EFFECT ON THE PERIPHERAL NERVOUS-SYSTEM OF THE SHORT-TERM INTRAVENOUSADMINISTRATION OF PACLITAXEL IN THE RAT

The effectiveness of paclitaxel (Taxo(R)) in the treatment of differen t tumors is well-known but, on the other hand, there is little informa tion regarding ifs neurotoxicity and the mechanism(s) underlying this potentially severe side effect. In this study, using behavioral, neuro physiological, morphological and morphometric methods, we evaluated th e effect of infra venous administration of paclitaxel on the rat nervo us system. After 2 pilot studies, 40 female Wistar rats were treated w ith intravenous paclitaxel via a catheter placed in the jugular vein, while 20 animals were used as controls. Paclitaxel dissolved in ethano l/Tween 80/saline (5/5/90%) was administered 5 times over a period of 10 days. At the end of the experiment half the surviving animals in ea ch group were evaluated and sacrificed (day 11), while the rest of the rats were evaluated and sacrificed on day 25. On day 11 the treated a nimals had significant impairment in pain perception (tail-flick test) , coordination (rota-rod test) and nerve conduction velocity in the ta il nerve. At the light microscope minimal axonal damage and Schwann ce ll activation were observed in the sciatic nerve. At the electron micr oscope microtubular accumulation was present within the axons in dorsa l and ventral spinal roots and in the sciatic nerve. On day 25 the beh avioral tests were normal in treated rats, while the nerve conduction velocity was still moderately reduced in comparison with the controls. At the electron microscope a morphological examination evidenced that microtubular accumulation was less severe, but still evident, especia lly in the sciatic nerve. Morphometric determinations performed on day s 11 and 25 did not evidence differences between paclitaxel-treated ra ts and controls. The results of this study, the first in which an exte nded examination of the nervous system of animals treated intravenousl y with paclitaxel has been carried out, suggest that short-term admini stration of the drug induces mainly reversible changes in the peripher al nerves and spinal roots. Microtubules seem to be the main target of paclitaxel neurotoxicity, in much the same way as has been described for its antineoplastic activity. Finally, no pathological changes were seen in the neuronal bodies of the spinal cord and dorsal root gangli a. This model may be used for further studies with combination treatme nts with other antineoplastic or neuroprotective agents. (C) 1997 Into x Press, Inc.