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Title: ABCB1 and MGMT mediated drug resistance in medulloblastoma
Author: Othman, Ramadhan T.
ISNI:       0000 0004 6349 7667
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2014
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Background: Medulloblastoma (MB) is the most common malignant paediatric brain tumour. Recurrence and progression of disease occurs in a substantial number of patients with current multimodal treatment. Drug resistance is a major obstacle to successful chemotherapy treatment of MB. Chemotherapeutic drugs must remain in the tumour cell long enough to damage DNA and this damage must not be accurately repaired. The expression of multidrug efflux transporter ABCB1 and DNA repair protein 06-methylguanine-DNA-methyltransferase (MGMT) might be involved in chemotherapeutic drug resistance. In this study, I investigated the correlation of ABCB1 expression with clinicopathological features in MB patients. Additionally, I evaluated expression and function of ABCB1 and MGMT as putative drug resistance mechanisms in a panel of MB cell lines. Material and Methods: Immunohistochemistry analysis of patient tissue microarrays was used to assess ABCB1 expression in paediatric MB. Expression of ABCB1 and MGMT was assessed by quantitative reverse transcription polymerase chain reaction, western blotting and flow cytometry in MB cell lines. Clonogenic- assays were used to assess cell survival in response to chemotherapeutics. Wound healing-assay was used to assess MB cell migration in vitro. Results: ABCB1 expression was expressed in 43 % (112/260) of tumours, showed significant association with high-risk (P= 0.035) patients and metastatic disease (P= 0.04). In cell line analysis, inhibition of ABCB1 using vardenafil or verapamil resulted in a significant increase in sensitivity to etoposide (ABCB1 substrate) in ABCB1-expressing MB cell lines (P< 0.0001). In the presence of verapamil or vardenafil. the capacity of MED1 cells (high ABCB1-expressing cell line) to migrate in vitro was significantly inhibited (P< 0.01). Sensitivity to temozolomide (TMZ) was MGMT-dependent, but two novel imidazotetrazine derivatives (N-3 sulfoxide and N-3 propargyl) demonstrated a significantly higher cytotoxicity compared to TMZ that was independent of MGMT and base excision repair. Conclusion: Data from this study indicate that ABCB1 is clinically associated with high-risk MB and MB cell invasion/metastasis. Thus, inhibition of ABCB1 by vardenafil may represent a valid approach in high-risk MB patients. In addition imidazotetrazine analogues of TMZ are promising clinical approaches to overcome resistance to alkylating drugs in MB tumours expressing MGMT.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available