Abstract
The diaminocyclohexane platinum (Pt(DACH)) derivatives ormaplatin and oxaliplatin have caused severe and dose-limiting peripheral sensory neurotoxicity in a clinical trial. We hypothesized that this toxicity could vary in relation to the biotransformation and stereochemistry of these Pt(DACH) derivatives. We prepared pure R,R and S,S enantiomers of ormaplatin (Pt(DACH)Cl4), oxaliplatin (Pt(DACH)oxalato) and their metabolites (Pt(DACH)Cl2 and Pt(DACH)methionine) and assessed their peripheral sensory neurotoxicity and tissue distribution in the rat and in vitro anti-tumour activity in human ovarian carcinoma cell lines. The R,R enantiomers of Pt(DACH)Cl4, Pt(DACH)oxalato and Pt(DACH)Cl2, induced peripheral sensory neurotoxicity at significantly lower cumulative doses (18 +/- 5.7 vs 32 +/- 2.3 micromol kg(-1); P < 0.01) and at earlier times (4 +/- 1 vs 6.7 +/- 0.6 weeks; P = 0.016) during repeat-dose treatment than the S,S enantiomers. Pt(DACH)methionine enantiomers showed no biological activity. There was no difference between Pt(DACH) enantiomers in the platinum concentration in sciatic nerve, dorsal root ganglia, spinal cord, brain or blood at the end of each experiment. Three human ovarian carcinoma cell lines (41 M, 41 McisR and SKOV-3) showed no (or inconsistent) chiral discrimination in their sensitivity to Pt(DACH) enantiomers, whereas two cell lines (CH-1 and CH-1cisR) showed modest enantiomeric selectivity favouring the R,R isomer (more active). In conclusion, Pt(DACH) derivatives exhibit enantiomeric-selective peripheral sensory neurotoxicity during repeated dosing in rats favouring S,S isomers (less neurotoxic). They exhibited less chiral discrimination in their accumulation within peripheral nerves and in vitro anti-tumour activity.
Highlights
MethodsTrans-1,2-diaminocyclohexane, (+)- and (-)-tartaric acids, potassium tetrachloroplatinate(II), chlorine gas and d6-dimethyl sulphoxide were obtained from Aldrich Chemical (AR grade)
Tissue platinum levels after treatment for 8-weeks with Pt(DACH)methionine enantiomers ranged from 2 to 6 ng g-' but were 100-fold lower than those taken from rats treated with the other Pt(DACH) analogues (Figure 3)
There was no enantiomeric selectivity in the platinum concentrations in sciatic nerve, dorsal root ganglia, spinal cord and brain, despite differences between
Summary
Trans-1,2-diaminocyclohexane, (+)- and (-)-tartaric acids, potassium tetrachloroplatinate(II), chlorine gas and d6-dimethyl sulphoxide were obtained from Aldrich Chemical (AR grade). Nuclear magnetic resonance (NMR) experiments were carried out on a Bruker AC200 spectrometer, using d6dimethyl sulphoxide as solvent. Infrared spectra were obtained on Bio-rad FTS-Bruker IFS66V spectrometers as potassium bromide and polyethylene discs respectively. Optical activity of the resolved tartrate salts of 1,2-diaminocyclohexane was measured on a PolAAr 2001 polarimeter at 24°C using the sodium D line at 589 nm, in which water was used as the solvent and the concentration was 1 g 100 ml-'. The diamines were recovered immediately before use by adding 10 M sodium hydroxide to the suspension of their corresponding tartrate salts in water until the pH reached 14, followed by extraction with dichloromethane, drying over anhydrous sodium sulphate, filtration and solvent removal at reduced pressure at 40°C.
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