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

Jamieson SM, Liu J, Hsu T, Baguley BC, McKeage MJ - Br. J. Cancer (2003)

Bottom Line: 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).In conclusion, paclitaxel induces nucleolar enlargement in dorsal root ganglion neurons after pharmacologically relevant doses in vivo and reduces oxaliplatin nucleolar damage and neurotoxicity.

View Article: PubMed Central - PubMed

Affiliation: 1Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Private Bag 92019, Auckland, New Zealand.

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.

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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.
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fig3: 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.

Mentions: To determine the functional significance of these nucleolar changes, nerve conduction velocity was measured in rats at various times after treatment with single doses of paclitaxel or oxaliplatin. A single dose of paclitaxel of 10 mg kg−1 had no effect on sensory nerve conduction velocity (Figure 3AFigure 3


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

Jamieson SM, Liu J, Hsu T, Baguley BC, McKeage MJ - Br. J. Cancer (2003)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2741119&req=5

fig3: 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.
Mentions: To determine the functional significance of these nucleolar changes, nerve conduction velocity was measured in rats at various times after treatment with single doses of paclitaxel or oxaliplatin. A single dose of paclitaxel of 10 mg kg−1 had no effect on sensory nerve conduction velocity (Figure 3AFigure 3

Bottom Line: 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).In conclusion, paclitaxel induces nucleolar enlargement in dorsal root ganglion neurons after pharmacologically relevant doses in vivo and reduces oxaliplatin nucleolar damage and neurotoxicity.

View Article: PubMed Central - PubMed

Affiliation: 1Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Private Bag 92019, Auckland, New Zealand.

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.

Show MeSH
Related in: MedlinePlus