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4. The role of nitric oxide as a hypoxic cell radiosensitizer

Author

Folkes, Lisa K., O'Neill, Peter, and Vojnovic, Borivoj

Subjects
616.99, Medical sciences, Radiation, Tumours, tumour hypoxia, nitric oxide, radosensitizer, DNA damage
Abstract

Many tumours contain regions of hypoxia which are difficult to treat by conventional radiotherapy. There is much interest in the ability of nitric oxide (•NO) to radiosensitize hypoxic mammalian cells as a possible adjunct to radiotherapy but mechanisms for its action are unclear. It has been proposed that •NO may radiosensitize cells by ‘fixing’ radiation-induced DNA free radicals, and elevated radiation response by •NO in cells has been partly attributed to increased formation of DNA double strand breaks. In the work carried out for this thesis it is shown that reaction of •NO with radiation-induced nucleobase radicals produces some novel products. New pathways for the reactions of radiation-induced hydroxyl radicals with purine radicals are proposed. In addition, the effects of •NO on the yields of radiation-induced single strand breaks in anoxic plasmid DNA, and on anoxic mammalian cell radiosensitivity are investigated. Kinetics of formation and repair of radiation-induced double strand breaks indicate different effects of •NO on radiation-induced clustered and non-clustered DNA damage involving replication-induced DNA breaks. As •NO is an inhibitor of ribonucleotide reductase, some of the radiosensitizing properties of •NO may be due to reduction in the availability of 2-deoxyribonucleotides. Through studying reactions of •NO with tyrosine radicals, essential components of ribonucleotide reductase, this work has enhanced understanding into how •NO may inhibit the enzyme, which may offer new insights into the development of •NO-releasing anti-cancer agents. The potential for delivery of •NO to hypoxic tissue for radiotherapy has also been investigated in this work, through the development of bioreductively-activated pro-drugs. These novel agents are stable until reduced by one-electron reductants, when a •NO-releasing pro-drug is rapidly evolved, only in those regions which are sufficiently hypoxic. By increasing our understanding into the mechanisms involved in the ability of •NO to radiosensitize hypoxic cells, especially the reactivity of •NO with DNA radicals, knowledge has been gained into the identification, development and repair of radiation-induced DNA damage in cells, including clustered damage, in the presence of •NO. These studies contribute to further development of novel anti-cancer therapies based upon the release of •NO in hypoxic cells.

Published
2013

5. Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial

Author

Lyon, Paul C, Gray, Michael D, Mannaris, Christophoros, Folkes, Lisa K, Stratford, Michael, Campo, Leticia, Chung, Daniel Y F, Scott, Shaun, Anderson, Mark, Goldin, Robert, Carlisle, Robert, Wu, Feng, Middleton, Mark R, Gleeson, Fergus V, and Coussios, Constantin C

Published
2018
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8. Supplementary Methods from Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non–Small Cell Lung Cancer

Author

Skwarski, Michael, primary, McGowan, Daniel R., primary, Belcher, Elizabeth, primary, Di Chiara, Francesco, primary, Stavroulias, Dionisios, primary, McCole, Mark, primary, Derham, Jennifer L., primary, Chu, Kwun-Ye, primary, Teoh, Eugene, primary, Chauhan, Jagat, primary, O’Reilly, Dawn, primary, Harris, Benjamin H.L., primary, Macklin, Philip S., primary, Bull, Joshua A., primary, Green, Marcus, primary, Rodriguez-Berriguete, Gonzalo, primary, Prevo, Remko, primary, Folkes, Lisa K., primary, Campo, Leticia, primary, Ferencz, Petra, primary, Croal, Paula L., primary, Flight, Helen, primary, Qi, Cathy, primary, Holmes, Jane, primary, O’Connor, James P.B., primary, Gleeson, Fergus V., primary, McKenna, W. Gillies, primary, Harris, Adrian L., primary, Bulte, Daniel, primary, Buffa, Francesca M., primary, Macpherson, Ruth E., primary, and Higgins, Geoff S., primary

Published
2023
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9. Supplementary Data from Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non–Small Cell Lung Cancer

Author

Skwarski, Michael, primary, McGowan, Daniel R., primary, Belcher, Elizabeth, primary, Di Chiara, Francesco, primary, Stavroulias, Dionisios, primary, McCole, Mark, primary, Derham, Jennifer L., primary, Chu, Kwun-Ye, primary, Teoh, Eugene, primary, Chauhan, Jagat, primary, O’Reilly, Dawn, primary, Harris, Benjamin H.L., primary, Macklin, Philip S., primary, Bull, Joshua A., primary, Green, Marcus, primary, Rodriguez-Berriguete, Gonzalo, primary, Prevo, Remko, primary, Folkes, Lisa K., primary, Campo, Leticia, primary, Ferencz, Petra, primary, Croal, Paula L., primary, Flight, Helen, primary, Qi, Cathy, primary, Holmes, Jane, primary, O’Connor, James P.B., primary, Gleeson, Fergus V., primary, McKenna, W. Gillies, primary, Harris, Adrian L., primary, Bulte, Daniel, primary, Buffa, Francesca M., primary, Macpherson, Ruth E., primary, and Higgins, Geoff S., primary

