Subsequent studies have shown that paclitaxel administration inhibits the usual regenerative response of axons and Schwann cells to nerve crush injuries in rodent models. These studies demonstrated that paclitaxel induced the formation of unusual aggregates of microtubules in both axons and Schwann cells, resulting in acute demyelination and chronic loss of axoplasmic transport. Įfforts to examine the effects of paclitaxel on neurons in vivo involved direct injection of the drug into rat sciatic nerve. Risk factors that may predispose to developing severe peripheral neurotoxicity include significant prior exposure to known neurotoxic agents, and antecedent medical disorders that are also capable of inducing peripheral neurotoxicity, such as diabetes mellitus. ![]() Overall, it is likely that paclitaxel induces both a sensory axonopathy and ganglioneuropathy, the latter occurring with higher single and cumulative doses, or in combination with cisplatin. Īlthough in vitro studies have shown paclitaxel to affect Schwann cells, it is not clear that only a demyelinating process is involved. In vivo studies have shown that direct injection of paclitaxel into the rat sciatic nerve causes the formation of unusual microtubule aggregates resulting in demyelination and loss of axoplasmic transport. Paclitaxel induced neuropathy is probably due to dysfunctional microtubules in dorsal root ganglia, axons and Schwann cells. Intermediate concentrations of paclitaxel were present in the sciatic nerve and spinal cord, possibly due to paclitaxel transport along the centrifugal and centripetal branches of the dorsal root ganglia neuron axons. Paclitaxel was shown to accumulate in the dorsal root ganglia, as well as access the brain, albeit at very low concentrations. Paclitaxel formulated in Cremophor-ethanol (Taxol®) has been shown to distribute within the central and peripheral nervous system in a rat model. In vitro studies have demonstrated that large abnormal microtubule arrays in spinal cord-sensory ganglion explant cultures are formed following exposure to paclitaxel, resulting in abnormal neurite outgrowth and neuronal death. Given the fact that paclitaxel disrupts microtubule assembly, it is not unexpected that neuronal development and function could be dramatically impaired. Microtubules also provide important structural support for neurons. Microtubule elongation contributes toward the growth of neurites through interactions with the growth cone, and they are the major participating elements mediating axonal transport in the neuron. Microtubules are important for the development and maintenance of neurons. In patients, this is results in the desired effect on the tumor, however, this is not without toxicity to normal tissue. In tissue culture, paclitaxel promotes the formation of abnormal bundles of microtubules within the cytoplasm, leading to the disruption of normal cell function and proliferation. The primary site of pathogenesis of the peripheral neuropathy associated with paclitaxel therapy is not clear. PATHOGENESIS OF PACLITAXEL-MEDIATED NEUROPATHY Peripheral sensory neuropathy is the most commonly reported neurotoxic effect of paclitaxel and it limits treatment with high and cumulative doses of paclitaxel when given alone or in combination with other neurotoxic antineoplastic agents such as cisplatin. As a consequence, neuropathy is one of its toxic side effects. Paclitaxel exerts its antitumor activity by promoting microtubule assembly. Paclitaxel is an antineoplastic agent originally derived from the bark of the western yew tree, Taxus brevifolia, with activity against several tumors including carcinoma of the ovary, breast, lung and the head and neck. Many cytotoxic agents are reported to be neurotoxic, but for only a few drugs such as paclitaxel is peripheral neuropathy an important and often dose-limiting side-effect. Involvement of autonomic nerve fibers with orthostatic hypotension, impotence and incontinence may further reduce the quality of life. Severity may range from loss of sensory function and mild paresthesias to neuropathic pain, severe ataxia and weakness leading to pronounced disability. ![]() Chemotherapeutic agents can cause toxic effects on peripheral nerves.
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