UVM Theses and Dissertations
Format:
Print
Author:
Mukherjee, Nabanita
Dept./Program:
Biology
Year:
2013
Degree:
PhD
Abstract:
Chemotherapy is a common treatment for many types of cancer. However, chemotherapy comes with multiple side effects including taste alteration. Clinical studies report in 50-80% of the patients, taste deficits ranging from complete loss (ageusia) or reduced sensitivity (hypogeusia), or distorted taste perception (dysgeusia). Chemotherapy-induced taste alterations have been explained from a psychological view-point by the phenomenon of conditioned taste. aversion (CTA). However, the biological reasons behind chemotherapy-induced taste loss have seldom been accessed.
We tested the above problem using cyclophosphamide (CYP) as the chemotherapy drug. CYP is one of the most commonly prescribed drugs for chemotherapy. We adopted an innovative method of co-relating cellular and behavioral studies using a mouse model. We found a two phase disturbance in taste after a single-IP injection of CYP and the disturbance in taste loss juxtaposed with loss of mature taste cells.
The first phase, lasting between 2-4 days post injection, was due to the detrimental effect of the drug on fungiform taste buds and accessory structures like the von-Ebner gland. The second phase lasted between 8-12 days was due to disturbance in the normal taste cell replacement kinetics. CYP disrupted the normal taste cell renewaI cycle by depleting the proliferative pool of basal cells and causing massive cell death. The fungiform papillae were found to be more sensitive to the effect of the drug than the circumvallate papillae.
The last part of this dissertation sheds light on the possible therapeutic target that' can be used to alleviate the disturbance in taste relating to chemotherapeutics such as CYP. Amifostine (AMF), a cytoprotecting agent, protects non-cancerous cells by scavenging free. radicals produced by drug toxicity. AMF has been previously shown to be effective in preventing radiationinduced mucositis and nephrotoxicy. However, its protective efficacy has never been tested with chemotherapy-induced taste alteration. We found that administering AMF in conjugation with CYP prevent the depletion of the proliferative cells to a significant extent.
This research has yielded new insights into: [1] how chemotherapy disrupts the taste system, [2] a juxtaposed time course of CYP-induced behavioral changes with morphological changes in taste buds, [3] how taste sensory cells and the epithelium supporting taste buds are repopulated after chemical injury, and [4] ways of protecting normal proliferating cells, from the deleterious effects of chemotherapy.
We tested the above problem using cyclophosphamide (CYP) as the chemotherapy drug. CYP is one of the most commonly prescribed drugs for chemotherapy. We adopted an innovative method of co-relating cellular and behavioral studies using a mouse model. We found a two phase disturbance in taste after a single-IP injection of CYP and the disturbance in taste loss juxtaposed with loss of mature taste cells.
The first phase, lasting between 2-4 days post injection, was due to the detrimental effect of the drug on fungiform taste buds and accessory structures like the von-Ebner gland. The second phase lasted between 8-12 days was due to disturbance in the normal taste cell replacement kinetics. CYP disrupted the normal taste cell renewaI cycle by depleting the proliferative pool of basal cells and causing massive cell death. The fungiform papillae were found to be more sensitive to the effect of the drug than the circumvallate papillae.
The last part of this dissertation sheds light on the possible therapeutic target that' can be used to alleviate the disturbance in taste relating to chemotherapeutics such as CYP. Amifostine (AMF), a cytoprotecting agent, protects non-cancerous cells by scavenging free. radicals produced by drug toxicity. AMF has been previously shown to be effective in preventing radiationinduced mucositis and nephrotoxicy. However, its protective efficacy has never been tested with chemotherapy-induced taste alteration. We found that administering AMF in conjugation with CYP prevent the depletion of the proliferative cells to a significant extent.
This research has yielded new insights into: [1] how chemotherapy disrupts the taste system, [2] a juxtaposed time course of CYP-induced behavioral changes with morphological changes in taste buds, [3] how taste sensory cells and the epithelium supporting taste buds are repopulated after chemical injury, and [4] ways of protecting normal proliferating cells, from the deleterious effects of chemotherapy.