Published
2023
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10. Supplementary Data from Targeting IGF Perturbs Global Replication through Ribonucleotide Reductase Dysfunction

Author

Rieunier, Guillaume, primary, Wu, Xiaoning, primary, Harris, Letitia E., primary, Mills, Jack V., primary, Nandakumar, Ashwin, primary, Colling, Laura, primary, Seraia, Elena, primary, Hatch, Stephanie B., primary, Ebner, Daniel V., primary, Folkes, Lisa K., primary, Weyer-Czernilofsky, Ulrike, primary, Bogenrieder, Thomas, primary, Ryan, Anderson J., primary, and Macaulay, Valentine M., primary

Published
2023
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11. Data from Targeting IGF Perturbs Global Replication through Ribonucleotide Reductase Dysfunction

Author

Rieunier, Guillaume, primary, Wu, Xiaoning, primary, Harris, Letitia E., primary, Mills, Jack V., primary, Nandakumar, Ashwin, primary, Colling, Laura, primary, Seraia, Elena, primary, Hatch, Stephanie B., primary, Ebner, Daniel V., primary, Folkes, Lisa K., primary, Weyer-Czernilofsky, Ulrike, primary, Bogenrieder, Thomas, primary, Ryan, Anderson J., primary, and Macaulay, Valentine M., primary

Published
2023
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15. Long‐term treatment of cancer‐prone germline PTEN mutant mice with low‐dose rapamycin extends lifespan and delays tumour development

Author

Tibarewal, Priyanka, primary, Rathbone, Victoria, additional, Constantinou, Georgia, additional, Pearce, Wayne, additional, Adil, Mahreen, additional, Varyova, Zofia, additional, Folkes, Lisa, additional, Hampson, Alix, additional, Classen, Gala Anastasia Electra, additional, Alves, Adriana, additional, Carvalho, Sara, additional, Scudamore, Cheryl L, additional, and Vanhaesebroeck, Bart, additional

Published
2022
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29. Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non–Small Cell Lung Cancer

Author

Skwarski, Michael, primary, McGowan, Daniel R., additional, Belcher, Elizabeth, additional, Di Chiara, Francesco, additional, Stavroulias, Dionisios, additional, McCole, Mark, additional, Derham, Jennifer L., additional, Chu, Kwun-Ye, additional, Teoh, Eugene, additional, Chauhan, Jagat, additional, O’Reilly, Dawn, additional, Harris, Benjamin H.L., additional, Macklin, Philip S., additional, Bull, Joshua A., additional, Green, Marcus, additional, Rodriguez-Berriguete, Gonzalo, additional, Prevo, Remko, additional, Folkes, Lisa K., additional, Campo, Leticia, additional, Ferencz, Petra, additional, Croal, Paula L., additional, Flight, Helen, additional, Qi, Cathy, additional, Holmes, Jane, additional, O’Connor, James P.B., additional, Gleeson, Fergus V., additional, McKenna, W. Gillies, additional, Harris, Adrian L., additional, Bulte, Daniel, additional, Buffa, Francesca M., additional, Macpherson, Ruth E., additional, and Higgins, Geoff S., additional

Published
2021
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31. Targeting IGF Perturbs Global Replication through Ribonucleotide Reductase Dysfunction

Author

Rieunier, Guillaume, primary, Wu, Xiaoning, additional, Harris, Letitia E., additional, Mills, Jack V., additional, Nandakumar, Ashwin, additional, Colling, Laura, additional, Seraia, Elena, additional, Hatch, Stephanie B., additional, Ebner, Daniel V., additional, Folkes, Lisa K., additional, Weyer-Czernilofsky, Ulrike, additional, Bogenrieder, Thomas, additional, Ryan, Anderson J., additional, and Macaulay, Valentine M., additional

Published
2021
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33. IGF targeting perturbs global replication through ribonucleotide reductase dysfunction

Author

Rieunier, Guillaume, primary, Wu, Xiaoning, additional, Harris, Letitia, additional, Mills, Jack, additional, Nandakumar, Ashwin, additional, Colling, Laura, additional, Seraia, Elena, additional, Hatch, Stephanie B., additional, Ebner, Daniel, additional, Folkes, Lisa K., additional, Weyer-Czernilofsky, Ulrike, additional, Bogenrieder, Thomas, additional, Ryan, Anderson J., additional, and Macaulay, Valentine M., additional

