507 Sensitization of hypoxic cells to ionising radiation by a hypoxia activated inhibitor of DNA dependent protein kinase

Lindquist, Kirstin E.; Cran, Jordan; Kordic, K.; Kyle, Alastair H.; Minchinton, A.I.

doi:10.1016/s1359-6349(10)72214-x

Cited by 1 publication

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“…This is in part due to the nature of such research, complicated by tumor reoxygenation that often occurs as a result of spontaneous changes in blood flow and therapy with subsequent impact on DDR pathways [48] . An example of how improved understanding of the DDR machinery provides an opportunity for combination therapy was demonstrated by Lindquist et al [49] who investigated the potential for inhibiting DNA double strand break repair in hypoxic cells by targeting DNA-dependent protein kinase (DNA-PK). BCCA621C, a DNA-PK inhibitor was shown to be able to radiosensitize NCI-H460 cells under hypoxic but not normoxic conditions using a range of clinically relevant ionising radiation doses.…”

Section: Combination Treatment With Hapsmentioning

confidence: 99%

Current challenges and opportunities in treating hypoxic prostate tumors

McKenna¹,

Errington²,

Pors³

2018

JCMT

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Hypoxia is a well-established characteristic of prostate tumors and is now recognised as a major contributory factor to both tumor progression and increased resistance to therapy. One strategy to target hypoxic tumor cells is the development of hypoxia-activated prodrugs (HAPs), which are activated in low oxygen environments. Several HAPs have been developed but despite encouraging results from preclinical studies many of these have performed disappointingly in clinical trials. In the developing era of precision medicine, it is clear that more strategic deployment of these agents is required, based on reliable methods that can identify patients who will benefit from HAP treatment, either alone or in combination with other drugs. This review discusses the primary limitations of using HAPs to treat hypoxic tumors and explains how these challenges can be addressed. In particular, it emphasises the importance of tumor imaging and identification of reliable biomarkers for measuring hypoxia and monitoring cellular response to treatment in individual patients. Developing predictive assays for clinical use will be paramount in demonstrating the patient impact and effectiveness of HAPs for personalised medicine.

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Section: Combination Treatment With Hapsmentioning

confidence: 99%