Oxidation therapy: the use of a reactive oxygen species-generating enzyme system for tumour treatment.
Oxygen radicals induce cytotoxicity via a variety of mechanisms, including DNA damage, lipid peroxidation and protein oxidation. Here, we explore the use of a polyethylene glycol (PEG)-stabilised enzyme capable of producing reactive oxygen species (ROS), glucose oxidase (GO), for the purpose of harnessing the cytotoxic potential of ROS for treating solid tumours. PEG-GO (200 U), administered by two intratumoral injections 3 h apart, produced a significant growth delay in subcutaneous rat 9L gliomas as compared with control animals receiving heat-denatured PEG-GO. Rats were protected from systemic toxicity by subsequent i.v. administration of PEG-superoxide dismutase (PEG-SOD) and PEG-catalase. In vivo tumour metabolic changes, monitored using 31P magnetic resonance spectroscopy (31P-MRS) 6 h following initial administration of PEG-GO, revealed a 96 +/- 2% reduction in the ATP/Pi ratio and a 0.72 +/- 0.10 unit decline in intracellular pH. A 3-fold sensitisation of 9L glioma cells in vitro to hydrogen peroxide could be achieved by a 24 h preincubation with buthionine sulphoximine (BSO). This study suggests that oxidation therapy, the use of an intratumoral ROS-generating enzyme system for the treatment of solid tumours, is a promising area which warrants further exploration.
Ben-Yoseph
O
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Department of Radiology, University of Michigan, Ann Arbor 48109-0553.
Ross
B D
BD
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D005949:Glucose Oxidase / Q000008:administration & dosage* / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000633:toxicity; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010710:Phosphates / Q000378:metabolism; D011092:Polyethylene Glycols; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species; D014407:Tumor Cells, Cultured
D010710:Phosphates; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase