Microtubule targeting agents (MTAs) are chemotherapeutics commonly
used in the treatment of breast, ovarian, lung, and lymphoma cancers. There are
two main classes of MTAs based upon their effects on microtubule stability. The
two classes are the destabilizing agents, which include the drug vincristine, and
the stabilizing agents, which include paclitaxel and epothilone B. These drugs
are highly effective antineoplastics, but their use is often accompanied by several
side effects, one of which is peripheral neuropathy. Peripheral neuropathy can
be characterized by burning pain, tingling, loss of proprioception, or numbness in
the hands and feet. In some patients, the MTA-induced peripheral neuropathy is
debilitating and dose-limiting; however, there are no effective prevention
strategies or treatment options for peripheral neuropathy as the mechanisms
mediating this side effect are unknown. The goal of this work was to investigate
MTA-induced effects on neuronal activity and morphology in order to elucidate
the underlying mechanisms involved in the development of MTA-induced
peripheral neuropathy.
As an indicator of sensory neuronal activity, the basal and
stimulated release of the putative nociceptive peptide, calcitonin gene-related
peptide (CGRP), was measured from sensory neurons in culture after exposure to the MTAs paclitaxel, epothilone B, and vincristine. Neurite length and
branching were also measured in sensory neuronal cultures after treatment with
these MTAs. The results described in this thesis demonstrate that MTAs alter
the stimulated release of CGRP from sensory neurons in differential ways
depending on the MTA agent employed, the CGRP evoking-stimulus used, the
concentration of the MTA agent, the duration of exposure to the MTA agent, and
the presence of NGF. It was also observed that MTA agents decrease neurite
length and branching, independent of the concentration of NGF in the culture
media. Thus, this thesis describes MTA-induced alterations of sensory neuronal
sensitivity and neurite morphology and begins to elucidate the underlying
mechanisms involved in MTA-induced alterations of sensory neurons. These
findings will undoubtedly be used to help elucidate the mechanisms underlying
MTA-induced peripheral neuropathy.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/6294 |
| Date | 11 1900 |
| Creators | Pittman, Sherry Kathleen |
| Contributors | Fehrenbacher, Jill C., Cummins, Theodore R., Hingtgen, Cynthia M., Hudmon, Andrew, Vasko, Michael R. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Detected Language | English |
| Type | Thesis |
| Rights | CC0 1.0 Universal, http://creativecommons.org/publicdomain/zero/1.0/ |
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