O

Figure 10.24 • Structure of mitomycin C.

ment, but there is actually little selectivity for hypoxic cells. Activation can occur enzymatically by both one- and two-electron processes. Reductive enzymes such as NADPH-CYP reductase and DT-diaphorase have been implicated in these processes.141 Involvement of one-electron processes such as those seen for the anthracylines result in redox cycling and the production of ROS that may result in DNA damage, but the cytotoxicity of mitomycin C is primarily associated with its ability to alkylate DNA. The hydro-quinone can result from a single two-electron process or a one-electron process followed by disproportionation to give the hydroquinone (Scheme 10.30).142-144 The electrons of the amine are no longer withdrawn by the quinone system and are now free to expel methoxide followed by loss of a proton to give the leuco-aziridinomitosene. This reduction renders positions C-1 and C-10 reactive to nucleophilic attack because of the fact that there are leaving groups attached, and they are now benzylic positions so that the intermediate carbocations can be stabilized. Several pathways are possible from this point, and the specific route is dependent on the conditions in the cell. Shown in Scheme 10.30 is one possible pathway that occurs under more acidic conditions and results in the formation of interstrand and intrastrand cross-links. Protonation of the aziridine is followed by ring opening to give the carbocation, which can be stabilized by resonance involving the hydroquinone system. Nucleophiles on DNA may attack at C-1 with concomitant electron movement. This can be repeated in a similar manner at C-10, which allows for cross-linking. There are several other possibilities under different conditions. DNA is alkylated by mitomycin C at both the N-2 and N-7 positions of guanine

MITOMYCIN C (MITC, MTC, MUTAMYCIN)

Mitomycin C is available in 5-, 20-, and 40-mg vials for IV administration in the treatment of cancers of the stomach and pancreas when other treatments have failed. Other uses have included breast, NSCLC, cervical, bladder, and head and neck cancers. Mechanisms of resistance include increased synthesis of nucleophilic detoxifying compounds such as glutathione, decreased expression of activating enzymes such as DT-diaphorase, and increased efflux by Pgp. The drug is rapidly cleared from the plasma after administration and widely distributed but does not cross the blood-brain barrier. The parent and metabolites are excreted mainly in the feces with an elimination half-life of 50 minutes. Adverse effects include dose-limiting myelosuppres-sion, mild nausea and vomiting, mucositis, anorexia, fatigue, and interstitial pneumonitis.

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Body Detox Made Easy

Body Detox Made Easy

What exactly is a detox routine? Basically a detox routine is an all-natural method of cleansing yourbr body by giving it the time and conditions it needs to rebuild and heal from the damages of daily life and the foods you eat and other substances you intake. There are many different types of known detox routines.

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