Published
2020
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35. An essential role for dNTP homeostasis following CDK-induced\ud replication stress

Author

Pai, Chen-Chen, Hsu, Kuo-Feng, Durley, Samuel C, Keszthelyi, Andrea, Kearsey, Stephen E, Rallis, Charalampos, Folkes, Lisa K, Deegan, Rachel, Wilkins, Sarah E, Pfister, Sophia X, De León, Nagore, Schofield, Christopher J, Bähler, Jürg, Carr, Antony, and Humphrey, Timothy C

Subjects
enzymes and coenzymes (carbohydrates), heterocyclic compounds
Abstract

Replication stress is a common feature of cancer cells, and thus a potentially important therapeutic target. Here, we show that cyclindependent kinase (CDK)-induced replication stress, resulting from Wee1 inactivation, is synthetic lethal with mutations disrupting dNTP homeostasis in fission yeast. Wee1 inactivation leads to increased dNTP demand and replication stress through CDK-induced firing of dormant replication origins. Subsequent dNTP depletion leads to inefficient DNA replication, DNA damage and to genome instability. Cells respond to this replication stress by increasing dNTP supply through histone methyltransferase Set2-dependent MBF-induced expression of Cdc22, the catalytic subunit of ribonucleotide reductase (RNR). Disrupting dNTP synthesis following Wee1 inactivation, through abrogating Set2-dependent H3K36 trimethylation or DNA integrity checkpoint inactivation results in critically low dNTP levels, replication collapse and cell death, which can be rescued by increasing dNTP levels. These findings support a ‘dNTP supply and demand’ model in which maintaining dNTP homeostasis is essential to prevent replication catastrophe in response to CDK-induced replication stress.

Published
2019

36. Factors controlling the substrate specificity of peroxidases: kinetics and thermodynamics of the reactions of horseradish peroxidase compound I with phenols and indole-3-acetic acids

Author

Candeias, Luis P., Folkes, Lisa K., and Wardman, Peter

Subjects
Enzyme kinetics -- Analysis, Peroxidase -- Analysis, Biological sciences, Chemistry
Abstract

The kinetics and thermodynamics of the reaction of horseradish peroxidase compound I with phenols and indole-3-acetic acids were evaluated through the use of stop-flow measurements and pulse radiolysis. Data indicated that the rate of the reaction is determined by the oxizability of the substrates. The enzyme-substrate disassociation constants determine the differing oxidation properties of each substrate.

Published
1997

37. Rates of reaction of indoleacetic acids with horseradish peroxidase compound I and their dependence on the redox potentials

Author

Candeias, Luis P., Folkes, Lisa K., Porssa, Manuchehr, Parrick, John, and Wardman, Peter

Subjects
Enzyme kinetics -- Research, Chemical reaction, Rate of -- Measurement, Peroxidase -- Analysis, Biological sciences, Chemistry
Abstract

The stopped-flow method was used to determine the reaction rates of seven indole-3-acetic acid derivatives (I3AA) with horseradish peroxidase compound I (HPCI) while pulse radiolysis was used to determine the ionization constants and reduction potentials of the I3AA radical cations. The results show that I3AA reaction rates with HPCI are similar to aniline and phenol reaction rates with HPCI, indicating that reaction rates depend on the redox potential of the substrate rather than substrate structure.

Published
1996

41. Recombinant horseradish peroxidase variants for targeted cancer treatment

Author

Bonifert, Günther, Folkes, Lisa, Gmeiner, Christoph, Dachs, Gabi, and Spadiut, Oliver

Subjects
MDA‐MB‐231 breast carcinoma, Indoleacetic Acids, horseradish peroxidase, Cell Survival, T24 bladder carcinoma, food and beverages, Antineoplastic Agents, Recombinant Proteins, indole‐3‐acetic acid, Enzyme Activation, Isoenzymes, Inhibitory Concentration 50, Pichia pastoris, Antibody directed enzyme prodrug therapy (ADEPT), Cell Line, Tumor, Humans, Prodrugs, Original Research, Cancer Biology
Abstract

