The bleomycins require a reduced transition metal, Fe (II) or perhaps Cu (I), oxygen, and a one-electron reduction to generate an ''activated'' bleomycin. The primary mechanism of action of the bleomycins is the generation of single- and double-strand DNA breaks and is initiated by the abstraction of a desoxyribose 4'-hydrogen. The species directly responsible for the removal of this hydrogen atom is an ''activated'' bleomycin complex 4.35, arising from one-electron reduction of the bleomycin-Fe (II)-oxygen ternary complex. The electron may come from external reductors such as ascorbic acid or thiols, or from another molecule of 4.34, which would then be transformed into the inactive Fe (III) species 4.36. Reaction of 4.35 with DNA involves abstraction of the ribose 4'-hydrogen, and proceeds as previously discussed (Figs. 4.8-4.10). Finally, 4.33 can be regenerated from 4.36 by an NADH-dependent enzyme system in the nucleus or by reduction of external thiols, creating a cyclic process. This redox cycling (Fig. 4.25) is important for bleomycin activity because very small amounts of the drug enter the tumor cells.

A mechanism explaining the chemical details of the activation of the bleomy-cin ternary complex is shown in Fig. 4.26. Addition of one electron and one proton to the bleomycin-Fe (II)-oxygen ternary complex 4.34 gives an Fe (III) hydroper-oxy complex 4.37, which has been detected experimentally by a variety of techniques.72 One possible mechanism explaining the formation of the activated bleomycin species 4.35, which is analogous to the one postulated for the case of heme-dependent enzymes like cytochrome P450, involves the heterolytic cleavage of the O-O bond, initiated by a protonation step. This reaction gives a bleomycin-Fe (V)=O species 4.35 or its alternative Fe (IV) resonating form, which can abstract a hydrogen atom from DNA, initiating the series of events that culminate in strand cleavage.

Alternatively, the O-O bond in 4.37 could break homolytically, giving the bleomycin-Fe (IV)=O species 4.39 and a hydroxyl radical, either of which can abstract the DNA 4'-hydrogen (Fig. 4.27). A concerted reaction of 4.37 with DNA with concomitant O-O bond homolysis to give 4.39 is also possible.73

DNA strand cleavage

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment