Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat
Introduction
Oxaliplatin [(trans-l)1,2-diaminocyclohexaneoxalatoplatinum(II)] is a platinum-based chemotherapeutic agent with a 1,2-diaminocyclohexane carrier ligand that produces bulkier DNA conjugates due to the restricted freedom of motion of the platinum atom [1]. Several in vitro studies in cultured human cancer cell lines and in vivo studies in mice have demonstrated the superior anti-proliferative activity of oxaliplatin in comparison to cisplatin for different human malignancies including colon, ovarian and lung cancer 2, 3. Oxaliplatin is effective against metastatic colorectal cancer as a monotherapy and in combination with other agents 4, 5, 6, 7, 8 and against cisplatin-resistant ovarian cancer [9] and is not associated with nephrotoxicity [1].
Oxaliplatin, therefore, is a very promising antineoplastic drug, although neurotoxicity is a dose-limiting symptom [10]. In humans, two different types of neurological symptoms occur during oxaliplatin treatment. Acute neurotoxicity manifests as pareasthesias and dysesthesias in the extremities, triggered or enhanced by exposure to the cold. This neuropathy remains unexplained, is dose-limiting after low total cumulative doses of oxaliplatin, is always reversible, and does not require discontinuation of therapy. No relevant model has yet been determined for studying this type of neuropathy. Chronic and cumulative peripheral neurotoxicity presents as symptoms similar to those seen with cisplatin. It depends on the cumulative dose of oxaliplatin and generally occurs at total cumulative doses >600 mg/m2 over four cycles or more of therapy [11]. This neurological toxicity is generally reversible, but may last for several months [1].
The features of the peripheral neurotoxicity observed following the use of the platinum-based drugs can be studied with neurophysiological, pathological and analytical methods in several well-characterised animal models 12, 13, 14, 15. The neuropathy induced by the platinum derivatives in these models is characterised by a decrease in nerve conduction velocity induced by damage to neuronal cell bodies (decrease in somatic, nuclear and nucleolar area) and peripheral axonopathy. The major site of damage appears to be the dorsal root ganglia (DRG), a result which is consistent with the platinum accumulation studies in humans [16].
In preclinical studies, Holmes and colleagues [15] studied the neurotoxicity of oxaliplatin in a rat model. Up to now, however, no comparison of neurotoxicity between different schedules of oxaliplatin has been performed.
In our experiment, we used neurophysiological, pathological and analytical methods to compare the effect on the peripheral nervous system of different intervals between each single-dose administration and of increasing by more than 30% the cumulative dose of oxaliplatin with a fixed interval between administrations. Moreover, in the latter groups we also compared the effect of high-dose oxaliplatin treatment on the auditory pathway, which is damaged by treatment with cisplatin.
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Animal treatments
All animal procedures were performed according to the European Economic Community (EEC) Council directive 86/609. During the experiment, the animals were kept in individual cages, fed with commercial cubes and drinkable water ad libitum and maintained in an air-conditioned housing room with a 12 h light–dark cycle. A total of 50 female Wistar rats weighing 180–200 g on arrival at the housing room were used. By random selection they were divided into five groups (10 rats in each group) and
General toxicity
All the treated animals completed the treatment period of the study, while three animals died in the follow-up period (one in group 1, one in group 2 and one in group 4). All the surviving animals had only a mild reduction in motility during the treatment period with a rapid and complete recovery occurring in all the rats which did not develop any intraperitoneal fluid accumulation (see below) in the follow-up period.
Mean body weight changes in the treatment period are reported in Fig. 1. At
Discussion
Our experiment was designed to evaluate how the treatment schedule and the total dose of oxaliplatin influence the development of peripheral neurotoxicity in an animal model.
The general toxicity observed in the oxaliplatin-treated rats during the administration period was acceptable, although a decrease in weight gain was observed in all the animals belonging to the treated groups compared with controls. In the follow-up period, on the contrary, peritonitis with abdominal bloating frequently
Acknowledgements
The expert technical work of E. Barazzetta and A. Jerome in the animal treatments, of M. Gaman in specimen preparations and of E. Genton in the revision of the manuscript is gratefully acknowledged by the authors. Oxaliplatin was provided by Debiopharm SA, Lausanne, Switzerland.
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