Phase 1 dose escalation study of AQ4N, a selective hypoxic cell cytotoxin, with fractionated radiotherapy (RT): First report

Benghiat, A.; Steward, W.; Loadman, Paul M.; Middleton, Mark R.; Talbot, D C; Patterson, Laurence H.; Ford, Steven; Turner, A

doi:10.1200/jco.2004.22.14_suppl.2091

Cited by 2 publications

(4 citation statements)

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“…(1)) is an aliphatic N-oxide, with two N-oxide groups in one molecule. It is a water soluble compound that is currently being studied in Phase I clinical trials [81]. The N-oxide groups in this compound are bioreductively reduced under hypoxic conditions by enzymes of the cytochrome P450 family to form AQ4 (1,4 -bis [{2 -(dimethylamino) ethyl} amino] 5,8 -dihydroxyanthracene-9-10-dione).…”

Section: N-oxide-based Bioreductive Agentsmentioning

confidence: 99%

Sensor/Effector Drug Design with Potential Relevance to Cancer

Fry¹,

Jacob

2006

CPD

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Many cancer cells exhibit a disturbed intracellular redox balance, making them distinctively different from their 'healthy' counterparts. Some tumors, such as solid lung carcinoma, are hypoxic, and its cells are therefore more reducing than normal, while others, such as the ones of breast and prostate cancer, proliferate under oxidative stress (OS). These biochemical differences between normal and tumor tissue are significant, and can be used to design effective, yet selective redox drugs. The resulting drug design can follow different avenues. The bioreductive approach is perhaps the most advanced, and uses changes in intracellular redox enzyme concentrations to activate otherwise inactive pro-drug molecules inside cancer cells by a reductive step, often followed by further chemical transformations, such as hydrolysis. Related anti-cancer compounds, such as varacin, employ an intricate combination of reduction and oxidation processes to develop their therapeutic potential inside cells. Another, just emerging approach considers the use of pro-oxidants and catalysts, taking advantage of the inherent efficiency and selectivity associated with OS-induced cell death. Even more complex tactics, such as chelator-assisted photodynamic therapy, exploit the intracellular metal homeostasis to target cancer cells. Together, all of these avenues try to endow molecules with a combination of sensor and effector properties, which might allow them to single out and selectively kill cancer cells without the need for cell-selective drug delivery systems. In the long term, such agents could be associated with high efficiency, good selectivity and dramatically reduced drug side effects.

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Section: N-oxide-based Bioreductive Agentsmentioning

confidence: 99%

Sensor/Effector Drug Design with Potential Relevance to Cancer

Fry¹,

Jacob

2006

CPD

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“…These design assets are supported by an extensive literature on the anti‐cancer properties of AQ4N including safety and low toxicity in several clinical studies 100–106 . Multiple preclinical studies have highlighted the potential of AQ4N to enhance significantly both radiotherapy 107–111 and chemotherapy 76,108,112–114 since AQ4N provides the ability to target hypoxic cells which are significantly resistant to these modalities.…”

Section: Prodrug Activation: Haps and Uhapsmentioning

confidence: 97%

“…99 These design assets are supported by an extensive literature on the anti-cancer properties of AQ4N including safety and low toxicity in several clinical studies. [100][101][102][103][104][105][106] Multiple preclinical studies have highlighted the potential of AQ4N to enhance significantly both radiotherapy [107][108][109][110][111] and chemotherapy 76,108,[112][113][114] since AQ4N provides the ability to target hypoxic cells which are significantly resistant to these modalities. In addition, AQ4N has been shown to inhibit both deleterious genetic changes and metastatic spread of prostate tumours in a preclinical model.…”

Section: Aq4nmentioning

confidence: 99%

“…In summary, the key properties of an activated uHAP that targets the hTME are as follows: (i) capacity to be delivered to the hTME, 100 (ii) the selectivity for activation in hTME without significant systemic toxicity, [100][101][102][103][104][105][106] (iii) the prolonged residence of activated prodrug at DNA sites due to high affinity for the target, 135 (iv) the availability of activated drug from sequestered cellular stores, 96 (v) persistent co-location of activated uHAP within poorly vascularised tumour regions, 118 (vi) the targeted long-lived trapping of TOP2A/TOP2B ternary complexes. 138…”

Section: Cell Cycle Topoisomerases and The Htmementioning

confidence: 99%

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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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Phase 1 dose escalation study of AQ4N, a selective hypoxic cell cytotoxin, with fractionated radiotherapy (RT): First report

Cited by 2 publications

References 0 publications

Sensor/Effector Drug Design with Potential Relevance to Cancer

Sensor/Effector Drug Design with Potential Relevance to Cancer

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

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