DNA-damaging antitumor

Another DNA-damaging antitumor agent is kedarcidin from an actinomycete which consists of an apoprotein and an enediyne chromophore (189) with a chloropyridine moiety [151,152]. 

Richmond RC, Zimbrick JD, Hykes DL. Radiation-induced DNA damage and lethality in e-coli as modified by the antitumor agent cis-dichlorodiammineplatinum (II). Radiat Res 1977 71 447. 

The mechanisms by which antitumor-promoters suppress the tumor promotion are not known, but may be due to the following effects (i) inhibition of polyamine metabolism (ii) inhibition of arachidonic acid metabolism (iii) protease inhibition (iv) induction of differentiation (v) inhibition of oncogene expression (vi) inhibition of PKC and (vii) inhibition of oxidative DNA damage [3,6,91]. The polyamine content of cells is correlated to their proliferative, and often, their neoplastic capabilities. A key enzyme in the polyamine biosynthetic pathway, ornithine decarboxylase (ODC), catalyzes the convertion of ornithine to putrescine. Phorbol ester promoters such as TPA cause increased ODC activity and accumulation of polyamines in affected tissues. Diacylglycerol activated PKC, and the potent tumor promoter, TPA, binds to, and activates PKC, in competition with diacylglycerol. PKC stimulation results in phosphorylation of regulatory proteins that affect cell proliferation. Some chemopreventive agents have inhibitory activity towards PKC. Refer to recent review articles for further discussion [3,6,91]. 

There is another important aspect of DNA damages. A unique feature of many cancerous tumors is the existence of hypoxic regions, that is, regions of oxygen-poor cells (J.M. Brown 1999). Such cells are often resistant to more conventional forms of antitumor treatment, such as radiotherapy and chemotherapy (Denny Wilson 2000). There has been considerable effort to identify potential antitumor drugs that specifically target such cells. One such class of potential hypoxia-specific drugs is the benzotriazine A, A -dioxides, of... 

Additional results indicated that pazopanib (1) sensitized tumor cells bound to endothelial cells to DNA-damaging agents, such as melphalan. Moreover, pazopanib (1) exerted antiangiogenic and antitumor effects in vivo in a mouse multiple myeloma xenograft model. 

The altered structure of the DNA duplex attracts proteins involved in DNA damage recognition and high-mobility group domain (HMG) proteins, which have been postulated to mediate the antitumor activity of cisplatin. 

Finally, a notable antitumor effect of free or clustered aminosaccharides should be mentioned. Some aminosaccharides such as D-galactosamine have direct cytotoxic effects on certain experimental tumors [181], while D-mannosamine is selectively toxic for human malignant T-lymphoid cell lines [182]. It has been shown that aminosugars, especially D-mannosamine, produce hydrogen peroxide to cause DNA damage, which mediates apoptosis resulting in tumor growth inhibition [183]. 

Other enediyne antitumor antibitotics (neocarzinostatin, esperamycin, dynemicin) may have similar or different mechanisms of activation, but they all use cy-cloaromatization as the key step in generating the DNA-damaging species. 

A metal binding site is on left-hand side of the molecule and a spermidine tail on the right-hand side of the molecule. The metal binding site traps the metal (iron or cobalt have been the two commonly cited metals) and provides the ROS generation site for the molecule. The spermidine tail enables the drug to interact with DNA through intercalation and delivers the metal to the DNA to maximize ROS-induced DNA damage. Loss of either portion of the molecule results in complete loss of antitumor activity. 

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