Anti neoplastic agent

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Oxaloplatin is an anti neoplastic agent with the molecular formula C8H14N2O4Pt and the chemical name of cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] [oxalato(2-)-O,O'] platinum. Oxaliplatin is an organo platinum complex in which the platinum atom is complexed with 1,2-diaminocyclohexane (DACH) and with an oxalate ligand as a leaving group. The molecular weight is 397.3. Oxaliplatin is slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, and practically insoluble in ethanol and acetone.

Oxaliplatin undergoes non enzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter- and intra-strand Pt-DNA cross links are formed. Cross links are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. Oxaliplatin exerts its antitumor effects by covalent modification of DNA

Oxaliplatin is known to form DNA cross links in vitro (wonynarowski,2000).Thus, our aim was to determine the oxaliplatin-induced DNA crossinks within human lymphocytes by using an modified alkaline Comet assay. The DNA strand break was studied by Comet assay, sister chromatid exchange assay, Micronucleus assay.

The study conducted by Hah et al., 2007 reported that Oxaliplatin mediates the formation of DNA cross links. They reported that in cultured platinum-sensitive testicular (833K) and platinum-resistant breast and bladder (MDA-MB-231 and T24, respectively. They treated the cells with supra pharmacological concentrations of oxaliplatin at .2µM. Determination of Oxaliplatin-DNA Adduct Distribution by HPLC-AMS was performed. The study concluded that monoadducts initially form, followed by an increase in Pt-DNA cross-links over time. We found that 1 h of continuous exposure to oxaliplatin resulted in approximately 18% Pt-dG or Pt-dA monoadducts, 8.9% Pt- 1,2-d(GpG), and 3.4% Pt-1,2-d(ApG) or Pt-1,2-d(GpA) intrastrand cross-links. The remaining major radiocarbon-containing peaks were assigned as 8% Pt-(dA)2 interstrand cross-links and 14% 1,3-d(GpNpG) intrastrand cross-links or interstrand crosslinks between guanine nucleotides. The latter peaks were inconclusively assigned due to coelution of radiocarbon, since Pt-(dG)2 could be produced from either type of adduct after enzymatic digestion (24). A 5 h incubation of oxaliplatin with naked DNA resulted in approximately 26% monoadducts, 8.3% Pt-1,2-d(GpG) and 4.7% Pt-1,2-d(GpA) or Pt-1,2-d(ApG) intrastrand cross-links, 7.8% Pt-(dA)2 interstrand cross-links, and 31% Pt-1,3-d(GpNpG) intrastrand or Pt-(dG)2 interstrand cross-links. After a 24 h incubation of oxaliplatin with naked DNA, the distribution of radiocarbon in the HPLC fractions consisted of approximately 2.6% monoadducts, 9.5% Pt-1,2- d(GpG) and 3.8% Pt-1,2-d(GpA) or Pt-1,2-d(ApG) intrastrand cross-links, 14% Pt-(dA)2 interstrand cross-links, and 36% Pt- 1,3-d(GpNpG) intrastrand or Pt-(dG)2 interstrand cross-links.

Malina et al., 2007 reported the process of DNA cross linking of cisplatin and Oxaliplatin. They demonstrated the following major differences in the properties of the cross-links of oxaliplatin and cisplatin that is i), the formation of the cross-link by oxaliplatin is more deleterious energetically in all three sequence contexts; ii), the cross-link of oxaliplatin bends DNA slightly but systematically less in all sequence contexts tested; iii), the affinity of HMG domain protein to the cross-link of oxaliplatin is considerably lower independent of the sequence context; and iv), the Klenow fragment of DNA polymerase I pauses considerably more at the cross-link of oxaliplatin in all sequence contexts tested.

Spingler et al., 2001 reported X-ray structure of a platinated DNA duplex derived from an active platinum anticancer drug other than cisplatin. The overall geometry and crystal packing of the complex, refined to 2.4 Å resolution, are similar to those of the cisplatin structure, despite the fact that the two molecules crystallize in different space groups. The platinum atom of the {Pt(R,R-DACH)}2+ moiety forms a 1,2-intrastrand cross-link between two adjacent guanosine residues in the sequence 5¢-d(CCTCTGGTCTCC), bending the double helix by _30° toward the major groove. Both end-to-end and end-to-groove packing interactions occur in the crystal lattice. The latter is positioned in the minor groove opposite the platinum cross-link. A novel feature of the present structure is the presence of a hydrogen bond between the pseudoequatorial NH hydrogen atom of the (R,R)-DACH ligand and the O6 atom of the 3¢-G of the platinated d(GpG) lesion. This finding provides structural evidence for the importance of chirality in mediating the interaction between oxaliplatin and duplex DNA.

Scheeff et al., 1999, reported that intra strand DNA adducts are produced by Cisplatin and Oxaliplatin. Analysis of the resulting structures indicated that the covalent effects of oxaliplatin coordination on DNA structure were very similar to those of cisplatin. The most prominent difference between the two structures resulted from the presence of the 1,2-diaminocyclohexane ring in the oxaliplatin adduct. The modeling indicated that this ring protrudes directly outward into, and fills much of, the narrowed major groove of the bound DNA, forming a markedly altered and less polar major groove in the area of the adduct. The differences in the structure of the adducts produced by cisplatin and oxaliplatin are consistent with the observation that they are differentially recognized by the DNA mismatch repair system.