Nucleic acids cisplatin

Recent reviews in the field of platinum anticancer drugs focus on platinum-nucleobase chemistry [7], biological processing of platinum-modified DNA [8], trans-platinum anticancer drugs [5], cisplatin and derived anticancer drugs [4,9], proteins and cisplatin [10], trans-diam-mineplatinum(II) and nucleic acids [11], and catalytic activity and DNA [12], just to mention a few. The aim of this review is to explore the chemistry in the interaction of various platinum compounds with nucleic... 

Lee YJ, Park SJ, Ciccone SL, Kim CR, Lee SH (2006) An in vivo analysis of MMC-induced DNA damage and its repair. Carcinogenesis 27(3) 446-453 Loehrer PJ, Einhom LH (1984) Drugs five years later. Cisplatin. Ann Intern Med 100(5) 704-713 Li G, Widom J (2004) Nucleosomes facilitate their own invasion. Nat Struct Mol Biol 11 763-769 Liu W, Sun D, Hurley LH (2005) Binding of G-quadruplex interactive agents to distinct G-quadruplexes induces different biological effects in MiaPaca cells. Nucleosides Nucleotides Nucleic Acids 24(10-12) 1801-1815... 

Coste F, Malinge J-M, Serre L, Shepard W, Roth M, Leng M, Zelwer C. Crystal structure of a double-stranded DNA containing a cisplatin interstrand crosslink at 1.63°A resolution hydration at the platinated site. Nucleic Acids Res 1999 27 1837-1184. 

De Silva lU, McHugh PJ, Clingen PH et al. Defects in interstrand cross-link uncoupling do not account for the extreme sensitivity of ERCCl and XPF eells to cisplatin. Nucleic Acids Res 2002 30 3848-3856. 

Heavier metal ions and metal complexes can find sites on nitrogen atoms of the nucleic acid bases. Examples are the platinum complex cisplatin and the DNA-cleaving antibiotic neocarzinostatin (Box 5-B). Can metals interact with the n electrons of stacked DNA bases A surprising result has been reported for intercalating complexes of ruthenium (Ru) and rhodium (Rh). Apparent transfer of electrons between Ru (II) and Rh (III) over distances in excess of 4.0 nm, presumably through the stacked bases, has been observed,181 as has electron transfer from other ions.181a Stacked bases are apparently semiconductors.182... 

Interestingly, the emission of [Pt(tpy)(OH)]+ is quenched in water, but is restored upon intercalation with double-stranded nucleic acids [poly(dA-dT)]2 and [poly(dI-dC)]2 [73]. Although intercalation can also occur at G-C-rich sequences - and indeed it does so more strongly than for A-T - emission is then quenched by electron-transfer from guanine, the most readily oxidized of the nucleobases. The initial intercalative interactions are probably followed by covalent platination of the DNA, most likely by purine-N7 displacing the OH ligand, reminiscent of cisplatin. The absorption... 

After administration, the drug circulates in the blood, primarily as the chloride (for cisplatin), or as another rather inert form (such as the biscar-boxylate in carboplatin). In the blood, also reactions with proteins and rescue agents can take place. Upon passing through cell walls (either actively or passively), intracellular reactions with peptides and proteins may take place, presumably followed by transfer to nucleic acids. Given the strong (kinetic) preference of Pt compounds to react with class-B donor atoms (such as those from thiolates and thioethers), binding to nucleic-acid bases (a thermodynamic end product) must at least occur partially via labile intermediates. 

Recovery from nephrotoxic acute renal failure requires replacement of damaged tubule cells with new ones that are actively dividing. Recovery from cisplatin induced acute renal failure is accompanied by increased mitosis in renal epithelial cells, which is preceded by increases in nucleic acid synthesis [33]. 

More valuable information on nucleic acids has been obtained from pyrolysis data when it was possible to evaluate the nature and abundance of the purine/pyrimidine bases. The information on these bases is important for monitoring in vitro DNA synthesis [5,6], for the evaluation of chromosome modifications [7], and for the study of complex formation of DNA with cisplatin [11,12]. As indicated previously, the DIP technique was reported to be more useful for detecting the base component of the nucleic acid. However, some information on the bases can be obtained also by Curie point Py-MS, as it can be seen from the spectrum of NADPH (nicotinamide adenine dinucleotide phosphate) shown in Figure 13.2.3. The spectrum was obtained in similar conditions as spectra for DNA and RNA shown previously [8]. 

Cisplatin reacts with nucleosides and nucleic acids and can cross-link cellular DNA. The effects on cross-linking with DNA appear to differ among cell type however, the effects on cross-linking are most pronounced during the S-phase of the cell cycle. In addition, cisplatin inhibits a number of enzymes that contain a catalytically active sulfydryl group. Ribonucleotide reductase is extremely sensitive to the effects of cisplatin, with greater than 90% inhibition observed in vitro in the presence of a two-molar excess of cisplatin. The inhibition was nearly instantaneous and was irreversible. 

Turchi J.J., Henkels K.M., and Zhou Y., Cisplatin-DNA adducts inhibit translocation of the Ku subunits of DNA-PK, Nucleic Acids Res., 2000,28,4634-4641. 

Increased nucleic acid repair mechanisms Alkylating agents, cisplatin... 

---