produced by MC and DMC. Access to DNA substrates bearing cis and trans MC/DMC lesions is essential to verify this hypothesis. Synthetic oligonucleotides bearing trans lesions can be obtained by bio-mimetic methods. However, this approach does not yield cis adducts. This report presents the first chemical synthesis of a cis mitosene DNA adduct. We also examined the stereopreference exhibited by the two drugs at the mononucleotide level by analyzing the formation of cis and trans adducts in the reaction of deoxyguanosine with MC or DMC using a variety of activation conditions. In addition, we performed Density Functional Theory calculations to evaluate the energies of these reactions. Direct alkylation under autocatalytic or bifunctional conditions yielded preferentially alpha adducts with both MC and DMC. DFT calculations showed that under bifunctional activation, the thermodynamically favored adducts are alpha, trans, for MC and beta, cis, for DMC. This suggests that the duplex DNA structure may stabilize/oriente the activated pro-drugs so that, with DMC, formation of the thermodynamically favored beta products are possible in a cellular environment.
Topics: DNA Adducts; Deoxyguanosine; Mitomycin; Mitomycins; Molecular Conformation; Quantum Theory
PubMed: 26894558
DOI: 10.1016/j.bioorg.2016.02.003 -
International Journal of Hyperthermia :... 2019Laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) has been used to treat various peritoneal malignancies. Cisplatin and mitomycin C (MMC) are agents...
BACKGROUND
Laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) has been used to treat various peritoneal malignancies. Cisplatin and mitomycin C (MMC) are agents commonly used in these procedures and, individually, each has been associated with acute kidney injury (AKI). There is limited literature on the complications associated with the use of both agents in HIPEC. Therefore, we sought to determine the incidence of nephrotoxicity and electrolyte abnormalities in patients undergoing laparoscopic HIPEC using this chemotherapeutic combination.
METHODS
We retrospectively evaluated patients undergoing laparoscopic HIPEC for gastric or gastroesophageal adenocarcinoma using both cisplatin and MMC. Sodium thiosulfate was given for renal protection and kidney function was evaluated daily up to postoperative day #2. Details regarding patient characteristics, selection criteria, chemotherapeutic regimen, perioperative lab values and anesthetic management were collected.
RESULTS
Twenty-three patients underwent 31 laparoscopic HIPEC procedures. Fifteen (65%) were male and the median age was 57 (range 21-75). Thirteen procedures were associated with an elevation in creatinine (Cr) with the median difference between POD#2 and baseline being 0.09 mg/dL (range 0-0.43). The glomerular filtration rate median difference between POD#2 and baseline was -17 mL/min/1.37 sq. m (range -42 to 11). No cases demonstrated AKI, defined as a 50% increase in Cr levels above baseline. An 84% incidence of postoperative hypophosphatemia (26/31) and 94% incidence of postoperative hypocalcemia (29/31) was observed.
CONCLUSION
The laparoscopic approach to HIPEC using both cisplatin and MMC in our cohort was not associated with an increased incidence of AKI. The incidence of hypophosphatemia and hypocalcemia needs further evaluation to determine the exact etiology. Precis' statement: We retrospectively studied the association of AKI with the combined use of cisplatin and MMC in laparoscopic HIPEC.
Topics: Acute Kidney Injury; Adult; Aged; Cisplatin; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Laparoscopy; Male; Middle Aged; Mitomycin; Retrospective Studies; Young Adult
PubMed: 30935256
DOI: 10.1080/02656736.2019.1597175