Retinoic acid reduces chemotherapy-induced neuropathy in an animal model and patients with lung cancer

Abstract

Objective:To evaluate the effect of all-trans retinoic acid (ATRA) as treatment for chemotherapyinduced peripheral neuropathy in an experimental animal model and in a randomized, doubleblinded, controlled trial in patients with non-small-cell lung cancer (NSCLC). Methods:Forty male Wistar rats were randomized in 5 groups: group A, control; groups B and C, treated with cisplatin; and groups D and E, treated with paclitaxel. ATRA (20 mg/kg PO) was administered for 15 days in groups C and E. We evaluated neuropathy and nerve regenerationrelated morphologic changes in sciatic nerve, the concentration of nerve growth factor (NGF), and retinoic acid receptor (RAR)-␣ and RAR-␤ expression. In addition, 95 patients with NSCLC under chemotherapy treatment were randomized to either ATRA (20 mg/m 2 /d) or placebo. Serum NGF, neurophysiologic tests, and clinical neurotoxicity were assessed. Results:The experimental animals developed neuropathy and axonal degeneration, associated with decreased NGF levels in peripheral nerves. Treatment with ATRA reversed sensorial changes and nerve morphology; this was associated with increased NGF levels and RAR-␤ expression. Patients treated with chemotherapy had clinical neuropathy and axonal loss assessed by neurophysiology, which was related to decreased NGF levels. ATRA reduced axonal degeneration demonstrated by nerve conduction velocity and clinical manifestations of neuropathy grades Ն2.Conclusions: ATRA reduced chemotherapy-induced experimental neuropathy, increased NGF levels, and induced RAR-␤ expression in nerve. In patients, reduction of NGF in serum was associated with the severity of neuropathy; ATRA treatment reduced the electrophysiologic alterations. Classification of evidence:This study provides Class II evidence that ATRA improves nerve conduction in patients with chemotherapy-induced peripheral neuropathy. Neurology ® 2011;77:987-995 GLOSSARY ATRA ϭ all-trans retinoic acid; CI ϭ confidence interval; CIPN ϭ chemotherapy-induced peripheral neuropathy; CP ϭ cisplatin/paclitaxel; DM ϭ diabetes mellitus; NGF ϭ nerve growth factor; NSCLC ϭ non-small-cell lung cancer; OR ϭ odds ratio; QOL ϭ quality of life; qRT-PCR ϭ quantitative reverse transcriptase and real-time PCR; RAR ϭ retinoic acid receptor; RT ϭ radiation therapy.Platinum-based chemotherapy is the first-line therapy for non-small-cell lung cancer (NSCLC) and improves both survival and disease-related symptomatology. 1 However, chemotherapyinduced peripheral neuropathy is common and decreases quality of life (QOL) and may limit chemotherapy doses.2 Cisplatin promotes the formation of free radicals, while paclitaxel blocks axonal transport within peripheral nerves. As many as 38% of patients with NSCLC treated with these drugs develop a disabling sensory neuropathy. 3,4 Retinoids play a critical role in a variety of biological functions, particularly in epithelial and neural differentiation.5 Different types of retinoids possess variable selectivity to retinoidFrom the Laboratorio de Oncología Experimental (Ó ....

Tomato pomace powder ameliorated cisplatin-induced microanatomical alterations in brain of Wistar rats

“…Our findings that cisplatin-induced neurotoxicity was associated with histological alteration agreed with the reports of the reports of Al Moundhri et al (2013) and Arrieta et al (2011) who similarly reported this observation. This supported our findings of cisplatin's alteration of the histology of the densely packed layers of granule neurons of the dentate gyrus of the hippocampal formation and the pyramidal neurons of the CA3 zone of the hippocampus proper when compared with the neurons of the control rats.…”

Chemotherapy-Induced Peripheral Neuropathy

“…274,275 Furthermore, since embryonic neurons are dependent on NGF for survival, it is difficult to interpret the survival findings, since low concentrations of paclitaxel which alter neuronal sensitivity do not commonly cause neuronal death in cultures of DRG neurons derived from adult animals. 157 Other neurotrophic agents which have been investigated and have had positive results in preclinical animals include: prosaptide, 129 xaliproden, 276 retinoic acid, 277 and recombinant human glial growth factor 2 278 , but so far none have demonstrated appreciable efficacy in clinical trials. 279 Neurotrophic factors play an integral role not only in the survival of sensory neurons but also in the maintenance of the neurons, thus helping to establish the setpoints for neuronal sensitivity and growth.…”

Assessment and Treatment of Chemotherapy-induced Peripheral Neuropathy- a Physical Therapy Perspective

“…Acety-L-Carnitine [65], Alpha-lipoic acid [66], Amifostine [67], cholest-4-en-3-one, oxime (TRO19622) [68], Cannabinoid type-1 receptor [69], Gabapentin [70], Glutamine [71], Lamotrigine [72], recombinant human leukemia inhibitory factor (rhuLIF, AM424, emfilermin) [73], Neurosteroids [74], Palmitoylethanolamide [75] and Retinoic acid [76] were studied individually for their efficacy in randomized clinical trials.…”