Limits...
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.

Show MeSH

Related in: MedlinePlus

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.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2741119&req=5

fig5: 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.

Mentions: The effect of single doses of paclitaxel of 10 mg kg−1 in combination with oxaliplatin was next studied. Paclitaxel (10 mg kg−1) was given 24 h prior to oxaliplatin (10 mg kg−1). Nucleolus size was measured 24 h after oxaliplatin dosing. Sensory nerve conduction velocity was measured 3 weeks after treatment. To account for interoccasion variation in experimental parameters between different batches of animals, data were expressed as percentage of control. Nucleolus size was increased after paclitaxel alone (P<0.05), decreased after oxaliplatin alone (P<0.01) but not significantly altered after giving paclitaxel and oxaliplatin in combination (Figure 5AFigure 5


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: 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.
Mentions: The effect of single doses of paclitaxel of 10 mg kg−1 in combination with oxaliplatin was next studied. Paclitaxel (10 mg kg−1) was given 24 h prior to oxaliplatin (10 mg kg−1). Nucleolus size was measured 24 h after oxaliplatin dosing. Sensory nerve conduction velocity was measured 3 weeks after treatment. To account for interoccasion variation in experimental parameters between different batches of animals, data were expressed as percentage of control. Nucleolus size was increased after paclitaxel alone (P<0.05), decreased after oxaliplatin alone (P<0.01) but not significantly altered after giving paclitaxel and oxaliplatin in combination (Figure 5AFigure 5

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