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Article ; Online: Design, Synthesis and Anticancer Evaluation of Nitroimidazole Radiosensitisers.

Liew, Lydia P / Shome, Avik / Wong, Way W / Hong, Cho R / Hicks, Kevin O / Jamieson, Stephen M F / Hay, Michael P

2023 Volume 28, Issue 11

Abstract: The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy ... ...

Abstract	The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy herald new opportunities for classical oxygen-mimetic radiosensitisers. Only nimorazole is used clinically as a radiosensitiser, and there is a dearth of new radiosensitisers in development. In this report, we augment previous work to present new nitroimidazole alkylsulfonamides and we document their cytotoxicity and ability to radiosensitise anoxic tumour cells in vitro. We compare radiosensitisation with etanidazole and earlier nitroimidazole sulfonamide analogues and we identify 2-nitroimidazole and 5-nitroimidazole analogues with marked tumour radiosensitisation in ex vivo assays of surviving clonogens and with in vivo tumour growth inhibition.
MeSH term(s)	Humans ; Cell Hypoxia ; Nitroimidazoles/pharmacology ; Radiation-Sensitizing Agents/pharmacology ; Hypoxia ; Neoplasms/drug therapy ; Neoplasms/radiotherapy
Chemical Substances	Nitroimidazoles ; Radiation-Sensitizing Agents
Language	English
Publishing date	2023-05-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules28114457
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Article ; Online: An Intratumor Pharmacokinetic/Pharmacodynamic Model for the Hypoxia-Activated Prodrug Evofosfamide (TH-302): Monotherapy Activity is Not Dependent on a Bystander Effect.

Hong, Cho Rong / Wilson, William R / Hicks, Kevin O

Neoplasia (New York, N.Y.)

2018 Volume 21, Issue 2, Page(s) 159–171

Abstract: Tumor hypoxia contributes to resistance to anticancer therapies. Hypoxia-activated prodrugs (HAPs) selectively target hypoxic cells and their activity can extend to well-oxygenated areas of tumors via diffusion of active metabolites. This type of ... ...

Abstract	Tumor hypoxia contributes to resistance to anticancer therapies. Hypoxia-activated prodrugs (HAPs) selectively target hypoxic cells and their activity can extend to well-oxygenated areas of tumors via diffusion of active metabolites. This type of bystander effect has been suggested to be responsible for the single agent activity of the clinical-stage HAP evofosfamide (TH-302) but direct evidence is lacking. To dissect the contribution of bystander effects to TH-302 activity, we implemented a Green's function pharmacokinetic (PK) model to simulate the spatial distribution of O
MeSH term(s)	Algorithms ; Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Biological Transport ; Bystander Effect ; Cell Culture Techniques ; Cell Line, Tumor ; Chromatography, Liquid ; Humans ; Hydroxylamine/administration & dosage ; Hydroxylamine/pharmacokinetics ; Hydroxylamine/pharmacology ; Hypoxia/metabolism ; Models, Biological ; Nitroimidazoles/administration & dosage ; Nitroimidazoles/pharmacokinetics ; Nitroimidazoles/pharmacology ; Phosphoramide Mustards/administration & dosage ; Phosphoramide Mustards/pharmacokinetics ; Phosphoramide Mustards/pharmacology ; Prodrugs ; Tandem Mass Spectrometry
Chemical Substances	Antineoplastic Agents ; Nitroimidazoles ; Phosphoramide Mustards ; Prodrugs ; TH 302 ; Hydroxylamine (2FP81O2L9Z)
Language	English
Publishing date	2018-12-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1483840-0
ISSN	1476-5586 ; 1522-8002
ISSN (online)	1476-5586
ISSN	1522-8002
DOI	10.1016/j.neo.2018.11.009
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Article: Tissue Pharmacokinetic Properties and Bystander Potential of Hypoxia-Activated Prodrug CP-506 by Agent-Based Modelling.

Jackson-Patel, Victoria / Liu, Emily / Bull, Matthew R / Ashoorzadeh, Amir / Bogle, Gib / Wolfram, Anna / Hicks, Kevin O / Smaill, Jeff B / Patterson, Adam V

Frontiers in pharmacology

2022 Volume 13, Page(s) 803602

Abstract: Hypoxia-activated prodrugs are bioactivated in oxygen-deficient tumour regions and represent a novel strategy to exploit this pharmacological sanctuary for therapeutic gain. The approach relies on the selective metabolism of the prodrug under ... ...

Abstract	Hypoxia-activated prodrugs are bioactivated in oxygen-deficient tumour regions and represent a novel strategy to exploit this pharmacological sanctuary for therapeutic gain. The approach relies on the selective metabolism of the prodrug under pathological hypoxia to generate active metabolites with the potential to diffuse throughout the tumour microenvironment and potentiate cell killing by means of a "bystander effect". In the present study, we investigate the pharmacological properties of the nitrogen mustard prodrug CP-506 in tumour tissues using
Language	English
Publishing date	2022-02-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2022.803602
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Article: Efficient Protocol for the Identification of Hypoxic Cell Radiosensitisers.

Hong, Cho Rong / Wang, Jingli / Hicks, Kevin O / Hay, Michael P

Advances in experimental medicine and biology

2016 Volume 899, Page(s) 269–290

Abstract: An evolution in radiotherapy practice is leading to greater use of stereotactic body radiotherapy (SBRT), raising the prospect of increased hypoxic cell radioresistance. New clinical interest in nitroimidazole radiosensitisers, combined with appropriate ... ...

Abstract	An evolution in radiotherapy practice is leading to greater use of stereotactic body radiotherapy (SBRT), raising the prospect of increased hypoxic cell radioresistance. New clinical interest in nitroimidazole radiosensitisers, combined with appropriate biomarkers, signals a revival for radiosensitisers in the context of SBRT. Our interest in modifiers of radiation therapy led us to revisit this area and we have identified a new class of nitroimidazole radiosensitiser. We have developed an abbreviated screening protocol suitable for an academic drug discovery laboratory which allows expeditious triage of compounds with poor physicochemical and in vitro properties and combines in vitro radiosensitisation data with tumour pharmacokinetic data to efficiently select candidates for further evaluation.
MeSH term(s)	Animals ; Biological Transport/drug effects ; Biomarkers/metabolism ; Cell Hypoxia/drug effects ; Female ; HCT116 Cells ; Humans ; Mice, Nude ; Neoplasms/pathology ; Radiation-Sensitizing Agents/analysis ; Radiation-Sensitizing Agents/pharmacokinetics ; Radiation-Sensitizing Agents/pharmacology ; Radiosurgery
Chemical Substances	Biomarkers ; Radiation-Sensitizing Agents
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-319-26666-4_16
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Article: Hypoxia-directed drug strategies to target the tumor microenvironment.

Hay, Michael P / Hicks, Kevin O / Wang, Jingli

Advances in experimental medicine and biology

2014 Volume 772, Page(s) 111–145

Abstract: Hypoxia is an important component of the tumor microenvironment and has been the target of drug discovery efforts for almost half a century. These efforts have evolved from offsetting the impact of hypoxia on radiotherapy with oxygen-mimetic ... ...

Abstract	Hypoxia is an important component of the tumor microenvironment and has been the target of drug discovery efforts for almost half a century. These efforts have evolved from offsetting the impact of hypoxia on radiotherapy with oxygen-mimetic radiosensitizers to using hypoxia as a means to selectively target tumors. The more recent description of hypoxia-inducible factors and their role in the hypoxia response network has revealed a host of new drug targets to selectively target tumors. We are developing hypoxia-directed drugs in each of the following areas: novel radiosensitizers for hypofractionated radiotherapy, a second-generation benzotriazine di-N-oxide hypoxia-activated prodrug, and a hypoxia-inducible factor-1-dependent cytotoxin that targets glucose transport. These projects are discussed in the context of hypoxia-directed drug discovery.
MeSH term(s)	Animals ; Antineoplastic Agents/therapeutic use ; Cell Hypoxia/genetics ; DNA Repair/physiology ; Drug Discovery/methods ; Humans ; Hypoxia-Inducible Factor 1/antagonists & inhibitors ; Molecular Targeted Therapy/methods ; Neoplasms/drug therapy ; Radiation-Sensitizing Agents/therapeutic use ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/physiology
Chemical Substances	Antineoplastic Agents ; Hypoxia-Inducible Factor 1 ; Radiation-Sensitizing Agents
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-1-4614-5915-6_6
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Article ; Online: Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue.

