RESUMO
Chloroammine and similar complexes of platinum(II) having the ammine ligands in the cis configuration are effective antitumor agents but the corresponding trans isomers are not. This is possibly due to the different manner in which these drugs attack DNA. There is considerable controversy in the literature over the type of DNA lesion caused by cis-platinum(II) complexes. Some have proposed an attack on a single guanine base via chelation to N(7) and O(6) as being the biologically important interaction. However, much indirect evidence suggests that binding to adjacent guanine bases in the same strand of DNA is important to the mechanism of action. Following initial binding to guanine bases, DNA is then locally denatured, exposing additional crosslinking sites. Thus, the selectivity of cis-platinum(II) complexes in inhibiting tumor growth may be due to a combination of intrastrand and interstrand crosslinking to DNA at areas of specific base sequences.
Assuntos
Cisplatino/metabolismo , DNA/metabolismo , Modelos Químicos , Animais , Sequência de Bases , Sítios de Ligação , Cisplatino/farmacologia , Reagentes de Ligações Cruzadas , Guanina , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Raman spectra have been obtained for dTMP and its complex with CH3Hg (II) in aqueous solution as a function of pH. Difference spectroscopy is employed to increase the sensitivity of the Raman technique. The binding reaction is essentially quantitative from pH 3 to 9, and the value of the equilibrium constant for CH3HgOH2+ + dThd in equilibrium CH3Hg(dThdH--1) + H30+ is estimated from intensity measurements to be 0.6 in reasonable agreement with an earlier value based upon uv spectrophotometric data. Binding is to N(3) with substitution of CH3Hg+ for the proton. A similar reaction occurs with 1-MeThy. Raman spectra for aqueous and crystalline 1-MeThy and for the complex CH3Hg(1-MeThyH--1) are reported. The spectrum of crystalline Hg(1-MeThyH--1)2, for which the crystal structure is known, also was obtained for comparison. Raman difference spectroscopy was used to confirm that CH3Hg (II) binds to N(3) of dTMP and N(1) of GMP at r = 0.2 (MeHg+: phosphate) ratios with mixtures of GMP + CMP + AMP + dTMP. In contrast, native calf thymus DNA does not appear to bind CH3Hg(II) at these sites at r = 0.15, although no significant amount of free CH3HgOH is present. With r = 0.3, extensive binding occurs both to the Thy and Gua bases. Raman difference spectroscopy is a valuable technique for studying the binding of ions and molecules to polynucleotides in moderately dilute aqueous solution.
Assuntos
DNA , Compostos de Metilmercúrio , Nucleotídeos de Timina , Timina/análogos & derivados , Monofosfato de Adenosina , Animais , Sítios de Ligação , Bovinos , Nucleotídeos de Citosina , Nucleotídeos de Guanina , Concentração de Íons de Hidrogênio , Análise Espectral Raman , TimoRESUMO
The diaquo species of cis-dichlorodiammineplatinum (II) reacts with pyrimidines and substituted pyrimidines to form very soluble, deep blue complexes. These are believed to consist of mainly monomeric species containing one pyrimidine moiety liganded to each platinum. The structures of the complexes are largely uncertain at this time. We describe the methods of synthesis and characterization of approximately 70 such complexes, with a suggested classification scheme, incluse complexes show superior activity against the ascites Sarcoma 180 tumor in Swiss mice when compared to cis-dichlorodiammineplatinum (II). Initial screening test results and dose schedule-dependency results indicate we can achieve 100% cures in this tumor-host system. Activity is also shown against the Rauscher leukemia, Ehrlich ascites, and ADJ/PC6A tumors. Microscopic histopathologic studies of resulting kidney lesions show that the "platinum-uracil blue" complex causes only minor focal damage to the proximal convoluted tubules at a therapeutic dose level, rather than the generalized degenerative changes so prominent and dose limiting noted with cis-dichlorodiammineplatinum (II).