The unidirectional hypoxia‐activated prodrug OCT1002 inhibits growth and vascular development in castrate‐resistant prostate tumors

Nesbitt, Heather; Worthington, Jenny; Errington, Rachel J.; Patterson, Laurence H.; Smith, Paul J.; McKeown, Stephanie; McKenna, Declan

doi:10.1002/pros.23434

Cited by 9 publications

(5 citation statements)

References 44 publications

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“…OCT1002 has shown significant anti-cancer activity in prostate cancer models in which hypoxia has been confirmed, 118,123 demonstrating growth inhibition and suppression of metastasis. This aligns with earlier in vivo studies with AQ4N that have shown anti-angiogenic 124,125 and anti-metastatic activities.…”

Section: Oct1002mentioning

confidence: 99%

TargetingDNAtopoisomeraseIIα(TOP2A) in the hypoxic tumour microenvironment using unidirectional hypoxia‐activated prodrugs (uHAPs)

2022

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The hypoxic tumour microenvironment (hTME), arising from inadequate and chaotic vascularity, can present a major obstacle for the treatment of solid tumours. Hypoxic tumour cells compromise responses to treatment since they can generate resistance to radiotherapy, chemotherapy and immunotherapy.The hTME impairs the delivery of a range of anti-cancer drugs, creates routes for metastasis and exerts selection pressures for aggressive phenotypes; these changes potentially occur within an immunosuppressed environment. Therapeutic strategies aimed at the hTME include targeting the molecular changes associated with hypoxia. An alternative approach is to exploit the prevailing lack of oxygen as a principle for the selective activation of prodrugs to target cellular components within the hTME. This review focuses on the design concepts and rationale for the use of unidirectional Hypoxia-Activated Prodrugs (uHAPs) to target the hTME as exemplified by the uHAPs AQ4N and OCT1002. These agents undergo irreversible reduction in a hypoxic environment to active forms that target DNA topoisomerase IIα (TOP2A). This nuclear enzyme is essential for cell division and is a recognised chemotherapeutic target. An activated uHAP interacts with the enzyme-DNA complex to induce DNA damage, cell cycle arrest and tumour cell death. uHAPs are designed to overcome the shortcomings of conventional HAPs and offer unique pharmacodynamic properties for effective targeting of TOP2A in the hTME. uHAP therapy in combination with standard of care treatments has the potential to enhance outcomes by coaddressing the therapeutic challenge presented by the hTME.

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Section: Oct1002mentioning

confidence: 99%

TargetingDNAtopoisomeraseIIα(TOP2A) in the hypoxic tumour microenvironment using unidirectional hypoxia‐activated prodrugs (uHAPs)

2022

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“…OCT1002, a deuterated analog of AQ4N, was not only able to inhibit LNCaP, 22Rv1, and PC3 tumor growth and revascularization but could also enhance the antitumor synergistic effects with other chemotherapeutic agents. 56,57 Synergistic liposomes containing both hypoxia-activated AQ4N and photosensitizer chlorin e6 have been introduced in hypoxic tumor therapy, in which hypoxia induced by photosensitizer chlorin e6 in PDT was used to subsequently trigger AQ4N activation. 58 Shen et al investigated AQ4N and gossypol combination chemotherapy in HA@AQ4N-Cu(II)-gossypol NPs and demonstrated that AQ4N could function as self-carrier material and auto-fluorescence indicator.…”

Section: N-oxidesmentioning

confidence: 99%

Hypoxia-activated prodrugs and redox-responsive nanocarriers

Ma¹,

Zhan²,

Xu³

et al. 2018

IJN

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Hypoxia is one of the marked features of malignant tumors, which is associated with several adaptation changes in the microenvironment of tumor cells. Therefore, targeting tumor hypoxia is a research hotspot for cancer therapy. In this review, we summarize the developing chemotherapeutic drugs for targeting hypoxia, including quinones, nitroaromatic/nitroimidazole, N-oxides, and transition metal complexes. In addition, redox-responsive bonds, such as nitroimidazole groups, azogroups, and disulfide bonds, are frequently used in drug delivery systems for targeting the redox environment of tumors. Both hypoxia-activated prodrugs and redox-responsive drug delivery nanocarriers have significant effects on targeting tumor hypoxia for cancer therapy. Hypoxia-activated prodrugs are commonly used in clinical trials with favorable prospects, while redox-responsive nanocarriers are currently at the experimental stage.

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“…Mitoxantrone (MTX; Novantrone®), (1,4‐dihydroxy‐5,8‐bis[[2‐[(2‐hydroxyethyl)amino]ethyl]amino]‐9,10‐anthracenedione) is a anthracenedione—structurally related to the classical anthracyclines. MTX has also provided an impetus for the generation of derivatives including prodrug forms for a more selective targeting of tumor cell populations . Its behavior in the chromatin environment is an exemplar of multi‐level action .…”

Section: One Man's Probe Is Another Man's Poisonmentioning

confidence: 99%

Nuclear cytometry and chromatin organization

2018

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The nuclear-targeting chemical probe, for the detection and quantification of DNA within cells, has been a mainstay of cytometry-from the colorimetric Feulgen stain to smart fluorescent agents with tuned functionality. The level of nuclear structure and function at which the probe aims to readout, or indeed at which a DNA-targeted drug acts, is shadowed by a wide range of detection modalities and analytical methods. These methods are invariably limited in terms of the resolution attainable versus the volume occupied by targeted chromatin structures. The scalar challenge arises from the need to understand the extent and different levels of compaction of genomic DNA and how such structures can be re-modeled, reported, or even perturbed by both probes and drugs. Nuclear cytometry can report on the complex levels of chromatin order, disorder, disassembly, and even active disruption by probes and drugs. Nuclear probes can report defining features of clinical and therapeutic interest as in NETosis and other cell death processes. New cytometric approaches continue to bridge the scalar challenges of analyzing chromatin organization. Advances in super-resolution microscopy address the resolution and depth of analysis issues in cellular systems. Typical of recent insights into chromatin organization enabled by exploiting a DNA interacting probe is ChromEM tomography (ChromEMT). ChromEMT uses the unique properties of the anthraquinone-based cytometric dye DRAQ5™ to reveal that local and global 3D chromatin structures effect differences in compaction. The focus of this review is nuclear and chromatin cytometry, with linked reference to DNA targeting probes and drugs as exemplified by the anthracenediones.

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The unidirectional hypoxia‐activated prodrug OCT1002 inhibits growth and vascular development in castrate‐resistant prostate tumors

Abstract: These studies provide the first evidence that OCT1002 can be an effective agent in treating hypoxic, castrate-resistant prostate tumors, either singly or in combination with established chemotherapeutics for prostate cancer.

Cited by 9 publications

References 44 publications

TargetingDNAtopoisomeraseIIα(TOP2A) in the hypoxic tumour microenvironment using unidirectional hypoxia‐activated prodrugs (uHAPs)

TargetingDNAtopoisomeraseIIα(TOP2A) in the hypoxic tumour microenvironment using unidirectional hypoxia‐activated prodrugs (uHAPs)

Hypoxia-activated prodrugs and redox-responsive nanocarriers

Nuclear cytometry and chromatin organization

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