Cytotoxicity, crosslinking and biological activity of three mitomycins.

While interstrand crosslinks (ICLs) have been considered as one type of DNA damage in the past, there is mounting evidence suggesting that these highly cytotoxic lesions are processed differently by the cellular machinery depending upon the ICL structure. In this study, we examined the crosslinking ability of three mitomycins, the structure of the ICLs they produce and the cytotoxicity of the drugs toward three different cell lines. The drugs are: mitomycin C (1), decarbamoylmitomycin C (2), and a mitomycin-conjugate (3) whose mitosane moiety is linked to a N-methylpyrrole carboxamide. We found that, overall, both MC and compound 3 show strong similarities regarding their alkylation of DNA, while DMC alkylating behavior is markedly different. To gain further insight into the mode of action of these drugs, we performed high throughput gene expression and gene ontology analysis to identify gene expression and cellular pathways most impacted by each drug treatment in MCF-7 cell lines. We observed that the novel mitomycin derivative (3) specifically causes changes in the expression of genes encoding proteins involved in cell integrity and tissue structure. Further analysis using bioinformatics (IPA) indicated that the new derivative (3) displays a stronger downregulation of major signaling networks that regulate the cell cycle, DNA damage response and cell proliferation when compared to MC and DMC. Collectively, these findings demonstrate that cytotoxic mechanisms of all three drugs are complex and are not solely related to their crosslinking abilities or the structure of the ICLs they produce.

Interdependent Sequence Selectivity and Diastereoselectivity in the Alkylation of DNA by Decarbamoylmitomycin†C.

Mitomycin C (MC), an antitumor drug, and decarbamoylmitomycin C (DMC), a derivative of MC, alkylate DNA and form deoxyguanosine monoadducts and interstrand crosslinks (ICLs). Interestingly, in mammalian culture cells, MC forms primarily deoxyguanosine adducts with a 1"-R stereochemistry at the guanine-mitosene bond (1"-α) whereas DMC forms mainly adducts with a 1"-S stereochemistry (1"-ß). The molecular basis for the stereochemical configuration exhibited by DMC has been investigated using biomimetic synthesis. Here, we present the results of our studies on the monoalkylation of DNA by DMC. We show that the formation of 1"-ß-deoxyguanosine adducts requires bifunctional reductive activation of DMC, and that monofunctional activation only produces 1"-α-adducts. The stereochemistry of the deoxyguanosine adducts formed is also dependent on the regioselectivity of DNA alkylation and on the overall DNA CG content. Additionally, we found that temperature plays a determinant role in the regioselectivity of duplex DNA alkylation by mitomycins: At 0 °C, both deoxyadenosine (dA) and deoxyguanosine (dG) alkylation occur whereas at 37 °C, mitomycins alkylate dG preferentially. The new reaction protocols developed in our laboratory to investigate DMC-DNA alkylation raise the possibility that oligonucleotides containing DMC 1"-ß-deoxyguanosine adducts at a specific site may be synthesized by a biomimetic approach.

Sequence-Dependent Diastereospecific and Diastereodivergent Crosslinking of DNA by Decarbamoylmitomycin C.

Mitomycin C (MC), a potent antitumor drug, and decarbamoylmitomycin C (DMC), a derivative lacking the carbamoyl group, form highly cytotoxic DNA interstrand crosslinks. The major interstrand crosslink formed by DMC is the C1'' epimer of the major crosslink formed by MC. The molecular basis for the stereochemical configuration exhibited by DMC was investigated using biomimetic synthesis. The formation of DNA-DNA crosslinks by DMC is diastereospecific and diastereodivergent: Only the 1''S-diastereomer of the initially formed monoadduct can form crosslinks at GpC sequences, and only the 1''R-diastereomer of the monoadduct can form crosslinks at CpG sequences. We also show that CpG and GpC sequences react with divergent diastereoselectivity in the first alkylation step: 1"S stereochemistry is favored at GpC sequences and 1''R stereochemistry is favored at CpG sequences. Therefore, the first alkylation step results, at each sequence, in the selective formation of the diastereomer able to generate an interstrand DNA-DNA crosslink after the "second arm" alkylation. Examination of the known DNA adduct pattern obtained after treatment of cancer cell cultures with DMC indicates that the GpC sequence is the major target for the formation of DNA-DNA crosslinks in vivo by this drug.

Accidental Extravasation of Mitomycin C into the Subcutaneous Tissue.

