Hypoxia-selective radiosensitisation by SN38023, a bioreductive prodrug of DNA-dependent protein kinase inhibitor IC87361.

Autor: Wong WW; Auckland Cancer Society Research Centre, University of Auckland, New Zealand., Jackson RK; Auckland Cancer Society Research Centre, University of Auckland, New Zealand., Liew LP; Auckland Cancer Society Research Centre, University of Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand., Dickson BD; Auckland Cancer Society Research Centre, University of Auckland, New Zealand., Cheng GJ; Auckland Cancer Society Research Centre, University of Auckland, New Zealand., Lipert B; Auckland Cancer Society Research Centre, University of Auckland, New Zealand., Gu Y; Auckland Cancer Society Research Centre, University of Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand., Hunter FW; Auckland Cancer Society Research Centre, University of Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand., Wilson WR; Auckland Cancer Society Research Centre, University of Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand. Electronic address: wr.wilson@auckland.ac.nz., Hay MP; Auckland Cancer Society Research Centre, University of Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2019 Nov; Vol. 169, pp. 113641. Date of Electronic Publication: 2019 Sep 18.
DOI: 10.1016/j.bcp.2019.113641
Abstrakt: DNA-dependent protein kinase (DNA-PK) plays a key role in repair of radiation-induced DNA double strand breaks (DSB) by non-homologous end-joining. DNA-PK inhibitors (DNA-PKi) are therefore efficient radiosensitisers, but normal tissue radiosensitisation represents a risk for their use in radiation oncology. Here we describe a novel prodrug, SN38023, that is metabolised to a potent DNA-PKi (IC87361) selectively in radioresistant hypoxic cells. DNA-PK inhibitory potency of SN38023 was 24-fold lower than IC87361 in cell-free assays, consistent with molecular modelling studies suggesting that SN38023 is unable to occupy one of the predicted DNA-PK binding modes of IC87361. One-electron reduction of the prodrug by radiolysis of anoxic formate solutions, and by metabolic reduction in anoxic HCT116/POR cells that overexpress cytochrome P450 oxidoreductase (POR), generated IC87361 efficiently as assessed by LC-MS. SN38023 inhibited radiation-induced Ser2056 autophosphorylation of DNA-PK catalytic subunit and radiosensitised HCT116/POR and UT-SCC-54C cells selectively under anoxia. SN38023 was an effective radiosensitiser in anoxic HCT116 spheroids, demonstrating potential for penetration into hypoxic tumour tissue, but in spheroid co-cultures of high-POR and POR-null cells it showed no evidence of bystander effects resulting from local diffusion of IC87361. Pharmacokinetics of IC87361 and SN38023 at maximum achievable doses in NIH-III mice demonstrated sub-optimal exposure of UT-SCC-54C tumour xenografts and did not provide significant tumour radiosensitisation. In conclusion, SN38023 has potential for exploiting hypoxia for selective delivery of a potent DNA-PKi to the most radioresistant subpopulation of cells in tumours. However, prodrugs providing improved systemic pharmacokinetics and that release DNA-PKi that elicit bystander effects are needed to maximise therapeutic utility.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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