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You searched for subject:(Hypoxia Activated Prodrugs). Showing records 1 – 3 of 3 total matches.

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University of Oxford

1. Collins, Sarah. Hypoxia-activated small molecule-induced gene expression.

Degree: PhD, 2018, University of Oxford

Hypoxia, conditions of insufficient oxygen, can occur in a wide variety of biological environments, including solid tumours, bacterial biofilms, and plants. Hypoxic tumours are associated with aggressive tumour phenotypes, increased resistance to radio- and chemotherapy, and poor patient prognosis. In biofilms, low oxygen delivery to cells causes significant reduction in bacterial growth rates, which increases resistance to antibiotics. Plants most commonly become hypoxic through flooding, which negatively impacts crop yields. Consequently, tools to study hypoxia are crucial. Hypoxia-activated prodrugs offer the ability to deliver compounds selectively to regions of hypoxia, through attachment of bioreductive groups, (e.g. 4 nitrobenzyl moiety). Oxygen-dependent nitroreductase enzymes catalyse reduction of the nitro group to form a radical nitro anion, which is re-oxidised back to the nitro group in the presence of oxygen. Under hypoxic conditions, this futile REDOX cycling cannot occur. The nitro anion radical is further reduced to form a hydroxylamine or amine; subsequent fragmentation releases the drug. This work combines the concept of hypoxia-activated prodrugs with an IPTG-inducible gene expression system in BL21 (DE3) E. coli bacteria. We hypothesised that protecting IPTG 76 with a bioreductive group would inhibit IPTG-induced expression. Only under hypoxic conditions will reduction of the bioreductive group, release of IPTG 76 and induction of gene expression occur. First, a hypoxia-activated resorufin-based fluorophore was employed to determine whether hypoxia-dependent bioreduction of a nitroaryl group would take place in bacteria using the BL21 (DE3) strain of E. coli. Then a range of derivatives of IPTG, protected with a bioreductive group were synthesised and analysed for their ability to undergo reduction and fragmentation to release IPTG 76. Using, sfGFP as a reporter gene, these were then tested for their ability to induce hypoxia-dependent gene expression in BL21 (DE3) E. coli. Through fluorescence and western blot analysis, compound 94 was shown to induce expression of sfGFP in a hypoxia-dependent manner. This work represents a proof-of-concept system for hypoxia- activated small molecule-induced gene expression.

Subjects/Keywords: Hypoxia-Activated Prodrugs

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APA (6th Edition):

Collins, S. (2018). Hypoxia-activated small molecule-induced gene expression. (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:cfcb4e32-b7b3-42d6-b728-4b3d18208c4c ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.780501

Chicago Manual of Style (16th Edition):

Collins, Sarah. “Hypoxia-activated small molecule-induced gene expression.” 2018. Doctoral Dissertation, University of Oxford. Accessed November 30, 2020. http://ora.ox.ac.uk/objects/uuid:cfcb4e32-b7b3-42d6-b728-4b3d18208c4c ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.780501.

MLA Handbook (7th Edition):

Collins, Sarah. “Hypoxia-activated small molecule-induced gene expression.” 2018. Web. 30 Nov 2020.

Vancouver:

Collins S. Hypoxia-activated small molecule-induced gene expression. [Internet] [Doctoral dissertation]. University of Oxford; 2018. [cited 2020 Nov 30]. Available from: http://ora.ox.ac.uk/objects/uuid:cfcb4e32-b7b3-42d6-b728-4b3d18208c4c ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.780501.

Council of Science Editors:

Collins S. Hypoxia-activated small molecule-induced gene expression. [Doctoral Dissertation]. University of Oxford; 2018. Available from: http://ora.ox.ac.uk/objects/uuid:cfcb4e32-b7b3-42d6-b728-4b3d18208c4c ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.780501


University of Toronto

2. SAGGAR, KAUR JASDEEP. Activity of Anticancer Drugs in Relation to the Tumour Microenvironment and Potential to Inhibit Repopulation and Enhance Therapeutic Outcome.

