Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peripheral neuropathy is a common and dose-limiting side effect of many chemotherapeutic drugs. These include platinum compounds, taxanes, vinca alkaloids, proteasome inhibitors, and others such as thalidomide and suramin. Although many rodent models have been developed using either mice or rats, there is limited consistency in the dose or mode of delivery of the drug; the sex, age, and genetic background of the animal used in the study; and the outcome measures used in evaluation of the peripheral neuropathy. Behavioral assays are commonly used to evaluate evoked sensory responses but are unlikely to be a good representation of the spontaneous sensory paresthesias that the patients experience. Electrophysiologic tests evaluate the integrity of large myelinated populations and are useful in drugs that cause either demyelination or degeneration of large myelinated axons but are insensitive to degeneration of unmyelinated axons in early stages of neuropathy. Histopathologic tools offer an unbiased way to evaluate the degree of axonal degeneration or changes in neuronal cell body but are often time consuming and require processing of the tissue after the study is completed. Nevertheless, use of drug doses and mode of delivery that are relevant to the clinical protocols and use of outcome measures that are both sensitive and objective in evaluation of the length-dependent distal axonal degeneration seen in most chemotherapy-induced peripheral neuropathies may improve the translational utility of these rodent models.
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PMID:Rodent models of chemotherapy-induced peripheral neuropathy. 2461 40

Neurotoxic anticancer drugs, such as platinum-based anticancer drugs, taxanes, vinca alkaloids, and proteasome/angiogenesis inhibitors are responsible for chemotherapy-induced peripheral neuropathy (CIPN). The health consequences of CIPN remain worrying as it is associated with several comorbidities and affects a specific population of patients already impacted by cancer, a strong driver for declines in older adults. The purpose of this review is to present a comprehensive overview of the long-term effects of CIPN in cancer patients and survivors. Pathophysiological mechanisms and risk factors are also presented. Neurotoxic mechanisms leading to CIPNs are not yet fully understood but involve neuronopathy and/or axonopathy, mainly associated with DNA damage, oxidative stress, mitochondria toxicity, and ion channel remodeling in the neurons of the peripheral nervous system. Classical symptoms of CIPNs are peripheral neuropathy with a "stocking and glove" distribution characterized by sensory loss, paresthesia, dysesthesia and numbness, sometimes associated with neuropathic pain in the most serious cases. Several risk factors can promote CIPN as a function of the anticancer drug considered, such as cumulative dose, treatment duration, history of neuropathy, combination of therapies and genetic polymorphisms. CIPNs are frequent in cancer patients with an overall incidence of approximately 38% (possibly up to 90% of patients treated with oxaliplatin). Finally, the long-term reversibility of these CIPNs remain questionable, notably in the case of platinum-based anticancer drugs and taxanes, for which CIPN may last several years after the end of anticancer chemotherapies. These long-term effects are associated with comorbidities such as depression, insomnia, falls and decreases of health-related quality of life in cancer patients and survivors. However, it is noteworthy that these long-term effects remain poorly studied, and only limited data are available such as in the case of bortezomib and thalidomide-induced peripheral neuropathy.
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PMID:Long-Term Effects, Pathophysiological Mechanisms, and Risk Factors of Chemotherapy-Induced Peripheral Neuropathies: A Comprehensive Literature Review. 2828 83