Kuiper, Caroline / Vissers, Margreet C M / Hicks, Kevin O

Free radical biology & medicine

2014 Volume 77, Page(s) 340–352

Abstract: Ascorbate is delivered to cells via the vasculature, but its ability to penetrate into tissues remote from blood vessels is unknown. This is particularly relevant to solid tumors, which often contain regions with dysfunctional vasculature, with impaired ... ...

Abstract	Ascorbate is delivered to cells via the vasculature, but its ability to penetrate into tissues remote from blood vessels is unknown. This is particularly relevant to solid tumors, which often contain regions with dysfunctional vasculature, with impaired oxygen and nutrient delivery, resulting in upregulation of the hypoxic response and also the likely depletion of essential plasma-derived biomolecules, such as ascorbate. In this study, we have utilized a well-established multicell-layered, three-dimensional pharmacokinetic model to measure ascorbate diffusion and transport parameters through dense tissue in vitro. Ascorbate was found to penetrate the tissue at a slightly lower rate than mannitol and to travel via the paracellular route. Uptake parameters into the cells were also determined. These data were fitted to the diffusion model, and simulations of ascorbate pharmacokinetics in normal tissue and in hypoxic tumor tissue were performed with varying input concentrations, ranging from normal dietary plasma levels (10-100 μM) to pharmacological levels (>1 mM) as seen with intravenous infusion. The data and simulations demonstrate heterogeneous distribution of ascorbate in tumor tissue at physiological blood levels and provide insight into the range of plasma ascorbate concentrations and exposure times needed to saturate all regions of a tumor. The predictions suggest that supraphysiological plasma ascorbate concentrations (>100 μM) are required to achieve effective delivery of ascorbate to poorly vascularized tumor tissue.
MeSH term(s)	Ascorbic Acid/metabolism ; Biological Transport ; Coenzymes/metabolism ; Diffusion ; HT29 Cells ; Humans ; Kinetics ; Mannitol/metabolism ; Models, Biological ; Tissue Distribution ; Urea/metabolism
Chemical Substances	Coenzymes ; Mannitol (3OWL53L36A) ; Urea (8W8T17847W) ; Ascorbic Acid (PQ6CK8PD0R)
Language	English
Publishing date	2014-12
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2014.09.023
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Zs.A 2109: Show issues

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Article ; Online: Schedule-dependent potentiation of chemotherapy drugs by the hypoxia-activated prodrug SN30000.

Mao, Xinjian / McManaway, Sarah / Jaiswal, Jagdish K / Hong, Cho R / Wilson, William R / Hicks, Kevin O

Cancer biology & therapy

2019 Volume 20, Issue 9, Page(s) 1258–1269

Abstract: Hypoxia-activated prodrugs (HAPs) are hypothesized to improve the therapeutic index of chemotherapy drugs that are ineffective against tumor cells in hypoxic microenvironments. SN30000 (CEN-209) is a benzotriazine di- ...

Abstract	Hypoxia-activated prodrugs (HAPs) are hypothesized to improve the therapeutic index of chemotherapy drugs that are ineffective against tumor cells in hypoxic microenvironments. SN30000 (CEN-209) is a benzotriazine di-
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Cell Hypoxia ; Cell Line, Tumor ; Cyclic N-Oxides/pharmacology ; Disease Models, Animal ; Drug Synergism ; Humans ; Prodrugs/pharmacology ; Triazines/pharmacology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; CEN-209 ; Cyclic N-Oxides ; Prodrugs ; Triazines
Language	English
Publishing date	2019-05-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2146305-0
ISSN	1555-8576 ; 1538-4047
ISSN (online)	1555-8576
ISSN	1538-4047
DOI	10.1080/15384047.2019.1617570
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Zs.A 5887: Show issues

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Article ; Online: Radiosensitisation of SCCVII tumours and normal tissues in mice by the DNA-dependent protein kinase inhibitor AZD7648.

Hong, Cho R / Buckley, Chantal D / Wong, Way W / Anekal, Praju V / Dickson, Benjamin D / Bogle, Gib / Hicks, Kevin O / Hay, Michael P / Wilson, William R

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

2021 Volume 166, Page(s) 162–170

Abstract: Background and purpose: Inhibitors of DNA-dependent protein kinase (DNA-PK) are effective radiation sensitisers in preclinical tumours, but little is known about risks of normal tissue radiosensitisation. Here, we evaluate radiosensitisation of head and ...

