Lack of neurotoxicity of the vascular targeting agent ZD6126 following repeated i.v. dosing in the rat

Steve A. Horner, Sarah Gould, James P. Noakes, Niccola J. Rattray, Sandra L. Allen, Elena Zotova, Joseph C. Arezzo

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The vascular targeting agent ZD6126 is a water-soluble prodrug of N-acetylcolchinol that acts by disrupting the cytoskeleton of tumor endothelial cells. It is currently undergoing clinical evaluation in man. As peripheral neuropathy is a major dose-limiting toxicity associated with tubulin binding agents, the neurotoxic potential of ZD6126 was investigated in male and female Wistar rats. ZD6126 was administered i.v. at up to maximum tolerated doses using subacute (0 to 20 mg/kg/d for 5 days) and chronic (0 to 10 mg/kg/d for 5 days, repeated monthly for 6 months) dosing regimens. A separate study examined a combination of ZD6126 (three cycles of ZD6126 given as in the chronic dosing regimen) and paclitaxel (12 mg/kg/wk for 9 weeks) to assess whether coadministration of ZD6126 altered the time course or magnitude of a paclitaxel-induced neuropathy. Neurotoxic potential was examined using a comprehensive series of tests including a functional observation battery, measurements of muscle strength (forelimb and hind limb grip strength), nociception (tail flick test), locomotor activity, neuropathology, and whole nerve electrophysiology. There was no evidence that ZD6126 induced neurotoxicity in the rat following either subacute or chronic i.v. dosing. In a chronic electrophysiology study, ZD6126 produced a slight slowing of the maturational increase of caudal nerve amplitude, with some evidence of reversibility. However, this was not associated with any changes in caudal nerve conduction velocity, motor nerve conduction velocity or amplitude, functional observation battery behavioral and function parameters (including no effects on tail flick latency), and neuropathology. As expected, paclitaxel administration was associated with a significant decrease in caudal nerve conduction velocity (P = 0.0001). Coadministration of ZD6126 did not increase the neurotoxicity of paclitaxel. These studies suggest that ZD6126 should not induce the peripheral neuropathy associated with other antitubulin chemotherapeutic agents and that ZD6126 may not exacerbate the neurotoxicity of other agents with dose-limiting neuropathies.

Original languageEnglish (US)
Pages (from-to)783-791
Number of pages9
JournalMolecular Cancer Therapeutics
Volume3
Issue number7
StatePublished - Jul 2004

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Blood Vessels
Paclitaxel
Neural Conduction
Electrophysiology
Peripheral Nervous System Diseases
Tail
N-acetylcochinol-O-phosphate
Nociception
Maximum Tolerated Dose
Forelimb
Prodrugs
Muscle Strength
Hand Strength
Locomotion
Tubulin
Cytoskeleton
Wistar Rats
Extremities
Endothelial Cells
Observation

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Horner, S. A., Gould, S., Noakes, J. P., Rattray, N. J., Allen, S. L., Zotova, E., & Arezzo, J. C. (2004). Lack of neurotoxicity of the vascular targeting agent ZD6126 following repeated i.v. dosing in the rat. Molecular Cancer Therapeutics, 3(7), 783-791.

Lack of neurotoxicity of the vascular targeting agent ZD6126 following repeated i.v. dosing in the rat. / Horner, Steve A.; Gould, Sarah; Noakes, James P.; Rattray, Niccola J.; Allen, Sandra L.; Zotova, Elena; Arezzo, Joseph C.

In: Molecular Cancer Therapeutics, Vol. 3, No. 7, 07.2004, p. 783-791.

Research output: Contribution to journalArticle

Horner, SA, Gould, S, Noakes, JP, Rattray, NJ, Allen, SL, Zotova, E & Arezzo, JC 2004, 'Lack of neurotoxicity of the vascular targeting agent ZD6126 following repeated i.v. dosing in the rat', Molecular Cancer Therapeutics, vol. 3, no. 7, pp. 783-791.
Horner SA, Gould S, Noakes JP, Rattray NJ, Allen SL, Zotova E et al. Lack of neurotoxicity of the vascular targeting agent ZD6126 following repeated i.v. dosing in the rat. Molecular Cancer Therapeutics. 2004 Jul;3(7):783-791.
Horner, Steve A. ; Gould, Sarah ; Noakes, James P. ; Rattray, Niccola J. ; Allen, Sandra L. ; Zotova, Elena ; Arezzo, Joseph C. / Lack of neurotoxicity of the vascular targeting agent ZD6126 following repeated i.v. dosing in the rat. In: Molecular Cancer Therapeutics. 2004 ; Vol. 3, No. 7. pp. 783-791.
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