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Title: Investigating the anti-tumour effect of zoledronic acid in Multiple Myeloma in vivo
Author: Gurubalan, Jayadevan
ISNI:       0000 0004 5350 3912
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2014
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Multiple myeloma remains an incurable disease due to the failure of currently available chemotherapies to eradicate all the tumour cells from bone. Tumour cells alter the processes of bone resorption and bone formation to promote the development of osteolytic bone disease. Targeting osteoclastic bone resorption with bisphosphonates, including zoledronic acid has been shown to be effective in preventing tumour-induced bone disease. In addition to preventing bone disease, there is increasing evidence to suggest that altering the bone microenvironment by inhibiting osteoclastic bone resorption reduces tumour burden in bone. However, the mechanisms responsible are not clear. In order to develop effective therapeutic strategies, it is essential to understand the interactions between tumour cells and the bone microenvironment during disease progression from single tumour cells that home to the bone to the development of overt tumour colonies. In order to characterise the interactions between tumour cells and the bone microenvironment, an in vivo murine model of myeloma was utilised by injecting 5TGM1 murine myeloma cells expressing eGFP and labelled with DID into C57BL/KaLwRij mice. Data presented in this thesis show myeloma cells engrafted in the bone as early as 3 days and formed colonies after 10 days post tumour cell injection. Tumour-induced alterations in bone remodelling occurred only at the end-stage of the disease when the mice showed signs of clinical illness. However, development of osteolytic lesions occurred as early as 10 days post tumour cell injection prior to an increase in osteoclast numbers and serum TRACP5b levels or a decrease in osteoblast numbers and serum P1NP levels. Furthermore, this is the first study to identify a subpopulation of quiescent myeloma cells in proximity to bone which suggests the existence of specific niches, which may render cells dormant. However, this warrants further investigation. Treatment studies showed that early initiation of zoledronic acid treatment (125 μg/kg, subcutaneously, twice-weekly) prior to tumour cell injection is effective not only at inhibiting the development of osteolytic lesions but also at inhibiting the late stage tumour burden in bone. Interestingly, ZA treatment started prior or after tumour cell injection did not affect the early stages of myeloma colony formation suggesting that the process of expansion from single cells to colonies is not reliant on a so called 'vicious cycle' in the 5TGM1 murine model of myeloma. In a separate experiment, zoledronic acid treatment started prior or at the time of tumour cell injection demonstrated a significant increase in disease-free survival when compared with untreated controls (24 vs. 21 days). Taken together, the data presented in this thesis demonstrate that zoledronic acid treatment, in the 5TGM1 murine model of myeloma started prior to tumour cell arrival in bone is not only able to prevent the development of bone disease but also reduce tumour burden and increase disease-free survival.
Supervisor: Croucher, Peter ; Eaton, Colby ; Lawson, Michelle Anne Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available