The effects of cisplatin treatment on tumourigenic potential of head and neck cancer cells.

Kim Poth (2010). The effects of cisplatin treatment on tumourigenic potential of head and neck cancer cells. PhD Thesis, University of Queensland Diamantina Institute, The University of Queensland.

       
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s33550905_phd_abstract.pdf Abstract from PhD thesis for Kim Poth (33550905) application/pdf 8.90KB 4
s33550905_phd_totalthesis.pdf Final PhD thesis for Kim Poth (33550905) application/pdf 4.85MB 23
Author Kim Poth
Thesis Title The effects of cisplatin treatment on tumourigenic potential of head and neck cancer cells.
School, Centre or Institute University of Queensland Diamantina Institute
Institution The University of Queensland
Publication date 2010-10
Thesis type PhD Thesis
Supervisor Associate Professor Nicholas Saunders
Dr Alexander Guminski
Total pages 264
Total colour pages 48
Total black and white pages 216
Subjects 11 Medical and Health Sciences
Abstract/Summary Head and neck cancer is the sixth most common cancer, with increasing incidence and a 5-year survival rate that has remained at 55% for several decades despite advances in diagnosis and treatment. It comprises up to 40% of diagnosed malignancies in countries such as India and Brazil, and approximately 50% of patients will relapse following initial treatment. Over 90% of head and neck cancers are squamous cell carcinomas (HNSCC), which are treated using a multimodal approach comprising combinations of surgical resection, radiation therapy and chemotherapy. Platinum-based drugs such as cisplatin are the mainstay of chemotherapeutic treatment for HNSCC. Systemic chemotherapies offer the best chance of combating the occurrence of loco-regional and distant metastatic disease, since surgery and radiation can only target local disease. However, despite improvements to dosing and scheduling, drug resistance and loco-regional and distant failure remain common. Furthermore, compliance with therapies such as cisplatin, which has severe dose limiting toxicities, is low in patients with poor performance status. Many HNSCC patients fall into this category, resulting in sub-optimal dosing of cisplatin in many patients. In order to better understand the role of drug resistance and sub-optimal treatment in disease recurrence this thesis has examined the role of cisplatin treatment on tumourigenic potential of surviving HNSCC cells. Use of xenograft models and in vitro assays of cisplatin-induced cytotoxicity demonstrated that significantly lower numbers of cisplatin treated cells were able to initiate tumours compared to untreated cells. Furthermore, this increased tumourigenic potential was a transient phenomenon associated with a distinct phenotype of small cell size and significantly enhanced expression of Interleukin-6 (IL-6), as well as significant differential expression of several other genes. Preliminary data suggests that IL-6 may be causally involved viii in mediating tumourigenesis by cisplatin treated cells. The increased tumourigenic potential mediated by cisplatin was not associated with significant changes in any known cancer stem cell markers. Furthermore, clonal analysis indicated that virtually all cells within the cell lines examined were capable of tumour initiation with varying efficiencies. Studies of cells cultured long-term following treatment indicated persisting effects of a single cisplatin treatment, such as abnormal morphology and growth characteristics, while tumourigenic potential returned to similar levels to the parental (untreated) cell lines, demonstrating that the effects of cisplatin varied with time post-exposure. Taken together, the data in this study demonstrate that cisplatin acts via a complex, stochastic mechanism to induce transient changes in tumourigenic potential in HNSCC cells, likely involving overexpression of IL-6. These results are clinically significant as they underline the need for well-tolerated, targeted systemic therapies for HNSCC and present IL-6 as a promising novel drug target to improve survival of HNSCC patients.
Keyword cisplatin
head and neck squamous cell carcinoma
tumourigenic potential
interleukin-6
Additional Notes 22, 24, 37, 61, 63, 66, 78, 88-95, 98, 101-103, 105, 116, 118-121, 123, 129, 130, 137, 148-150, 155, 157-160, 164, 173, 179, 185, 187, 192, 229, 246, 251, 261, 262

 
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Created: Fri, 15 Oct 2010, 21:02:58 EST by Mrs Kim Poth on behalf of Library - Information Access Service