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 chemotherapy-induced peripheral neuropathy in an experimental animal model and in a randomized, double-blinded, 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 regeneration-related morphologic changes in sciatic nerve, the concentration of nerve growth factor (NGF), and retinoic acid receptor (RAR)-α and RAR-β 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-β 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 ≥2.

Conclusions: ATRA reduced chemotherapy-induced experimental neuropathy, increased NGF levels, and induced RAR-β 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.

Figure 1. Effect of all-trans retinoic acid (ATRA) on nerve growth factor (NGF) contents and retinoic acid receptor (RAR)-β expression in sciatic nerve

(A) Content of NGF in sciatic nerve. ATRA increased NGF content in sciatic nerve of rat treated with chemotherapy. *p < 0.001 when compared with cisplatin, cisplatin/ATRA, and paclitaxel; **p = 0.004 when compared with paclitaxel/ATRA; ***p < 0.0001 when compared with cisplatin; ****p = 0.052 when compared with paclitaxel. (B) Percentage of RAR-β expression in sciatic nerve. (C) Relative quantification of RAR-β expressed by logarithm base 10. RAR-β is not expressed in peripheral nerve control group but ATRA increased its expression in rats treated with chemotherapy. *p = 0.22 when compared with cisplatin; **p < 0.001 when compared with paclitaxel.

Figure 2. Electronic micrographics of sciatic nerve of rats who received chemotherapy with or without all-trans retinoic acid (ATRA) and controls

(A) Myelinated axons with a myelin band according to their axonal diameter (M) in control group; preserved unmyelinated axons (AA) are shown. (B) Cisplatin group without ATRA treatment; degenerated myelinated axons (Dg) with altered myelin band and altered unmyelinated axons (A) were observed. (C) Cisplatin plus ATRA group showed normal appearance, myelinated axons with a myelin band according to their axonal diameter (M), conserved unmyelinated axons (A), and some had a diameter similar to those of small myelinated axons (arrows), probably indicating a remyelinated process, denoted by the thin myelin band (arrowhead). (D) In the paclitaxel-only treated group, degenerated myelinated axons (Dg) with altered myelin band and altered unmyelinated axons (A) are shown. There is endoneural damage denoted by spaces between myelinated axons and unmyelinated axon groups (asterisk). (E) Paclitaxel- and ATRA-treated group showed normal appearance, myelinated axons with a myelin band according to their axonal diameter (M), and conserved unmyelinated axons (A). There is a Schwann cell nucleus (N) surrounded by unmyelinated axon sprouts forming a regeneration band (Br). All electronic micrographics are at 6,860× and the quantifications are per square millimeter. Eight to 10 photographs were taken for each rat.

Figure 3. Consort diagram of clinical setting

ATRA = all-trans retinoic acid; CP = cisplatin and paclitaxel; NGF = nerve growth factor.