Cancer is a major cause of death. Common chemo‐ and radiation‐therapies damage healthy tissue and cause painful side effects. The enzyme horseradish peroxidase (HRP) has been shown to activate the plant hormone indole‐3‐acetic acid (IAA) to a powerful anticancer agent in in vitro studies, but gene directed enzyme prodrug therapy (GDEPT) studies showed ambivalent results. Thus, HRP/IAA in antibody directed enzyme prodrug therapy (ADEPT) was investigated as an alternative. However, this approach has not been intensively studied, since the enzyme preparation from plant describes an undefined mixture of isoenzymes with a heterogenic glycosylation pattern incompatible with the human system. Here, we describe the recombinant production of the two HRP isoenzymes C1A and A2A in a Pichia pastoris benchmark strain and a glyco‐engineered strain with a knockout of the α‐1,6‐mannosyltransferase (OCH1) responsible for hypermannosylation. We biochemically characterized the enzyme variants, tested them with IAA and applied them on cancer cells. In the absence of H2O2, HRP C1A turned out to be highly active with IAA, independent of its surface glycosylation. Subsequent in vitro cytotoxicity studies with human T24 bladder carcinoma and MDA‐MB‐231 breast carcinoma cells underlined the applicability of recombinant HRP C1A with reduced surface glycoslyation for targeted cancer treatment. Summarizing, this is the first study describing the successful use of recombinantly produced HRP for targeted cancer treatment. Our findings might pave the way for an increased use of the powerful isoenzyme HRP C1A in cancer research in the future.

Published
2016

42. Results of a phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumours

Author

Roberts, Corran, primary, Strauss, Victoria Y., additional, Kopijasz, Sylwia, additional, Gourley, Charlie, additional, Hall, Marcia, additional, Montes, Ana, additional, Abraham, Jacinta, additional, Clamp, Andrew, additional, Kennedy, Richard, additional, Banerjee, Susana, additional, Folkes, Lisa K., additional, Stratford, Michael, additional, and Nicum, Shibani, additional

Published
2019
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43. Results of first-in-man proof of concept study of ultrasound-triggered drug delivery in liver tumours

Author

Lyon, Paul C., primary, Gray, Michael, additional, Mannaris, Christophoros, additional, Folkes, Lisa, additional, Stratford, Michael, additional, Campo, Leticia, additional, Chung, Daniel, additional, Scott, Shaun, additional, Anderson, Mark, additional, Goldin, Robert, additional, Carlisle, Robert, additional, Wu, Feng, additional, Middleton, Mark, additional, Gleeson, Fergus, additional, and Coussios, Constantin, additional

Published
2019
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44. Focused Ultrasound Hyperthermia for Targeted Drug Release from Thermosensitive Liposomes: Results from a Phase I Trial

Author

Gray, Michael D., primary, Lyon, Paul C., additional, Mannaris, Christophoros, additional, Folkes, Lisa K., additional, Stratford, Michael, additional, Campo, Leticia, additional, Chung, Daniel Y. F., additional, Scott, Shaun, additional, Anderson, Mark, additional, Goldin, Robert, additional, Carlisle, Robert, additional, Wu, Feng, additional, Middleton, Mark R., additional, Gleeson, Fergus V., additional, and Coussios, Constantin C., additional

Published
2019
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50. A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

Author

Woodcock, Victoria K, Clive, Sally, Wilson, Richard H., Coyle, Vicky M, Stratford, Michael R L, Folkes, Lisa K, Eastell, Richard, Barton, Claire, Jones, Paul, Kazmi-Stokes, Shamim, Turner, Helen, Halford, Sarah, Harris, Adrian L, and Middleton, Mark R

Subjects
Adult, Male, Dose-Response Relationship, Drug, Maximum Tolerated Dose, ABL, Administration, Oral, Antineoplastic Agents, Middle Aged, targeted therapy, Phase I, src-Family Kinases, SDG 3 - Good Health and Well-being, Neoplasms, Clinical Study, AZD0424, Humans, Female, Proto-Oncogene Proteins c-abl, Protein Kinase Inhibitors, Src, Aged
Abstract

Background: Src is involved in cancer invasion and metastasis. AZD0424, an oral inhibitor of Src and ABL1, has shown evidence of anti-tumour activity in pre-clinical studies. Methods: A phase Ia, dose escalation study was performed to assess the safety of continuous oral dosing with AZD0424 in advanced solid tumours. Secondary objectives included investigation of AZD0424 pharmacokinetics, effect on Src activity using markers of bone turnover, and anti-tumour activity. Results: 41 patients were treated; 34 received AZD0424 o.d. at doses ranging from 5 mg to 150 mg, and seven received 40 mg b.d. 41.5% of patients experienced at least one AZD0424-related adverse event that was Grade 3-5 in severity, with patients treated at doses above 60 mg/day experiencing multiple treatment-related toxicities. The most commonly observed AZD0424-related adverse events were nausea, fatigue, anorexia and alopecia. Cmax and AUC increased linearly with dose and the mean ± SD t1/2 was 8.4 ± 2.8 hours. Clear evidence of Src target inhibition was seen at doses ≥ 20 mg/day. No responses were observed and seven patients (17.1%) achieved stable disease lasting 6 weeks or more. Conclusion: AZD0424 displayed no evidence of efficacy as monotherapy despite a clear pharmacodynamic effect. Further evaluation of AZD0424 monotherapy in patients with solid tumours is not recommended.

Published
2018
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