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عنوان فارسی مقاله:
طراحی منطقی آنالوگ مقاوم در برابر AKR1C3 از PR-104 برای آنزیم های پیش دارو درمانی
عنوان انگلیسی مقاله:
Rational design of an AKR1C3-resistant analog of PR-104 for enzyme-prodrug therapy
سال انتشار : 2016
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مقدمه انگلیسی مقاله:
1. Introduction
Gene-directed enzyme prodrug therapy (GDEPT) is an approach whereby cancer tropic vectors such as replication-competent viruses or bacteria are employed to deliver therapeutic genes to the tumor microenvironment. The exogenous gene typically introduces a new catalytic function into the tumor microenvironment that can confer conditional sensitivity to otherwise inert prodrugs [1]. The most widely studied nitroaromatic enzyme/prodrug combination for GDEPT is the nitroreductase (NTR) from Escherichia coli, NfsB, in combination with the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide); see review [2] and references therein. Although efficacy was demonstrated with this combination in cell culture models [3,4] and tumor xenografts using replication-defective viruses [5,6], to date this combination has demonstrated limited utility in human clinical trials. Poor aqueous solubility of CB1954 [7], modest kinetics of CB1954 reduction by NfsB [8], and dose-limiting hepatotoxicity in humans [9] are thought to be possible reasons for the lack of efficacy observed. The prodrug PR-104 (Fig. 1A), (2-((2-bromoethyl)(2-((2-hydro xyethyl)carbamoyl)-4,6-dinitrophenyl)amino) ethyl methanesulfonate phosphate ester) represents an alternative nitroaromatic substrate for NTRs. PR-104 is a water-soluble phosphate ester ‘pre-prodrug’ which undergoes facile conversion to the corresponding lipophilic alcohol PR-104A in plasma, and was initially designed and optimized as a hypoxia-activated prodrug (HAP) witha bystander effect (diffusion of active metabolites from the cell of origin [10]). One-electron reduction of the para nitro group on PR-104A (relative to the nitrogen mustard) by human oneelectron reductases such as cytochrome P450 oxidoreductase (POR) and methionine synthase reductase (MTRR) [11,12] creates a nitro radical anion intermediate. The radical anion is backoxidized in the presence of molecular oxygen or, in the absence of oxygen (anoxia), will undergo further electron addition to form the DNA alkylating hydroxylamine (PR-104H) or amine (PR-104M). PR-104H and PR-104M can cause inter-strand DNA crosslinks with disruption of the replication fork upon mitosis, the most likely mechanism of toxicity [13,14]. Hypoxia selectivity was demonstrated in a range of cancer cell lines, with hypoxia cytotoxicity ratios (HCR; aerobic IC50 value divided by anoxic IC50 value) ranging from 5 to 100-fold [10]. However despite clear evidence for hypoxia-selective activation, atypical aerobic sensitivity of some cell lines to PR-104A suggested the presence of an aerobic reductase. The human oxidoreductase AKR1C3 (aldo-keto reductase member 1C3; P42330) was subsequently shown to reduce PR-104A in an oxygen independent (two-electron) manner by bypassing the formation of the oxygen-sensitive nitro radical intermediate, and is now accepted as the major determinant of aerobic PR-104A sensitivity [15].
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کلمات کلیدی:
Pre-clinical activity of PR-104 as monotherapy and in ... - NCBI https://www.ncbi.nlm.nih.gov/pubmed/25869917 by MR Abbattista - 2015 - Cited by 8 - Related articles Apr 14, 2015 - PR-104 is a clinical stage bioreductive prodrug that is converted in vivo to its cognate alcohol, PR-104A. ... High expression of AKR1C3, along with extensive hypoxia, ... relatively resistant, while hypoxic selectivity of PR-104A cytotoxicity ... The results suggest that better-tolerated analogs of PR-104, without ... Pre-clinical activity of PR-104 as monotherapy and in ... - NCBI - NIH https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622463/ by MR Abbattista - 2015 - Cited by 8 - Related articles Apr 14, 2015 - Expression of AKR1C3 in HepG2 and PLC/PRF/5 xenografts was in the ... The results suggest that better-tolerated analogs of PR-104, without a ... resistance, suggestive of potential for synergy between PR-104 and sorafenib. Ackerley, DF; Smaill, Jeffrey; Patterson, Adam - NZResearch.org https://nzresearch.org.nz/records?i%5Bcreator%5D=Ackerley%2C+DF&locale=en Rational design of an AKR1C3-resistant analog of PR-104 for enzyme-prodrug therapy ... The clinical stage anti-cancer agent PR-104 has potential utility as a ... Williams EM[au] - PubMed Result erspublications.com/lookup/external-ref?access_num=Williams%20EM&link_type... ... Guise CP, Ackerley DF, Smaill JB, Patterson AV. Rational design of an AKR1C3-resistant analog of PR-104 for enzyme-prodrug therapy. Biochem Pharmacol. Alexandra M. Mowday - Google Scholar Citations scholar.google.com/citations?user=p1zJCCUAAAAJ&hl=en Research Fellow - auckland.ac.nz Rational design of an AKR1C3-resistant analog of PR-104 for enzyme-prodrug therapy. AM Mowday, A Ashoorzadeh, EM Williams, JN Copp, S Silva, MR Bull, . Bystander Effects of Bioreductive Drugs: Potential for Exploiting ... www.rrjournal.org › Radiation Research › June 2007 by WR Wilson - 2007 - Cited by 45 - Related articles (2016) Rational design of an AKR1C3-resistant analog of PR-104 for enzyme-prodrug therapy. Biochemical Pharmacology 116, 176-187. Online publication ... Engineering a Multifunctional Nitroreductase for Improved Activation of ... www.cell.com/cell-chemical-biology/references/S2451-9456(17)30035-1 Mar 2, 2017 - The bioreductive prodrug PR-104A is activated under aerobic conditions by .... Rational design of an AKR1C3-resistant analog of PR-104 for ...
