Platinum-DNA adducts

WARNING Administration only by provider experienced in CA chemo BM suppression possible, anaphylaxis may occur Uses Ovarian, lung, head neck, testicular, urothelial, brain CA, NHL allogeneic ABMT in high doses Action DNA cross-linker forms DNA-platinum adducts Dose 360 mg/m ... 

Resistance to cisplatin, but not oxaliplatin, is partly mediated by loss of function in mismatch repair (MMR) proteins. By contrast, MMR repair proficiency is not required for oxaliplatin cytotoxicity. In the absence of effective repair of DNA-platinum adducts, sensitive cells cannot replicate or transcribe affected portions of the DNA strand. Some DNA polymerases can bypass adducts, possibly contributing to resistance. Overexpression of Cu efflux transporters ATP7A and ATP7B correlates with poor survival after cisplatin-based therapy for ovarian cancer. 

The DNA crosslinks formed by cis-DDP interfere with DNA replication and eventually cause cell death. The activity of DNA polymerases is impaired by DNA-platinum adducts (54-56). Furthermore, although the cell is capable of repairing DNA-platinum adducts (50,57-59), the intrastrand DNA crosslinks produced by cis-DDP do not cause large distortions of the double helix and so may not be easily recognized and repaired (51,60,61). Despite cellular repair mechanisms, a sufficient concentration of cis-DDP will inhibit replication and prevent cell division (20-23,62-64). In some cells, cis-DDP appears to also impair the cell s ability to transcribe genes needed for mitosis (63,64), and even cells which manage to divide initially after cis-DDP treatment often do not display long-term survival (22,23). 

Anin, M.F., Gaucheron, F., and Leng, M. (1992) Lability of mono functional cis platinum adducts Role of DNA double helix. Nucleic Acids Res. 20, 4825-4830. 

Rate constants for reaction of cis-[Pt(NH3)2(H20)Cl]+ with phosphate and with S - and 5/ -nucleotide bases are 4.6xl0-3, 0.48, and 0.16 M-1s-1, respectively, with ring closure rate constants of 0.17 x 10 5 and 2.55x10-5s-1 for subsequent reaction in the latter two cases 220). Kinetic aspects of interactions between DNA and platinum(II) complexes such as [Pt(NH3)3(H20)]2+, ds-[Pt(NH3)2(H20)2]2+, and cis-[Pt(NH3)2(H20)Cl]+, of loss of chloride from Pt-DNA-Cl adducts, and of chelate ring formation of cis-[Pt(NH3)2(H20)(oligonucleotide)]"+ intermediates implicate cis-[Pt(NH3)2(H20)2]2+ rather than cis-[Pt(NH3)2 (H20)C1]+, as usually proposed, as the most important Pt-binder 222). The role of aquation in the overall scheme of platinum(II)/DNA interactions has been reviewed 223), and platinum(II)-nucleotide-DNA interactions have been the subject of molecular modeling investigations 178). 

Deoxyribonucleic acid footprinting studies have shown that HMG domains A and B inhibit cleavage by nucleases over a 12- to 15-base-pair region centered around the platinum adduct (81). The HMG proteins can modulate cisplatin cytotoxicity by inhibition of the excinuclease-mediated removal of Pt-d(GpG) adducts from DNA (82). However, this hypothesis has been questioned because there is no evidence for cellular protein shielding of Pt-d(GpG) adducts from repair enzymes (83). 

Fig. 19. Amounts of the platinum adducts, as a function of incubation time (h), found upon treatment of salmon sperm DNA with cisplatin at 37°...

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... 

The rate of formation of cisplatin-DNA adducts was found to be independent of superhelicity [59] and appears to be unaffected by the presence of histones in nucleosomes [29] and in chromatin [77], Therefore, isolated DNA in aqueous solution appears to be a relevant model for kinetic and mechanistic studies of cellular DNA-platination. It was early checked that the cisplatin-DNA adducts were stable for a least three days at 37 °C after their formation [78], There are now a few cases reported of unstable platinum adducts (vide supra) i) monoadducts with the diazapyrenium ligand [52], ii) a cisplatin intrastrand GG chelate rearranging into a GG interstrand crosslink [63], iii) cisplatin GG interstrand diadducts, slowly rearranging into intrastrand ones [65], tv) transplatin intrastrand GNG diadducts rearranging into interstrand crosslinks (J.-M. Malinge and M. Leng, Part 3). 

The aim of the present contribution is to critically review computational work related to platinum antitumor drugs, published prior to 1998. After a section devoted to molecular-orbital calculations on platinum antitumor complexes and related compounds, we address force-field calculations on platinum adducts with DNA constituents that have been used (mainly in combination with NMR spectroscopy) to evaluate the structure of the adduct. A brief outlook concludes this chapter. 

Wamke, U., Gysler, J., Hofte, B., Tjaden, U.R., van der Greef, J., Kloft, C., Schunack, W., Jaehde, U. Separation and identification of platinum adducts with DNA nucleotides by capillary zone electrophoresis and capillary zone electrophoresis coupled to mass spectrometry. Electrophoresis 22, 97-103 (2001)... 

The notion that DNA is the likely target for antitumour platinum complexes will be discussed on the basis of their interaction with nucleic acids in vitro and of their interactions with the DNA of both cells in culture and cells in whole animals. Biochemical studies suggest that interactions with cellular DNA result in an inactivation of the DNA template for DNA replication. Support for these views came from the demonstration that cells could remove DNA bound platinum adducts by an excision repair process that facilitated the recovery of cells from toxic damage. 

Fraval and Roberts ( 0) demonstrated removal of platinum adducts from DNA of exponentially growing Chinese hamster V79 cells. The half-life of total drug-DNA reaction products was approximately 28 hours. As such products are stable chemically under physiological conditions, removal of the DNA adducts could be attributed to repair. 

Variations in monofunctional adduct lifetimes were also invoked to explain the relative ratios of different platinum adducts formed by cis-DDP on DNA. When the reaction of PH][Pt(en)Cl2] with DNA was allowed to occur in the presence of thiourea, subsequent enzymatic digestion of the... 

Increased activity of DNA repair pathways, which may differ for the various alkylating agents. Thus, increased activity of the complex nucleotide excision repair (NER) pathway seems to correlate with resistance to most chloroethyl and platinum adducts. Alkyl guanine transferase (AGT) activity determines response to BCNU and to methylating drugs such as the triazenes, procarbazine, and busulfan ... 

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