Introduction: Mitomycin C (MMC) is a common chemotherapeutic agent used to treat a variety of solid tumors. Cutaneous adverse events are rare, but MMC is a known vesicant reported to cause tissue necrosis and sloughing, erythema, and ulceration if incorrectly infused into the subcutaneous tissue. Definitive treatment of extravasation injuries due to MMC depends on the severity of the cutaneous manifestation, which includes stopping the infusion, removing the catheter, or possible debridement. Case Presentation: We present the case of a 70-year-old female with extensive soft-tissue injury secondary to extravasation of MMC that required hospital admission and surgical intervention to remove the implantable venous access device. Conclusion: Extravasation injuries caused by vesicant drugs, such as MMC, often present as local skin irritation and inflammation. MMC extravasation may present a wide range of skin and soft tissue manifestations, ranging from erythema to ulcerations to necrosis. This rare but potentially detrimental complication of chemotherapy infusions should be recognized in cancer patients.

Quinone-Based Drugs: An Important Class of Molecules in Medicinal Chemistry.

BACKGROUND: Several quinones are on the pharmaceutical market as drugs for the treatment of several diseases. OBJECTIVE: The aim of this review was to provide an overview of the quinones that have become drugs for several therapeutic applications. METHODS: We have comprehensively and critically discussed all the information available in the literature about quinone-based drugs. RESULTS: In this review, the various aspects of the chemistry and biochemistry of these drugs are highlighted, including their repositioning, drug combination and their new uses. CONCLUSION: A number of studies related to quinone drugs for different pharmaceutical uses show that the interest in new applications is still increasing in recent years.

Effect of mitomycin C in reducing hypertrophic scar in rat traumatic osteomyelitis model / 中华创伤杂志

Objective To investigate the effect and mechanism of mitomycin C in reducing hypertrophic scar in rat traumatic osteomyelitis model.Methods A total of 120 Wistar rats were divided into control group (Group A,n =40),traumatic osteomyelitis group (Group B,n =40),traumatic osteomyelitis treated with Mitomycin C group (Group C,n =40),according to the random number table.The model of traumatic osteomyelitis was produced by Staphylococcus aureus.Muscle tissues around the focus were harvested at 15 d and 30 d postinjury.HE staining was used to observe the changes of muscle tissue structure.Immunohistochemistry was used to detect expression of transforming growth factor (TGF)-β1.Masson staining was used for collagen deposition evaluation.Western blot was used for detection of levels of TGF-β1 and collagen Ⅰ.Results HE staining revealed consistent alignment of fibers within the muscle in Group A.Fibrosis with the muscle was observed in both Group B and C,but the degree of muscle fiber disorder was decreased in Group C compared to Group B.Either 15 d or β0 d after injury,expressions intensity of TGF-β1,collagen fraction volume,and activation levels of TGF-β1 as well as collagen Ⅰ were higher in Group B and C than Group A,and all parameters were decreased in Group C compared to Group B (all P ＜ 0.05).Conclusion Mitomycin C can reduce hypertrophic scar formation in traumatic osteomyelitis model,and the potential mechanism relates to downregulated TGF-β1 and collagen Ⅰ.

A study on p38MAPK activity during mitomycin-induced apoptosis of cholangiocarcinoma cell lines / 中国普通外科杂志

Objective To observe the expression of p38MAPK activity during mitomycin-induced cell cycle arrest of cholangiocarcinoma. Using p38MAPK inhibitor SB203580 to analyze the effect on chemotherapy of cholangiocarcinoma. Methods The selected human cholangicarcinoma cell lines RBE was treated with mitomycin or together with SB203580, cell apoptosis was analysed by AnnexinV-FITC and propidium iodide(PI)double staining and flow cytometry (FCM), p38 and ATF-2 activity was detected by Western blot. Results Mitomycin induced apoptosis of RBE cell line, the ratio of apoptosis was (8.91?0.83)%( P

Study on the reversion of drug resistance in human cervical cancer cell lines / 中华妇产科杂志

Objective To determine the resistance reversion of mitomycin (MMC) by 3′-Keto-bmt 1-val 2-cyclosporin (SDZ PSC 833) in human cervical cancer in vitro and in vivo. Metheds A xenografted mitomycin resistant mice model of cervical cancer was devolped. The reversion of mitomycin resistance by SDZ PSC 833 (1 or 3 mg/L) was detected from human cervical cancer cell (Hela) and its resistant subline Hela/MMC in vitro and in vivo. Studies in vitro include drug resistance reversion experiment and the changes of morphology. Studies in vivo including tumor volume and tumor related histopathological changes in the autopsied specimen were evaluated by comparing random sections of each group. Results Nontoxic doses of SDZ PSC 833 could result in almost partial reversion of MMC-resistance of Hela/MMC.In vivo studies also showed SDZ PSC 833 augmented the growth inhibitory effect of mitomycin on Hela/MMC xenografted in nude mice. Conclusion SDZ PSC 833 can overcome mitomycin resistance of Hela/MMC in vitro and in vivo ,so SDZ PSC 833 will be a better candidate clinically for reversing multidrug resistance.