Disease relevance of Tetraplatin

• The human ovarian cancer cell lines A2780 and A2780/CP70 were studied to investigate the cellular basis for their relative sensitivities to tetrachloro(DL-trans)-1,2-diamminecyclohexaneplatinum(IV) (ormaplatin) [1].
• PURPOSE: Neurotoxicity is one of the major toxicities of platinum-based anticancer drugs, especially oxaliplatin and ormaplatin [2].

High impact information on Tetraplatin

• In the first group of experiments, WR-2721 (200 mg/kg, i.p.) was administered 30 min before ormaplatin (12.5 mg/kg, i.p.), and then peritoneal fluid, plasma, and tissues were harvested at 30 min after the ormaplatin administration [3].
• Our results suggest that a significant interaction between WR-2721 and ormaplatin is occurring in the peritoneal cavity [3].
• Both cell lines were treated with ormaplatin at doses ranging from 0.10 to 40 microM, for the purpose of studying drug accumulation and efflux, and DNA adduct formation and repair [1].
• The intrinsically cisplatin-resistant HCT8/S cell line showed only partial cross-resistance to ormaplatin [4].
• Ormaplatin-derived plasma ultrafilterable platinum (UF-Pt) exhibited linear pharmacokinetics over the dose range studied [5].

Chemical compound and disease context of Tetraplatin

• Ormaplatin is a platinum analog that was developed because of an altered toxicity profile and non-cross resistance to cisplatin in both in vitro and in vivo models [6].

Biological context of Tetraplatin

• As assessed by colony formation assays, the A2780/CP70 cell line [50% inhibitory dose (IC50) = 3.6 microM] was 9.5-fold more resistant to ormaplatin than the A2780 cell line [IC50 = 0.38 microM] [1].
• Ormaplatin exhibited a high degree of protein binding, with more than 70% of platinum protein bound by the end of the infusion [5].
• Organ-specific biotransformation of ormaplatin in the Fischer 344 rat [7].
• RESULTS: Our study indicated that Pt(dach)Cl2 and its hydrolysis products were more potent at inhibiting neurite outgrowth than the parent drugs oxaliplatin and ormaplatin [2].
• However, Pt-dach bound to plasma proteins fourfold more quickly for ormaplatin than for oxaliplatin, and the AUC for Pt-dach bound to plasma proteins was twofold higher for ormaplatin than for oxaliplatin [8].

Anatomical context of Tetraplatin

• Previous studies have established that the rank order of ormaplatin toxicity in Fischer 344 rats is spleen approximately gastrointestinal tract > kidney >> liver [7].
• We examined the intracellular biotransformation products of ormaplatin [(d,l-trans)1,2-diaminocyclohexanetetrachloroplatinum(IV)] (formerly called tetraplatin) in liver, kidney, spleen, small intestine, and plasma of the adult male Fischer 344 rat [7].
• Cisplatin and tetraplatin(IV) produced strong damage and DACH RR(II) and cis-[Pt(II)Cl,2(iPrNH2)2] weak DNA damage in intact HeLa cells [9].

Associations of Tetraplatin with other chemical compounds

• The diaminocyclohexane platinum (Pt(DACH)) derivatives ormaplatin and oxaliplatin have caused severe and dose-limiting peripheral sensory neurotoxicity in a clinical trial [10].
• The accumulation of ormaplatin was not inhibited by ouabain in either of the cell lines [11].
• Of the CDDP analogues tested, including carboplatin (CBDCA), [(glycolate-0,0') diammineplatinum (II) (254-S)], ormaplatin [tetrachloro-(d,1-trans)- 1,2-diaminocyclohexaneplatinum (IV) (OP)] and oxaliplatin [oxalato (trans-1-1,2-diaminocyclohexane) platinum (II) (1-OHP)], no agent showed superior antitumor activity compared to CDDP [12].

Gene context of Tetraplatin

• However, the accumulation of ormaplatin in PC-14/CDDP was almost the same as that in PC-14 [11].

Analytical, diagnostic and therapeutic context of Tetraplatin

• Tetraplatin (Ormaplatin) has good antitumor activity against some cisplatin-resistant cells and is currently being studied in clinical trials [13].
• Ormaplatin is a racemic, platinum(IV), anti-cancer drug which is currently involved in phase 1 clinical trials [14].
• Specifically, cells were damaged with cisplatin, a related analogue ormaplatin, and ultraviolet light, and PCR was performed on the DNA from 1000 cells after direct lysis with no purification [15].
• This report characterizes the pharmacokinetic profile of both the total plasma concentrations of elemental platinum and the unbound ultrafiltrate concentrations of elemental platinum, following a 30 min intravenous infusion of ormaplatin [16].

References