Chapter Sixteen - Chemotherapy-Induced Peripheral Neuropathy

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Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is common in patients receiving anticancer treatment and can affect survivability and long-term quality of life of the patient following treatment. The symptoms of CIPN primarily include abnormal sensory discrimination of touch, vibration, thermal information, and pain. There is currently a paucity of pharmacological agents to prevent or treat CIPN. The lack of efficacious therapeutics is due, at least in part, to an incomplete understanding of the mechanisms by which chemotherapies alter the sensitivity of sensory neurons. Although the clinical presentation of CIPN can be similar with the various classes of chemotherapeutic agents, there are subtle differences, suggesting that each class of drugs might induce neuropathy via different mechanisms. Multiple mechanisms have been proposed to underlie the development and maintenance of neuropathy; however, most pharmacological agents generated from preclinical experiments have failed to alleviate the symptoms of CIPN in the clinic. Further research is necessary to identify the specific mechanisms by which each class of chemotherapeutics induces neuropathy.

Section snippets

Chemotherapy-Induced Neuropathy: An Introduction

With considerable advances in the development of anticancer agents over the past 20–30 years, patients diagnosed with cancer are surviving and living longer following treatment.1 With this increase in survival, researchers and patients are now shifting their focus toward a primary side effect of anticancer treatment, chemotherapy-induced peripheral neuropathy (CIPN). Peripheral neuropathy is an adverse effect following treatment with multiple classes of chemotherapeutics, including platinum

Microtubule-targeting agents

Alterations in microtubule dynamics are a common mechanism of blocking mitosis within dividing cells, which lead to subsequent apoptosis in cancer cells,31 and MTAs have been developed and used extensively as anticancer drugs.32 There are two main classes of MTAs, which are compounds that bind directly to the tubulin subunits to alter the dynamic rearrangement of microtubules. Compounds that bind free β-tubulin subunits and prevent polymerization into microtubules are called depolymerizing or

Clinical Assessment of CIPN

A limitation to the interpretation of some clinical studies is the subjective nature by which the presence and intensity of neuropathy is determined by the clinicians and patients. There is much debate regarding the proper endpoints to use to determine the severity of neuropathy in patients and the intensity of neuropathy is often difficult to gage. Several grading scales have been developed by the World Health Organization, Eastern Cooperative Oncology Group, and the National Cancer Institute

Experimental Studies: Animal Models of CIPN

Experimental animal models have been developed to examine the mechanisms of CIPN following exposure to paclitaxel, vincristine, epothilones, cisplatin, oxaliplatin, bortezomib, or thalidomide. Although these animal models have evolved over time to closely mimic the behavioral and neurophysical symptoms observed in patients receiving chemotherapy, the initial animal studies were performed using high doses of the chemotherapeutic drugs. These high doses of drugs caused sensory neuron death, overt

Experimental Studies: In Vitro Models of CIPN

To accurately delineate the intracellular signaling mechanisms by which chemotherapeutics alter the sensitivity of sensory neurons, investigators have broadened their research to include in vitro models of CIPN. Cultures of sensory neurons provide a tightly controlled system which allows relatively easy manipulation of protein expression and function via genetic and pharmacological tools. The limitation of neuronal cultures is that the neurons have been removed from their native environment and

Proposed Mechanisms Underlying CIPN

There have been multiple theories on the mechanisms by which each of the chemotherapeutics alters neuronal function. In this section, the use of pharmacological interventions that have been used for other types of neuropathic pain will be discussed. In addition, various putative mechanisms will be discussed in the context of the clinical and experimental evidence supporting or refuting that mechanism. It is appreciated that many of these proposed mechanisms may overlap, and thus, it is probable

Challenges to CIPN Research

There has been very little success in translating preclinical findings to efficacious therapies for patients suffering with CIPN. One caveat that has been largely unaddressed in CIPN research is the possibility that the presence of cancer may predispose patients to neuropathy or induce novel interactions with anticancer drugs to “prime” patients to develop a more robust neuropathy than that which is observed in preclinical models. The presence of cancer alone has been shown to induce central

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