Degree: PhD, 2014, University of Toronto

Tumours have a disorganized and convoluted vasculature. Tumour cells that reside close to patent blood vessels are nourished by oxygen and other nutrients and are rapidly proliferating while distally located cells slowly proliferating. Anticancer drugs must be delivered in adequate (toxic) concentrations to all tumour cells to be effective, and it is therefore important to study their distribution of activity in tumours. In order to assess the distribution of anticancer agents in tumours using immuno-histochemistry (IHC) and fluorescence imaging, drugs must be either inherently fluorescent or have antibodies that recognize their activity. As the vast majority of anticancer drugs fulfill neither of these criteria, the first objective of this thesis was to develop techniques to assess the pharmacodynamic activity of anticancer drugs in relation to distance from vasculature and hypoxic regions using biomarkers that could be recognized by antibodies using IHC. I found that GH2AX , a biomarker of DNA damage was activated in as little as 10 minutes following treatment. In addition, changes in biomarkers of apoptosis (cleaved caspase -3 or -6) and cell proliferation (Ki-67) could be used to determine drug activity at 24 hours following drug treatment. The second objective of this thesis addressed the ability of a novel hypoxia activated pro-drug, TH-302, used alone or with chemotherapy (doxorubicin or docetaxel) to modify the distribution of biomarkers in relation to blood vessels and regions of hypoxia. It was found that TH-302 increased DNA damage and apoptosis not only in hypoxic regions but also in vascularized areas and this effect was augmented through the addition of chemotherapy. TH-302 increased growth delay due to chemotherapy of human tumour xenografts, consistent with complementary effects of the drugs in different regions of the tumour microenvironment.The third objective of this thesis was to study changes in the tumour microenvironment after chemotherapy. I injected into tumour-bearing mice two markers of hypoxia, EF5 and pimonidazole, with a variable interval between injections. I studied the effects of chemotherapy alone on repopulation of hypoxic tumour cells and the ability of TH-302 to inhibit repopulation. It was found that (i) reoxygenation of previously hypoxic cells and repopulation of the tumour from them occurs after chemotherapy, and (ii) TH-302 was able to reduce tumour cell reoxygenation and repopulation. This supports the potential of TH-302 to increase therapeutic effects of chemotherapy. The work presented in this thesis highlights the importance of the tumour microenvironment and its ability to impact the distribution of anticancer drugs to cells. Advisors/Committee Members: Tannock, F Ian, Medical Biophysics.

Subjects/Keywords: Anticancer Drugs; Drug Distribution; Hypoxia; Hypoxia-activated prodrugs; Repopulation; Tumour Microenvironment; 0992

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

APA (6th Edition):

SAGGAR, K. J. (2014). Activity of Anticancer Drugs in Relation to the Tumour Microenvironment and Potential to Inhibit Repopulation and Enhance Therapeutic Outcome. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/68586

Chicago Manual of Style (16th Edition):

SAGGAR, KAUR JASDEEP. “Activity of Anticancer Drugs in Relation to the Tumour Microenvironment and Potential to Inhibit Repopulation and Enhance Therapeutic Outcome.” 2014. Doctoral Dissertation, University of Toronto. Accessed November 30, 2020. http://hdl.handle.net/1807/68586.

MLA Handbook (7th Edition):

SAGGAR, KAUR JASDEEP. “Activity of Anticancer Drugs in Relation to the Tumour Microenvironment and Potential to Inhibit Repopulation and Enhance Therapeutic Outcome.” 2014. Web. 30 Nov 2020.

Vancouver:

SAGGAR KJ. Activity of Anticancer Drugs in Relation to the Tumour Microenvironment and Potential to Inhibit Repopulation and Enhance Therapeutic Outcome. [Internet] [Doctoral dissertation]. University of Toronto; 2014. [cited 2020 Nov 30]. Available from: http://hdl.handle.net/1807/68586.

Council of Science Editors:

SAGGAR KJ. Activity of Anticancer Drugs in Relation to the Tumour Microenvironment and Potential to Inhibit Repopulation and Enhance Therapeutic Outcome. [Doctoral Dissertation]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/68586


University of Debrecen

3. Sulieman, Bashir. Synthesis and Characterization of Co(III) Complexes as Potential Hypoxia-activated Prodrugs .

Degree: DE – Természettudományi és Technológiai Kar – Kémiai Intézet, University of Debrecen

Co(III) complexes are known as inert (characterized by slow ligand exchange) but after reduction, the Co(II) state that is formed is labile (fast ligand exchange). Hypoxia as a common feature of cancer tissues means lack of adequate oxygen level, therefore a more reductive environment. When administered, rationally designed Co(III) complexes may be reduced selectively in these tissues and therefore may serve as carrier of drug molecules that are capable of killing cancer cells because the reduction and the release of the drug is more pronounced in the cancer cells. The type of drug molecules can be hydroxamic acids with proven anticancer activity. Advisors/Committee Members: Buglyó, Péter (advisor).

Subjects/Keywords: Synthesis; Characterization of Co(III); Potential Hypoxia-activated Prodrugs

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

APA (6th Edition):

Sulieman, B. (n.d.). Synthesis and Characterization of Co(III) Complexes as Potential Hypoxia-activated Prodrugs . (Thesis). University of Debrecen. Retrieved from http://hdl.handle.net/2437/220228

Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Sulieman, Bashir. “Synthesis and Characterization of Co(III) Complexes as Potential Hypoxia-activated Prodrugs .” Thesis, University of Debrecen. Accessed November 30, 2020. http://hdl.handle.net/2437/220228.

Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Sulieman, Bashir. “Synthesis and Characterization of Co(III) Complexes as Potential Hypoxia-activated Prodrugs .” Web. 30 Nov 2020.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Vancouver:

Sulieman B. Synthesis and Characterization of Co(III) Complexes as Potential Hypoxia-activated Prodrugs . [Internet] [Thesis]. University of Debrecen; [cited 2020 Nov 30]. Available from: http://hdl.handle.net/2437/220228.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.

Council of Science Editors:

Sulieman B. Synthesis and Characterization of Co(III) Complexes as Potential Hypoxia-activated Prodrugs . [Thesis]. University of Debrecen; Available from: http://hdl.handle.net/2437/220228

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.

.