Paclitaxel induces nucleolar enlargement in dorsal root ganglion neurons in vivo reducing oxaliplatin toxicity

Abstract

Paclitaxel and oxaliplatin are promising drugs for combination trials but both induce peripheral neurotoxicity. To investigate this toxicity, 10-week-old female Wistar rats were given single intraperitoneal doses of paclitaxel and oxaliplatin, alone or in combination. Neurotoxicity was assessed by L5 dorsal root ganglion morphometry and H-reflex-related sensory nerve conduction velocity. Platinum concentrations in dorsal root ganglia and plasma were measured by inductively coupled plasma mass spectrometry. Dorsal root ganglion nucleolus size was significantly increased following single doses of paclitaxel of 10 and 20 mg kg(-1) at 24 h and 6 days (P<0.02). In contrast, dorsal root ganglion nucleolus size was significantly decreased following single doses of oxaliplatin ranging from 3 to 30 mg kg(-1) at time points ranging from 2 h to 14 days. Sensory nerve conduction velocity was altered after a single dose of oxaliplatin but not after paclitaxel. In combination with oxaliplatin, paclitaxel did not alter the plasma pharmacokinetics or dorsal root ganglion accumulation of oxaliplatin-derived platinum. However, prior paclitaxel inhibited oxaliplatin-induced reductions of dorsal root ganglion nucleolar diameter (P<0.02). Sensory nerve conduction velocity was reduced after oxaliplatin alone (P&<0.05) but unchanged when paclitaxel was given before oxaliplatin. In conclusion, paclitaxel induces nucleolar enlargement in dorsal root ganglion neurons after pharmacologically relevant doses in vivo and reduces oxaliplatin nucleolar damage and neurotoxicity.

Figure 1

Photomicrographs of rat L5 dorsal root ganglia after treatment with paclitaxel (A), oxaliplatin (B) or control (C). Paclitaxel and oxaliplatin were given as single i.p. doses of 10 mg kg⁻¹. Dorsal root ganglia were collected 24 h after treatment. Nucleolus size appeared increased and decreased after treatment with paclitaxel and oxaliplatin, respectively. Magnification, × 630, bar represents 20 μm.

Figure 2

Dorsal root ganglion nucleolus size after treatment with paclitaxel (A) or oxaliplatin (B). Paclitaxel and oxaliplatin were given as a single i.p. dose of 0.3 mg kg⁻¹ (○), 1 mg kg⁻¹ (⧫), 3 mg kg⁻¹ (▾), 10 mg kg⁻¹ (▪), 20 mg kg⁻¹ (▴) or 30 mg kg⁻¹ (•) on day 0. Nucleolus diameter was expressed as the percentage of control. Control values were determined at each time point. Symbols represent average values (n=2–4) and the s.d.

Figure 3

Nerve conduction velocity after treatment with paclitaxel (A) or oxaliplatin (B). Paclitaxel and oxaliplatin were given as single i.p. doses of 10 mg kg⁻¹ (▴) on day 0. Controls were given the corresponding drug vehicle (▪) on day 0. Sensory nerve conduction velocity was measured at various times after treatment. Symbols represent averaged values (n=20–25) and the s.e.m. ^**, P<0.005; ^*, P<0.05.

Figure 4

Dorsal root ganglia nucleolus size after oxaliplatin alone (▪) or oxaliplatin given in combination with paclitaxel (▴). Paclitaxel was given as a single i.p. dose of 20 mg kg⁻¹. Oxaliplatin was given 24 h later as single i.p. doses of 1–30 mg kg⁻¹. Dorsal root ganglia were collected 24 h after oxaliplatin dosing to determine nucleolus size. Symbols represent averaged values (n=2–6) and the s.e.m. ^*, P<0.02.

Figure 5

Dorsal root ganglion nucleolus size (A) and nerve conduction velocity (B) after paclitaxel and oxaliplatin given alone or in combination. Paclitaxel was given as a single i.p. dose of 10 mg kg⁻¹. After 24 h later, oxaliplatin was given as a single i.p. dose of 10 mg kg⁻¹. Drug vehicle was given to controls at corresponding times. Dorsal root ganglia were collected for determining nucleolus size at 24 h after oxaliplatin dosing. Sensory nerve conduction velocity was measured 3 weeks after oxaliplatin dosing. Bars represent the mean and the s.e.m. n=3–4 for nucleolus size, n=23–25 for nerve conduction velocity; ^*, P<0.05; ^**, P<0.01.