DNA, platinum binding

Reed E, Sauerhoff S, Piorier MC. Quantitation of platinum-DNA binding in human tissues following therapeutic levels of drug exposure—a novel use of graphite furnace spectrometry. Atomic Spectroscopy 1988 9 93-95. 

Reaction with DNA of cells in culture. Studies with cultured cells have indicated the relevance of platinum-DNA binding to cytotoxicity. Pascoe and Roberts (, ) studied the interaction of several platinum compounds with macromolecules at measured levels of cell kill. 

Hambley and co-workers have reported the synthesis, DNA cross-linking, and in vitro anticancer properties of a platinum(II) complex that was designed to bind the macromolecule in an interstrand rather than intrastrand manner,162 the latter being the dominant mode of DNA-binding by platinum anticancer drugs such as cisplatin. The complex [PtCl2(hpip)] ((46) ... 

The preparation and DNA-binding properties of platinum(II) complexes of the type [Pt(bi-py)(n-R-py)2]2+ (R = CN, Cl, H, Ph, Me, NH2 =2-4), prepared by the reaction of excess pyridine with [PtCl2(bipy)], have been reported.220 The related [Pt(Ph2bipy)(4-R-py)2]2+ complexes were also studied.221... 

The DNA binding of trans-platinum complexes is thus quite rich and varied. The cellular effects of such adduct formation also appear to be significantly different from those of cisplatin. 

Over the past 20 years, cis-diamminedichloroplatinum(II), known for more than 145 years, has emerged as the classic compound in the context of antitumor drug therapy. Because it is generally accepted that binding of the compound to DNA is a major requirement for its biological activity, scientists have focused their attention especially on platinum-DNA interactions. In the present review, the latest results... 

A very interesting aspect of platinum-DNA interactions concerns the nature of the resulting adducts and their relative quantities. Due to the bifunctional nature of cis-Pt, several types of adducts in the DNA can be expected to be formed, to be distinguished in (1) interstrand chelates (binding of two nucleobases that are each positioned in one of the complementary DNA strands), (2) intrastrand chelates (binding of two nucleobases within the same DNA strands), (3) intrabase chelates (binding to two different atoms in one base), and (4) DNA-protein cross-links. 

Os-platinum (cisplatin) binds to intracellular DNA, causing both interstrand and intrastrand cross-linking. It is a cell-cycle phase nonspecific agent. Os-platinum, which is ineffective orally, is used for testicular, bladder, and head and neck cancers. It precipitates nephrotoxicity, ototoxicity, and gastrointestinal injury. 

Cellular sensitivity to different platinum compounds and the recognition of the platinum DNA adducts by mismatch repair protein complexes appear to be linked [103]. It may also be significant that hMSH2 is expressed to higher levels in testicular and ovarian tissue than in other organs such as heart, liver and colon [109], Whether or not mismatch repair plays a general role in the anticancer activity of cisplatin still remains debatable, however. Mismatch repair proteins bind to cisplatin-DNA adducts in vitro with weak specificity [109][113]. Although specificity is enhanced when aplat-inum lesion is combined with a mutation [113], it is still less than the affinity of these proteins for the unplatinated mutation [63] [108]. 

Accordingly, some effort has been devoted to studying the effects of cisplatin on transcription. In vitro experiments with RNA polymerases demonstrated that productive elongation activity was prematurely terminated by the whole spectrum of cisplatin-DNA adducts, but not by the /ran.y-DDP 1,3-intrastrand adducts [150-152], Selective bypass of trans-DDP adducts was also demonstrated in XPA cells, suggesting that repair of the DNA lesions did not contribute to differential transcription inhibition by the platinum compounds [153], In vivo, hormone-induced chromatin remodeling and subsequent transcription from the MMTV promoter was specifically inhibited by cisplatin [154], In this case, platinum adducts seemed to cause a decrease in the DNA binding of one of the transcription factors, NF1. Several chromatin-associated proteins, such as the linker histone protein HI or... 

As mentioned above, one consequence of stalled RNA polymerase II at a DNA adduct is activation of transcription-coupled repair [27], This effect may depend on the type of polymerase, however, since the removal of some types of DNA damage is slower from RNA-polymerase I transcribed ribosomal DNA than from a nuclear gene [160], The lower level of repair in the nucleolus could also reflect the influence of other transcription factors, such as the HMG-domain protein UBF, which bind to cisplatin-mod-ified DNA [145]. When HeLa cells were exposed to cisplatin at concentrations which did not seem to affect nuclear transcription, inhibition of rDNA gene expression was associated with the redistribution of UBF, along with other factors responsible for rRNA transcription [138], These observations indicate how cisplatin might exert a combination of effects. Transcription is stopped due to titration of essential factors by the platinum-DNA adducts, and the same proteins could shield the lesions from the repair activity. 

So, in principle, we have to consider three types of species, all competing for cisplatin, namely, the rescue agents, the peptides and proteins, and the DNA. Although, at present, much highly relevant information is available about Pt-DNA binding, information of other aspects of in vivo platinum chemistry has become recently available [18-20], A review devoted towards the interaction of (new, active, and some relevant inactive) platinum compounds (in model fluids in vitro and in vivo) with cellular components (DNA peptides) and additives (rescue agents) is highly relevant and timely, and the most important results available will be discussed below. 

In general terms, both steric effects and electronic factors are expected to play a role in determinating the reactivity of square-planar platinum complexes. The presence of planar amine ligands in cis- or /ran.y-Pt(anion )2 complexes and their orientation with respect to the coordination plane, as well as their substituents, can reduce the rates of DNA binding or thio binding compared to aliphatic ammine and amine complexes. Especially, substituents close to the coordination site should be expected to slow down axial substitution reactions at Pt. As there is now little doubt that DNA platina-tion is a key event (or THE key event) in the mechanism of action of platinum anticancer drugs, attention to the process of formation of the major adduct (GG) as an intrastrand cross-link between N(7) atoms of two adjacent guanine (G) residues, will remain important. 

---