Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Microtubule interacting drugs lead to peripheral neuropathy||AdverseOutcome|
Key Event Description
The peripheral nervous system (PNS) connects the central nervous system with peripheral tissues and can be divided into the visceral and the somatic nervous system.The somatic nervous system consists of sensory and motor neurons. While the motor neurons control the contraction of skeletal muscles, the sensory neurons receive information from joints, muscles and skin and send it to the CNS. Motor neuron cell bodies lie in the spinal cord but cell bodies of the sensory neurons are located in the dorsal root ganglia (DRG). In contrast to the central nervous system (CNS), the PNS is not protected by the blood-brain-barrier, the skull or the spinal column and is therefore highly vulnerable to toxicants and mechanical damage.  However, the PNS neurons exhibits a greater ability of regeneration compared to neurons of the CNS. 
Peripheral neuropathies mostly affect sensory neurons in a length-dependent manner and therefore are characterized by a stocking-and-glove distribution of the symptoms. Sensory symptoms occurring upon taxol treatment are for example numbness and paresthesia. [3-6] Reversibility of neuropathy upon discontinuation of treatment is reported. 
How It Is Measured or Detected
- Retrospective study: Patients are interviewed after chemotherapy treatment and symptoms are assessed. [8, 9]
- Abnormal pin perception: Measurement of the distance in centimeters from the tip of the great toe or index finger to a level where normal pin sensation was sensed.
- Abnormalities in vibration and position sensation: Measurement at distal phalanx of the great toe or index finger. [9, 10]
- Reductions in strength of toe extensors, index finger abductors, arm abductors, hip flexors, foot dorsiflexors: Measurement by using the MRC scale and dynamometer [9, 10]
- Nerve conduction studies: Electrophysiological measurement of nerve conduction amplitudes and velocities in sensory neurons [9, 10]
- Quantitative sensory testing of vibratory threshold: Measurement of vibratory latency in seconds between the patient and the examiner in toes and fingers. [9, 10] Automated measurement using e.g. ‘Vibration 2’ (Physitemp Instruments Inc., Clifton NJ) which can be adjusted to different vibration amplitudes and records vibration units. 
- Quantitative sensory testing of thermal threshold: Using the Thermal Sensitivity Tester or NTE-2 (Physitemp Instruments Inc., Clifton NJ), the ability to discriminate small temperature differences at the index finger or the great toe can be quantified. [6, 11, 12]
- Sural nerve biopsy: A part of the sural nerve (some millimetres) is removed, fixed and investigated via light or electron microscopy. 
Domain of Applicability
Regulatory Significance of the Adverse Outcome
1. Benoy V. , d.Y.C., Van Den Bosch L. , Charcot-Marie-Tooth Disease and other peripheral neuropathies, in Young Perspectives for Old Diseases, M.H. G., Editor. 2015, Bentham Science Publishers. p. pp. 269-325.
2. Yiu, G. and Z. He, Glial inhibition of CNS axon regeneration. Nature Reviews Neuroscience, 2006. 7: p. 617.
3. Rowinsky, E.K., et al., Neurotoxicity of Taxol. J Natl Cancer Inst Monogr, 1993(15): p. 107-15.
4. Rowinsky , E.K. and R.C. Donehower Paclitaxel (Taxol). New England Journal of Medicine, 1995. 332(15): p. 1004-1014.
5. Donehower, R.C., et al., Phase I trial of taxol in patients with advanced cancer. Cancer treatment reports, 1987. 71(12): p. 1171-1177.
6. Forsyth, P.a., et al., Prospective study of paclitaxel-induced peripheral neuropathy with quantitative sensory testing. Journal of Neuro-Oncology, 1997. 35(1): p. 47-53.
7. Brown, T., et al., A phase I trial of taxol given by a 6-hour intravenous infusion. Journal of Clinical Oncology, 1991. 9(7): p. 1261-1267.
8. Pignata, S., et al., Residual neurotoxicity in ovarian cancer patients in clinical remission after first-line chemotherapy with carboplatin and paclitaxel: The Multicenter Italian Trial in Ovarian cancer (MITO-4) retrospective study. BMC Cancer, 2006. 6(1): p. 5.
9. Rowinsky, E.K., et al., Sequences of taxol and cisplatin: a phase I and pharmacologic study. Journal of Clinical Oncology, 1991. 9(9): p. 1692-1703.
10. Chaudhry, V., et al., Peripheral neuropathy from taxol and cisplatin combination chemotherapy: Clinical and electrophysiological studies. Annals of Neurology, 1994. 35(3): p. 304-311.
11. Arezzo, J.C., H.H. Schaumburg, and C. Laudadio, Thermal Sensitivity Tester: Device for Quantitative Assessment of Thermal Sense in Diabetic Neuropathy. Diabetes, 1986. 35(5): p. 590-592.
12. Wiernik, P.H., et al., Phase I Clinical and Pharmacokinetic Study of Taxol. Cancer Research, 1987. 47(9): p. 2486-2493.
13. Behse, F., F. Buchthal, and F. Carlsen, Nerve biopsy and conduction studies in diabetic neuropathy. Journal of Neurology, Neurosurgery, and Psychiatry, 1977. 40(11): p. 1072-1082.