Elsevier

European Journal of Cancer

Volume 37, Issue 18, December 2001, Pages 2457-2463
European Journal of Cancer

Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat

https://doi.org/10.1016/S0959-8049(01)00300-8Get rights and content

Abstract

The aim of this study was to determine the influence of oxaliplatin scheduling on the onset of peripheral neurotoxicity and ototoxicity in a rat model. Animals were treated with four different schedules of oxaliplatin using two cumulative doses (36 and 48 mg/kg intraperitoneally (i.p.)). The neuropathological examination evidenced dorsal root ganglia (DRG) nucleolar, nuclear and somatic size reduction with nucleolar segregation in the treated rats. Sensory nerve conduction velocity (SNCV) was reduced after oxaliplatin treatment, while the auditory pathway was unaffected. After treatment, platinum was detected in the kidney, DRG and sciatic nerve. After a 5-week follow-up period, recovery of the pathological changes in the DRG and sciatic nerves occurred, although platinum was still detectable in these tissues. The following conclusions may be drawn: the main targets of oxaliplatin neurotoxicity were the DRG; the shorter the interval between the injections, the higher the severity of peripheral neuropathy and this was also related to the cumulative oxaliplatin dose; the peripheral neurotoxicity tended to be reversible; ototoxicity was absent even with high cumulative doses of oxaliplatin.

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.

Section snippets

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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