Abstract:
Peripheral neurotoxicity induced by some platinum chemotherapy agents is the dose limiting factor, seriously affecting the quality of life of chemotherapy patients who receive this treatment. The cause of the peripheral neurotoxicity remains unknown. Using an animal model, the neurotoxic profiles of a series of platinum compounds and their related stereoisomers were determined. The series consisted of cisplatin, carboplatin, oxaliplatin, S,S-oxaliplatin, ormaplatin, R,R- and S,S- ormaplatin and JM216. The neurotoxicity of these compounds in the animal model was correlated with their hydrophobicity, accumulation and reactivity. Also, using peripheral nerve tissues dissected at the end of treatment (or at specific timepoints) from the animals, morphological changes induced by the platinum compounds were also measured.
Animals were administered the platinum compounds at the maximally tolerated dose, for a period of eight weeks, to determine the onset of neurotoxicity as indicated by changes in the sensory nerve conduction velocity (SNCV). The cumulative doses at which the platinum compounds in the series induced neurotoxicity (neurotoxic dose potency) in the animal model varied. Oxaliplatin induced neurotoxicity at the smallest dose and therefore at the earliest timepoint (l5µmo1/kg, 3 weeks of treatment) and carboplatin induced neurotoxicity at the highest dose and the latest timepoint (322 µmo1/kg, 8 weeks of treatment). The neurotoxic dose potency was compared to data obtained from the literature of incidence of neurotoxicity in patients. There was a strong correlation (r2 = 0.9871).
It has previously been hypothesised (Gregg. et al. 1992) that platinum accumulation in peripheral nervous tissues plays a role in platinum induced neurotoxicity. Using tissues obtained from animal studies, the platinum concentration in peripheral nerve tissues was determined via Inductively Coupled Plasma-Mass Spectrometry. There was no correlation between the amount of platinum accumulated in these tissues (dorsal root ganglia, sural nerve and sciatic nerve) and neurotoxicity. Furthermore it was expected that the accumulation of these compounds in the peripheral nervous system would be related to the hydrophobicity of the compound. The inverse was found to be true. The more hydrophilic the platinum compound, the greater the accumulation in the peripheral nerve tissues, and the more hydrophobic the platinum compound the lesser the accumulation in the peripheral nerve tissue (eg. drg r2 = 0.99, P=0.004).
Using in vitro protein binding half life, the reactivity of compounds in the platinum series was assessed. It was determined that the neurotoxic compounds had a shorter half life and were more reactive than the non neurotoxic compounds. A positive correlation was also observed between reactivity and the incidence of neurotoxicity in patients (r2 = 0.89, P=0.0005).
Tissues obtained from the animals were used to measure changes in dorsal root ganglia nucleolar diameter, and comparison made between the nucleolar diameter of each of the treatment groups, and their changes in SNCV. Strong correlations were observed between nucleolar diameter changes and altered SNCV in animals (r2=0.9971).
From the above-mentioned studies, insight was gained into the physical parameters of the platinum compounds in the series that were associated with different neurotoxicity profiles. As yet a definite mechanism has not clearly defined but it is hypothesised to involve molecular nucleolar changes.