Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300 Mitigation of Radiation-Induced Lung Injury

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2017 Oct 4

PMID 28971289

Citations 16

Authors

Jace W Jones

Isabel L Jackson

Zeljko Vujaskovic

Michael D Kaytor

Maureen A Kane

Affiliations

Soon will be listed here.

Abstract

Purpose: Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival.

Methods: High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers.

Results: A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified.

Conclusions: These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.

Citing Articles

The radioprotectant nano-genistein enhances radiotherapy efficacy of lung tumors in mice.

Kaytor M, Serebrenik A, Lapanowski K, McFall D, Jones M, Movsas B Transl Lung Cancer Res. 2023; 12(5):999-1010.

PMID: 37323169 PMC: 10261856. DOI: 10.21037/tlcr-22-856.

A Review of Radiation-Induced Alterations of Multi-Omic Profiles, Radiation Injury Biomarkers, and Countermeasures.

Shakyawar S, Mishra N, Vellichirammal N, Cary L, Helikar T, Powers R Radiat Res. 2022; 199(1):89-111.

PMID: 36368026 PMC: 10279411. DOI: 10.1667/RADE-21-00187.1.

Serum Metabolomic Analysis of Radiation-Induced Lung Injury in Rats.

Feng Y, Gao Y, Tu W, Feng Y, Cao J, Zhang S Dose Response. 2022; 20(1):15593258211067060.

PMID: 35069051 PMC: 8753076. DOI: 10.1177/15593258211067060.

A Trans-Agency Workshop on the Pathophysiology of Radiation-Induced Lung Injury.

Satyamitra M, Cassatt D, Marzella L Radiat Res. 2021; 197(4):408-414.

PMID: 34714907 PMC: 9063325. DOI: 10.1667/RADE-21-00153.1.

Microbiome study in irradiated mice treated with BIO 300, a promising radiation countermeasure.

Cheema A, Li Y, Singh J, Johnson R, Girgis M, Wise S Anim Microbiome. 2021; 3(1):71.

PMID: 34627406 PMC: 8501697. DOI: 10.1186/s42523-021-00132-1.

References

Griese M . Pulmonary surfactant in health and human lung diseases: state of the art. Eur Respir J. 1999; 13(6):1455-76. DOI: 10.1183/09031936.99.13614779. View

. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69(3):89-95. DOI: 10.1067/mcp.2001.113989. View

Agrawal A, Kale R . Radiation induced peroxidative damage: mechanism and significance. Indian J Exp Biol. 2001; 39(4):291-309. View

Kolesnick R, Fuks Z . Radiation and ceramide-induced apoptosis. Oncogene. 2003; 22(37):5897-906. DOI: 10.1038/sj.onc.1206702. View

Houjou T, Yamatani K, Nakanishi H, Imagawa M, Shimizu T, Taguchi R . Rapid and selective identification of molecular species in phosphatidylcholine and sphingomyelin by conditional neutral loss scanning and MS3. Rapid Commun Mass Spectrom. 2004; 18(24):3123-30. DOI: 10.1002/rcm.1737. View

Chen P, Geballe M, Stansfeld P, Johnston A, Yuan H, Jacob A . Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling. Mol Pharmacol. 2005; 67(5):1470-84. DOI: 10.1124/mol.104.008185. View

Tang F, Yue S, Luo Z, Feng D, Wang M, Qian C . Role of N-methyl-D-aspartate receptor in hyperoxia-induced lung injury. Pediatr Pulmonol. 2005; 40(5):437-44. DOI: 10.1002/ppul.20299. View

Fleckenstein K, Zgonjanin L, Chen L, Rabbani Z, Jackson I, Thrasher B . Temporal onset of hypoxia and oxidative stress after pulmonary irradiation. Int J Radiat Oncol Biol Phys. 2007; 68(1):196-204. PMC: 1939695. DOI: 10.1016/j.ijrobp.2006.12.056. View

Orlando G, Wolf G, Engelmann M . Role of neuronal nitric oxide synthase in the regulation of the neuroendocrine stress response in rodents: insights from mutant mice. Amino Acids. 2008; 35(1):17-27. DOI: 10.1007/s00726-007-0630-0. View

10.

Day R, Barshishat-Kupper M, Mog S, McCart E, Prasanna P, Davis T . Genistein protects against biomarkers of delayed lung sequelae in mice surviving high-dose total body irradiation. J Radiat Res. 2008; 49(4):361-72. PMC: 2575019. DOI: 10.1269/jrr.07121. View

11.

Tyburski J, Patterson A, Krausz K, Slavik J, Fornace Jr A, Gonzalez F . Radiation metabolomics. 1. Identification of minimally invasive urine biomarkers for gamma-radiation exposure in mice. Radiat Res. 2008; 170(1):1-14. PMC: 2443732. DOI: 10.1667/RR1265.1. View

12.

Catala A . Lipid peroxidation of membrane phospholipids generates hydroxy-alkenals and oxidized phospholipids active in physiological and/or pathological conditions. Chem Phys Lipids. 2008; 157(1):1-11. DOI: 10.1016/j.chemphyslip.2008.09.004. View

13.

Wu G, Bazer F, Davis T, Kim S, Li P, Rhoads J . Arginine metabolism and nutrition in growth, health and disease. Amino Acids. 2008; 37(1):153-68. PMC: 2677116. DOI: 10.1007/s00726-008-0210-y. View

14.

Wu G . Amino acids: metabolism, functions, and nutrition. Amino Acids. 2009; 37(1):1-17. DOI: 10.1007/s00726-009-0269-0. View

15.

da Cunha A, Pauli V, Saciura V, Pires M, Constantino L, de Souza B . N-methyl-D-aspartate glutamate receptor blockade attenuates lung injury associated with experimental sepsis. Chest. 2009; 137(2):297-302. DOI: 10.1378/chest.09-1570. View

16.

Calveley V, Jelveh S, Langan A, Mahmood J, Yeung I, Van Dyk J . Genistein can mitigate the effect of radiation on rat lung tissue. Radiat Res. 2010; 173(5):602-11. PMC: 3139496. DOI: 10.1667/RR1896.1. View

17.

da Cunha A, Nunes F, Lunardelli A, Pauli V, Amaral R, de Oliveira L . Treatment with N-methyl-D-aspartate receptor antagonist (MK-801) protects against oxidative stress in lipopolysaccharide-induced acute lung injury in the rat. Int Immunopharmacol. 2011; 11(6):706-11. DOI: 10.1016/j.intimp.2011.01.016. View

18.

Lisa M, Cifkova E, Holcapek M . Lipidomic profiling of biological tissues using off-line two-dimensional high-performance liquid chromatography-mass spectrometry. J Chromatogr A. 2011; 1218(31):5146-56. DOI: 10.1016/j.chroma.2011.05.081. View

19.

Finkelstein J . Physiologic and toxicologic responses of alveolar type II cells. Toxicology. 1990; 60(1-2):41-52. DOI: 10.1016/0300-483x(90)90161-9. View

20.

Castro-Perez J, Roddy T, Nibbering N, Shah V, McLaren D, Previs S . Localization of fatty acyl and double bond positions in phosphatidylcholines using a dual stage CID fragmentation coupled with ion mobility mass spectrometry. J Am Soc Mass Spectrom. 2011; 22(9):1552-67. PMC: 3158848. DOI: 10.1007/s13361-011-0172-2. View