Open Access Theses and Dissertations

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You searched for subject:(MRP4 ABCC4). Showing records 1 – 2 of 2 total matches.

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University of New South Wales

1. Huynh, Tony. The Identification and Characterisation of Small Molecule Inhibitors of MRP4 for the Potential Treatment of Childhood Neuroblastoma.

Degree: Women's & Children's Health, 2016, University of New South Wales

URL: http://handle.unsw.edu.au/1959.4/57118  ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:42548/SOURCE02?view=true 

Multidrug resistance is one of the major causes of treatment failure in cancer therapy. While multidrug transporter proteins are known for their contributions to chemotherapy resistance and efflux of anti-cancer drugs from cancer cells, a significant body of evidence points to fundamental roles for these transporters in tumour biology, independent of cytotoxic drug efflux. We have investigated the ABCC subfamily of multidrug transporter genes in the highly malignant childhood solid tumour, neuroblastoma and found that high expression of MRP4 is a powerful independent indicator of clinical outcome. However, the agents used to treat the patients described in these studies are not known substrates of MRP4. Furthermore, biological studies show that siRNA-mediated knockdown of MRP4 results in reduced proliferation of neuroblastoma cells, in the absence of any cytotoxic drug treatment. The aim of the studies described in this thesis is to develop a potential new approach for the treatment of neuroblastoma through the inhibition of MRP4 using small molecule inhibitors.A cell-based screen of a diverse small molecule library had been undertaken, prior to the studies described in this thesis and used to isolate potent inhibitors of MRP4 that were able to sensitise HEK-293 cells overexpressing MRP4 to a cytotoxic MRP4 substrate, 6-mercaptopurine (6-MP). Filtering of compounds based upon their ability to cause 6-MP accumulation, together with focused library screening, resulted in the identification of several classes of compounds able to specifically block the efflux of a wide range of MRP4 substrates. As there were no specific inhibitors against MRP4 available, these new inhibitors offered the opportunity to test pharmacological inhibition of MRP4 as a strategy for neuroblastoma and other cancers expressing MRP4.Characterisation of these putative MRP4 inhibitors indicated that these compounds do not affect neuroblastoma growth or other cancers expressing MRP4 as single agents in vitro. Additionally, using an in vivo model of neuroblastoma, these compounds also failed to reduce tumour burden, although these compounds were well tolerated. As MRP4 is known to confer drug resistance to a number of cytotoxic substrates including 6-MP and irinotecan when highly expressed, attempts to sensitise tumours to these cytotoxic substrates failed in vivo.In addition to the characterisation of highly specific and potent MRP4 inhibitors, the studies described have also characterised another class of molecules identified in the original drug screen, which, unlike the specific MRP4 inhibitors, significantly reduced the growth of neuroblastoma cells in vitro and in vivo and further synergised with established chemotherapeutic agents 6-mercaptopurine and cisplatin. This class of inhibitors has since been determined to have inhibitory activity against Ectonucleoside triphosphate diphosphohydrolase 5 and 6 (ENTPD5 and ENTPD6). The potential importance of these diphosphohydrolases in neuroblastoma warrants further investigation. Advisors/Committee Members: Henderson, Michelle J , Women's & Children's Health, Faculty of Medicine, UNSW.

Subjects/Keywords: ATP-binding cassette transporter protein; neuroblastoma; MRP4/ABCC4

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Huynh, T. (2016). The Identification and Characterisation of Small Molecule Inhibitors of MRP4 for the Potential Treatment of Childhood Neuroblastoma. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/57118 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:42548/SOURCE02?view=true

Chicago Manual of Style (16th Edition):

Huynh, Tony. “The Identification and Characterisation of Small Molecule Inhibitors of MRP4 for the Potential Treatment of Childhood Neuroblastoma.” 2016. Doctoral Dissertation, University of New South Wales. Accessed April 16, 2021. http://handle.unsw.edu.au/1959.4/57118 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:42548/SOURCE02?view=true.

MLA Handbook (7th Edition):

Huynh, Tony. “The Identification and Characterisation of Small Molecule Inhibitors of MRP4 for the Potential Treatment of Childhood Neuroblastoma.” 2016. Web. 16 Apr 2021.

Vancouver:

Huynh T. The Identification and Characterisation of Small Molecule Inhibitors of MRP4 for the Potential Treatment of Childhood Neuroblastoma. [Internet] [Doctoral dissertation]. University of New South Wales; 2016. [cited 2021 Apr 16]. Available from: http://handle.unsw.edu.au/1959.4/57118 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:42548/SOURCE02?view=true.

Council of Science Editors:

Huynh T. The Identification and Characterisation of Small Molecule Inhibitors of MRP4 for the Potential Treatment of Childhood Neuroblastoma. [Doctoral Dissertation]. University of New South Wales; 2016. Available from: http://handle.unsw.edu.au/1959.4/57118 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:42548/SOURCE02?view=true

2. ZHANG JING. Role of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the resistance and toxicity of oxazaphosphorines.

Degree: 2009, National University of Singapore

URL: http://scholarbank.nus.edu.sg/handle/10635/16338 

Subjects/Keywords: cyclophosphamide; ifosfamide; multidrug-associated protein 4(MRP4/ABCC4)

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

JING, Z. (2009). Role of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the resistance and toxicity of oxazaphosphorines. (Thesis). National University of Singapore. Retrieved from http://scholarbank.nus.edu.sg/handle/10635/16338

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

JING, ZHANG. “Role of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the resistance and toxicity of oxazaphosphorines.” 2009. Thesis, National University of Singapore. Accessed April 16, 2021. http://scholarbank.nus.edu.sg/handle/10635/16338.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

JING, ZHANG. “Role of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the resistance and toxicity of oxazaphosphorines.” 2009. Web. 16 Apr 2021.

Vancouver:

JING Z. Role of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the resistance and toxicity of oxazaphosphorines. [Internet] [Thesis]. National University of Singapore; 2009. [cited 2021 Apr 16]. Available from: http://scholarbank.nus.edu.sg/handle/10635/16338.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

JING Z. Role of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the resistance and toxicity of oxazaphosphorines. [Thesis]. National University of Singapore; 2009. Available from: http://scholarbank.nus.edu.sg/handle/10635/16338

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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