Mitomycin Anthracyclines

In general, the mechanisms of action are not cell cycle specific, although some members of the class show greatest activity at certain phases of the cell cycle, such as S-phase (anthracyclins, mitoxantrone), Gl- and early S-phases (mitomycin C) and G2- and M-phases (bleomycins). 

Dimethylsulfoxide (DMSO) is the antidote of choice for anthracycline and mitomycin C extravasations. It readily penetrates tissues and increases diffusion in the tissue area. In addition, DMSO is a free-radical scavenger that functions to block this principal mechanism of anthracycline- and mitomycin C-mediated tissue injury. DMSO generally is well tolerated but may cause some mild burning and redness. Dexrazoxane is a free-radical scavenger typically used for cardio-protection from anthracyclines. Promising results have been seen with large-volume extravasations and in a mouse model.38... 

The anthracycline antibiotics, which include doxorubicin, daunorubicin, bleomycin, and mitomycin C, inhibit DNA and RNA synthesis. Doxorubicin also interfers with topoisomerase II (a DNA gyrase), the activity of which is markedly increased in proliferating cells. Structurally related to doxorubicin are epirubicin and mitozantrone. The cytotoxic antibiotics are used to treat leukaemias and lymphomas and also for solid tumours in the breast, lung, thyroid and ovary. Cardiotoxicity is the major dose-limiting factor, with arrhythmias and myocardial depression (Bacon and Nuzzo 1993). The chronic phase of cardiotoxicity is a dose-dependent cardiomyopathy that leads to congestive heart failure in 2-10% of patients. Myocardial injury is the result of oxygen free radical formation. Children are particularly sensitive to these cardiotoxic reactions and may require a heart transplant in their later years. Epirubicin is less cardiotoxic than doxorubicin. 

Screening of microbial products has led to the discovery of a number of growth-inhibiting compounds that have proved to be clinically useful in cancer chemotherapy. Many of these antibiotics bind to DNA through intercalation between specific bases and block the synthesis of RNA, DNA, or both cause DNA strand scission and interfere with cell replication. All of the anticancer antibiotics now being used in clinical practice are products of various strains of the soil microbe Streptomyces. These include the anthracyclines, bleomycin, and mitomycin. 

Pan, S., Andrews, P.A., Glover, C.J., and Bachur, N.R., 1984, Reductive activation of mitomycin C and mitomycin C metabolites catalysed by NADPH-cytochorome P-450 reductase and xantine oxidase. J. Biol. Chem. 259 959-962 Pollakis, G., Goormaghtigh, E., and Ruysschaert, J.-M., 1983, Role of quinone structure in the mitochondrial damage induced by antitumor anthracyclines. FEBS Lett. 155 267-272 Rappaport, S.M., McDonald, T.A., and Yeowell-O Connell, K., 1996, The use ofprotein adducts to investigate the disposition of reactive metabolites of benzene. Environ. Health Perspect. 104Suppl6 1235-1237... 

Microbial sources have been a very rich source for cancer chemotherapeutic agents. Of particular note is the Strep-tomyces spp., which has been responsible for the production of many approved anticancer agents that are in clinical practice. These agents are represented by highly diverse structural classes exemplified by the anthracycline family (e.g., doxom-bicin, 73) (72-74), actinomycin family (e.g., dactinomycin, 74), glycopeptides family (e.g., bleomycins A2 and B2, 75 and 76) (75), and mitomycin family (e.g., mitomycin C, 77) (72, 76). All these compounds specifically interact with DNA for then-mode of action. 

Most of the important antitumor compounds used for chemotherapy of tumors are microbially-produced antibiotics. These include actinomycin D, mitomycin, bleomycins and the anthracyclines, daunorubicin and doxorubicin. The recent successful molecule, taxol (=paclitaxel), was discovered in plants but also is a fungal metabolite. It is approved for breast and ovarian cancer and is the only antitumor drug known to act by blocking depolymerization of microtubules. In addition, taxol promotes tubulin polymerization and inhibits rapidly dividing mammalian cancer cells. It also inhibits fungi such as Pythium, Phytopthora and Aphanomyces spp. by the same mechanism. ... 

Antitumor antibiotics are amongst the most important of the cancer chemodierapeutic agents, which include members of the anthracycline, bleomycin, actinomycin, mitomycin and aureolic acid families. Clinically useful agents from these families are the daunomycin-... 

Cytotoxic antibiotics produce their effect mainly by direct action on DNA. Anthracyclines include the important drugs doxorubicin, aclarubicin and idarubicin. Related compounds are mitozantrone and epirubicin. Some others are the Streptomyces antibiotic dactinomycin. and the metalchelating glycopeptides especially bleomycins. Mitomycin effectively is a prodrug that is converted in the body to an alkylating agent. 

Among all ABC transporters, P-gp, also known as MDRl protein, ABCBl or CD243, is probably the most studied and characterized member. It was first found as a 170-kDa ATP-dependent membrane glycoprotein that acts as a drug efflux pump [15], P-gp is a broad-spectrum transporter, capable of transporting several structurally and functionally unrelated substrate molecules. Its substrates are typically hydrophobic, amphipathic products, including many chemotherapeutic compounds used for cancer treatment, e.g., vinca alkaloids (vincristine, vinblastine), taxanes (paclitaxel, docetaxel), epipodophyllotoxins (etoposide, teniposide), anthracyclines (doxorubicin, daunorubicin, epirubicin), topotecan, dactinomycin, and mitomycin-C [37]. 

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