Mechanism of taxane neurotoxicity

Abstract

The two taxanes (paclitaxel and docetaxel) are widely employed in standard antineoplastic practice. Although these agents are now well established, some toxic side effects have been reported. Toxicity of these agents includes bone marrow suppression (principally neutropenia), hypersensitivity reactions, cutaneous reactions, edema and neurotoxicity. The most prominent neurotoxicity is a sensory neuropathy. Controlling neuropathy is crucial for maintaining the quality of life of patients because it is usually persistent and hard to manage. The precise mechanism for taxane-induced neuropathy is still unknown. The taxanes are known to promote aggregation of intracellular microtubules. Abnormal aggregation of microtubules in the neuronal cells may cause this neuropathy. In addition, the taxanes have been suggested to have intrinsic toxicity and directly injure the cells. A better understanding of the mechanism for this neuropathy may improve the quality of life of patients who undergo taxane antineoplastic therapy.

Replication of Genetic Polymorphisms Reported to Be Associated with Taxane-Related Sensory Neuropathy in Patients with Early Breast Cancer Treated with Paclitaxel

“…Many different hypotheses have been postulated, including excessive microtubule assembly, which causes abnormal accumulation of disorganized microtubules and disrupts normal cellular activities such as axonal transport and Schwann cell function (7). It is likely that neuropathy secondary to taxanes occurs through a different mechanism, to that of neuropathy secondary to platinum agents and other neurotoxic chemotherapy agents (8).…”

Local Intracerebral Administration of Paclitaxel with the Paclimer® Delivery System: Toxicity Study in a Canine Model

“…Paclitaxel exhibits potent cytotoxic activity against malignant gliomas in vitro, but has failed to prolong survival of brain tumor patients in clinical trials when administered systemically (19)(20)(21). Systemic administration of paclitaxel also induces a dosedependent toxicity that ranges from sensory neuropathy and gastrointestinal disturbances to severe myelosuppression (22)(23)(24)(25). The lack of efficacy observed with systemic paclitaxel in patients with brain tumors could be attributed to the low permeability of the BBB to paclitaxel and the resultant inadequate bioavailability of paclitaxel in the CNS at maximally tolerated systemic doses of the drug (26)(27)(28).…”

Occurrence of myelodysplastic syndrome during paclitaxel- and carboplatin-based chemotherapy for recurrent ovarian cancer: Case report

“…Cytotoxic chemotherapeutic agents shows a marked activity in the treatment of a variety of types of cancers including endometrial and ovarian cancers and improve the overall survival rate of the patients [1,2]. Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder that may be caused by cytotoxic chemotherapy with alkylating agents and topoisomerase inhibitors and/ or radiation therapy [3][4][5].…”