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Oxidation therapy: the use of a reactive oxygen species-generating enzyme system for tumour treatment
1Department of Radiology, University of Michigan, Ann Arbor 48109-0553.
Abstract:
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.
Insights
This study introduces oxidation therapy using polyethylene glycol-stabilised glucose oxidase (PEG-GO) to generate reactive oxygen species (ROS) for solid tumor treatment. Intratumoral PEG-GO significantly delayed tumor growth in rats, showing promise for cancer therapy.
Area of Science:
- Biochemistry
- Oncology
- Biotechnology
Background:
- Reactive oxygen species (ROS) induce cytotoxicity through DNA damage, lipid peroxidation, and protein oxidation.
- Harnessing ROS's cytotoxic potential offers a novel strategy for solid tumor treatment.
Purpose of the Study:
- To explore the efficacy of polyethylene glycol (PEG)-stabilised glucose oxidase (GO) as an intratumoral agent for generating ROS to treat solid tumors.
- To evaluate the therapeutic effect and systemic toxicity of PEG-GO in a rat glioma model.
Main Methods:
- PEG-GO was administered via intratumoral injections in a rat 9L glioma model.
- Tumor growth delay was assessed and compared to controls receiving heat-denatured PEG-GO.
- Systemic toxicity was managed with PEG-superoxide dismutase (PEG-SOD) and PEG-catalase.
- In vivo tumor metabolic changes were monitored using 31P magnetic resonance spectroscopy (31P-MRS).
- In vitro sensitization of glioma cells to hydrogen peroxide using buthionine sulphoximine (BSO) was investigated.
Main Results:
- Intratumoral PEG-GO administration resulted in a significant delay in tumor growth compared to controls.
- Metabolic monitoring revealed a substantial reduction in the ATP/Pi ratio and intracellular pH in tumors.
- Rats were protected from systemic toxicity by PEG-SOD and PEG-catalase administration.
- In vitro studies showed a 3-fold sensitization of glioma cells to hydrogen peroxide with BSO preincubation.
Conclusions:
- Intratumoral PEG-GO demonstrates significant efficacy in delaying solid tumor growth, suggesting potential as an oxidation therapy.
- The PEG-stabilised enzyme system offers a method to harness ROS for cancer treatment while managing systemic toxicity.
- Further exploration of this ROS-generating enzyme system for solid tumor treatment is warranted.