Proteins severely treated, formation

Platinum compounds without antitumor activity (17) such as t2 ons-DDP and [Pt(dien)Cl]Cl (Figure 1) covalently bind to DNA in vivo. Several studies have compared the biological effects which result when equal amounts of these three platinum compounds are fixed on DNA (typically r j 10" -10"6), Cis-DDP is 5-10 times more toxic toward E, ooli ( ) and mammalian cells (j, U.) than t2 ans-DDP, The relative toxicity is correlated with the ability of these two isomers to inhibit DNA replication (, i3, J 4). The ois isomer is repaired more efficiently by E, ooli W and is at least 750 times more mutagenic in mammalian cells (11) than the trans isomer. The compound [Pt(dien)Cl]Cl binds covalently to the DNA of E, ooli and seems not to be repaired nevertheless this compound does not inhibit DNA synthesis or kill the bacteria ( ), Repair of platinum compounds by E, ooli may be under the control of the SOS system c s-DDP induces 5-10 times more recA protein in treated E. Coli than an equal amount of trans-DPP or [Pt(dien)Cl]Cl fixed on the DNA (18), It seems that different modes of fixation on DNA are responsible for the different mutagenicity, toxicity and DNA repair of these platinum complexes. These results suggest that the antitumor activity of platinum(II) compounds may also depend on the formation of particular platinum-DNA lesions. 

In a related study, streptozotocin-induced diabetic rats were treated with pyridox-amine, vitamin E, and enalapril (7V-(l-[ethoxycarbonyl -3-phcny I propyl)-Ala-Pro), an AGE/ALE inhibitor, an antioxidant, and an ACE-inhibitor, respectively.598 Diabetic hyperglycaemia was accompanied by severe dyslipidaemia. Treatment with pyridoxamine was the most effective in reducing lipid abnormalities and in retarding nephropathy, retinopathy, and protein modification. Vitamin E was the next most effective treatment in retarding nephropathy, but did not affect retinopathy or AGE/ALE formation. Enalapril normalised blood pressure and retarded nephropathy and the accumulation of CML in the kidney, but did not affect dyslipidaemia and retinopathy. Thus pyridoxamine is the most effective therapy overall. 

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