Abstract	Background and purpose: Inhibitors of DNA-dependent protein kinase (DNA-PK) are effective radiation sensitisers in preclinical tumours, but little is known about risks of normal tissue radiosensitisation. Here, we evaluate radiosensitisation of head and neck squamous cell carcinoma (HNSCC) cells by DNA-PK inhibitor AZD7648 under oxia and anoxia in vitro, and tumour (SCCVII), oral mucosa and small intestine in mice. Materials and methods: Radiosensitisation of human (UT-SCC-54C) and murine (SCCVII) HNSCC cells by AZD7648 under oxia and anoxia was evaluated by clonogenic assay. Radiosensitisation of SCCVII tumours in C3H mice by oral AZD7648 (75 mg/kg) was determined by ex vivo clonogenic assay 3.5 days post-irradiation, with evaluation of normal tissue surrogate endpoints using 5-ethynyl-2'-deoxyuridine to facilitate detection of regenerating crypts in the ileum and repopulating S-phase cells in the ileum and oral mucosa of the same animals. Results: AZD7648 potently radiosensitised both cell lines, with similar sensitiser enhancement ratios for 10% survival (SER Conclusion: AZD7648 is a potent radiation sensitiser of both oxic and anoxic tumour cells, but also markedly radiosensitises stem cells in the small intestine and oral mucosa.
MeSH term(s)	Animals ; DNA ; DNA-Activated Protein Kinase ; Head and Neck Neoplasms/drug therapy ; Head and Neck Neoplasms/radiotherapy ; Humans ; Hypoxia ; Mice ; Mice, Inbred C3H ; Purines ; Pyrans ; Squamous Cell Carcinoma of Head and Neck/radiotherapy ; Triazoles
Chemical Substances	AZD7648 ; Purines ; Pyrans ; Triazoles ; DNA (9007-49-2) ; DNA-Activated Protein Kinase (EC 2.7.11.1)
Language	English
Publishing date	2021-11-30
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605646-5
ISSN	1879-0887 ; 0167-8140
ISSN (online)	1879-0887
ISSN	0167-8140
DOI	10.1016/j.radonc.2021.11.027
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Zs.A 1926: Show issues

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Article ; Online: Spatially-resolved pharmacokinetic/pharmacodynamic modelling of bystander effects of a nitrochloromethylbenzindoline hypoxia-activated prodrug.

Hong, Cho Rong / Mehta, Sunali Y / Liyanage, H D Sarath / McManaway, Sarah P / Lee, Ho H / Jaiswal, Jagdish K / Bogle, Gib / Tercel, Moana / Pruijn, Frederik B / Wilson, William R / Hicks, Kevin O

Cancer chemotherapy and pharmacology

2021 Volume 88, Issue 4, Page(s) 673–687

Abstract: Purpose: Hypoxia-activated prodrugs (HAPs) have the potential for eliminating chemo- and radiation-resistant hypoxic tumour cells, but their activity is often compromised by limited penetration into hypoxic zones. Nitrochloromethylbenzindoline (nitroCBI) ...

Abstract	Purpose: Hypoxia-activated prodrugs (HAPs) have the potential for eliminating chemo- and radiation-resistant hypoxic tumour cells, but their activity is often compromised by limited penetration into hypoxic zones. Nitrochloromethylbenzindoline (nitroCBI) HAPs are reduced in hypoxic cells to highly cytotoxic DNA minor groove alkylating aminoCBI metabolites. In this study, we investigate whether a lead nitroCBI, SN30548, generates a significant bystander effect through the diffusion of its aminoCBI metabolite and whether this compensates for any diffusion limitations of the prodrug in tumour tissue. Methods: Metabolism and uptake of the nitroCBI in oxic and anoxic cells, and diffusion through multicellular layer cultures, was characterised by LC-MS/MS. To quantify bystander effects, clonogenic cell killing of HCT116 cells was assessed in multicellular spheroid co-cultures comprising cells transfected with cytochrome P450 oxidoreductase (POR) or E. coli nitroreductase NfsA. Spatially-resolved pharmacokinetic/pharmacodynamic (PK/PD) models, parameterised by the above measurements, were developed for spheroids and tumours using agent-based and Green's function modelling, respectively. Results: NitroCBI was reduced to aminoCBI by POR under anoxia and by NfsA under oxia, and was the only significant cytotoxic metabolite in both cases. In spheroid co-cultures comprising 30% NfsA-expressing cells, non-metabolising cells were as sensitive as the NfsA cells, demonstrating a marked bystander effect. Agent-based PK/PD models provided good prediction of cytotoxicity in spheroids, while use of the same parameters in a Green's function model for a tumour microregion demonstrated that local diffusion of aminoCBI overcomes the penetration limitation of the prodrug. Conclusions: The nitroCBI HAP SN30548 generates a highly efficient bystander effect through local diffusion of its active metabolite in tumour tissue.
MeSH term(s)	Bystander Effect/drug effects ; Cell Hypoxia ; Chromatography, Liquid ; Coculture Techniques ; Escherichia coli Proteins/genetics ; HCT116 Cells ; Humans ; Indoles/pharmacokinetics ; Indoles/pharmacology ; Models, Biological ; NADPH-Ferrihemoprotein Reductase/genetics ; Nitroreductases/genetics ; Prodrugs ; Spheroids, Cellular/cytology ; Tandem Mass Spectrometry
Chemical Substances	Escherichia coli Proteins ; Indoles ; Prodrugs ; indoline (6DPT9AB2NK) ; NADPH-Ferrihemoprotein Reductase (EC 1.6.2.4) ; NfsA protein, E coli (EC 1.7.-) ; Nitroreductases (EC 1.7.-)
Language	English
Publishing date	2021-07-10
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-021-04320-3
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Zs.A 1420: Show issues

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Article ; Online: An agent-based model for drug-radiation interactions in the tumour microenvironment: Hypoxia-activated prodrug SN30000 in multicellular tumour spheroids.

Mao, Xinjian / McManaway, Sarah / Jaiswal, Jagdish K / Patel, Priyanka B / Wilson, William R / Hicks, Kevin O / Bogle, Gib

PLoS computational biology

2018 Volume 14, Issue 10, Page(s) e1006469

Abstract: Multicellular tumour spheroids capture many characteristics of human tumour microenvironments, including hypoxia, and represent an experimentally tractable in vitro model for studying interactions between radiotherapy and anticancer drugs. However, ... ...

Abstract	Multicellular tumour spheroids capture many characteristics of human tumour microenvironments, including hypoxia, and represent an experimentally tractable in vitro model for studying interactions between radiotherapy and anticancer drugs. However, interpreting spheroid data is challenging because of limited ability to observe cell fate within spheroids dynamically. To overcome this limitation, we have developed a hybrid continuum/agent-based model (ABM) for HCT116 tumour spheroids, parameterised using experimental models (monolayers and multilayers) in which reaction and diffusion can be measured directly. In the ABM, cell fate is simulated as a function of local oxygen, glucose and drug concentrations, determined by solving diffusion equations and intracellular reactions. The model is lattice-based, with cells occupying discrete locations on a 3D grid embedded within a coarser grid that encompasses the culture medium; separate solvers are employed for each grid. The generated concentration fields account for depletion in the medium and specify concentration-time profiles within the spheroid. Cell growth and survival are determined by intracellular oxygen and glucose concentrations, the latter based on direct measurement of glucose diffusion/reaction (in multilayers) for the first time. The ABM reproduces known features of spheroids including overall growth rate, its oxygen and glucose dependence, peripheral cell proliferation, central hypoxia and necrosis. We extended the ABM to describe in detail the hypoxia-dependent interaction between ionising radiation and a hypoxia-activated prodrug (SN30000), again using experimentally determined parameters; the model accurately simulated clonogenic cell killing in spheroids, while inclusion of reversible cell cycle delay was required to account for the marked spheroid growth delay after combined radiation and SN30000. This ABM of spheroid growth and response exemplifies the utility of integrating computational and experimental tools for investigating radiation/drug interactions, and highlights the critical importance of understanding oxygen, glucose and drug concentration gradients in interpreting activity of therapeutic agents in spheroid models.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Cell Hypoxia/physiology ; Cyclic N-Oxides/pharmacology ; HCT116 Cells ; Humans ; Models, Biological ; Prodrugs/pharmacology ; Radiotherapy ; Triazines/pharmacology ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/radiation effects
Chemical Substances	Antineoplastic Agents ; CEN-209 ; Cyclic N-Oxides ; Prodrugs ; Triazines
Language	English
Publishing date	2018-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1006469
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