Neurophysiological and neuropathological evaluation of the bortezomib effect in myeloma-bearing mice

Bortezomib (BTZ) is a highly effective and widely used antineoplastic drug for the treatment of multiple myeloma. Despite its effectiveness, the use of this proteasome inhibitor is limited by its toxicity and in particular peripheral neurotoxicity is a major and clinically-relevant problem. In fact, since the earliest Phase I and Phase II studies, in a significant proportion of BTZ-treated patients a severe sensory peripheral neuropathy emerged as a dose-limiting side effect. Unfortunately, till now the management of BTZ-peripheral neurotoxicity is an unsolved issue. The use of animal models is one of the most widely used to investigate the neurotoxicity of anticancer drugs, provided they are able to reproduce the clinical use of the drug. Since it has been suggested that bortezomib peripheral neurotoxicity is more severe in myeloma patients that in those affected by solid cancers, the currently available animal models can be less reliable in the attempt to reproduce the clinical use of the drug. Therefore, we developed a myeloma-bearing animal model in which immunodeficient scid mice were intravenously treated with BTZ 1 mg/kg weekly for 5 weeks (q7dx5). Mice were s.c. injected into the right flank with 10x106 cell/0.1 mL/mouse of RPMI-8226 multiple myeloma cells. Treatments started three days after tumor injection.The results of this study evidenced that the administration of BTZ at a dose able to treat experimental myeloma and to induce proteasome activity inhibition comparable to that achieved in myeloma patients induced significant neurophysiological changes vs. vehicle-treated animals in conduction velocity in the caudal and digital nerves and in potential amplitude in the digital nerve. Moreover, the administration of BTZ induced evident pathological changes mostly due to axonopathy vs. vehicle-treated animals in caudal and sciatic nerve as well as in dorsal root ganglia (DRG). Therefore, this model able to mimic the clinical use of BTZ can be reliable and used to test neuroprotective strategies aimed at the reduction of BTZ peripheral neurotoxicity and to rule out their interference with BTZ anti-myeloma activity.