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Review
. 2018 Oct 4:13:6049-6058.
doi: 10.2147/IJN.S140462. eCollection 2018.

Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment

Kaitlin Graham  1 , Evan Unger  1
Affiliations
Review

Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment

Kaitlin Graham et al. Int J Nanomedicine. .

Abstract

Hypoxia exists to some degree in most solid tumors due to inadequate oxygen delivery of the abnormal vasculature which cannot meet the demands of the rapidly proliferating cancer cells. The levels of oxygenation within the same tumor are highly variable from one area to another and can change over time. Tumor hypoxia is an important impediment to effective cancer therapy. In radiotherapy, the primary mechanism is the creation of reactive oxygen species; hypoxic tumors are therefore radiation resistant. A number of chemotherapeutic drugs have been shown to be less effective when exposed to a hypoxic environment which can lead to further disease progression. Hypoxia is also a potent barrier to effective immunotherapy in cancer treatment. Because of the recognition of hypoxia as an important barrier to cancer treatment, a variety of approaches have been undertaken to overcome or reverse tumor hypoxia. Such approaches have included breathing hyperbaric oxygen, artificial hemoglobins, allosteric hemoglobin modifiers, hypoxia activated prodrugs and fluorocarbons (FCs). These approaches have largely failed due to limited efficacy and/or adverse side effects. Oxygen therapeutics, based on liquid FCs, can potentially increase the oxygen-carrying capacity of the blood to reverse tumor hypoxia. Currently, at least two drugs are in clinical trials to reverse tumor hypoxia; one of these is designed to improve permeability of oxygen into the tumor tissue and the other is based upon a low boiling point FC that transports higher amounts of oxygen per gram than previously tested FCs.

Keywords: dodecafluoropentane emulsion; fluorocarbon; oxygen therapeutics; solid tumor.

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Conflict of interest statement

Disclosure Ms Kaitlin Graham is an employee of NuvOx Pharma and owns stock in the company. Dr Evan Unger is President and CEO of NuvOx Pharma, serves on the Board of Directors, and owns stock in the company. Dr Unger is also a patent holder of the NuvOx Pharma technology. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Hypoxic tumor regions lie further from feeding vessels.
Figure 2
Figure 2
Tumor pO2 measurements from published clinical studies documenting the hypoxic state of various solid tumors. Note: Data from Vaupel et al. Abbreviation: pO2, pressure of oxygen.
Figure 3
Figure 3
Hypoxyprobe™-1IHC staining in human ovarian tissue sections. The A–C, and D–E, respectively represent three separate tissue sections from two ovarian tumors; Percent positive staining for Hypoxyprobe™-1 is indicated. All pictures are 20× magnification. Note: IHC staining performed by the Tissue Acquisition and Cellular/Molecular Analysis Shared Resource (TACMASS); the core at the University of Arizona Cancer Center and analysis done by Dr Amanda Baker. Abbreviation: IHC, immunohistochemistry.
Figure 4
Figure 4
DDFPe carries more oxygen than PFOBe or PFDe. Note: Reproduced with permission from Taylor & Francis Ltd, In vitro comparison of dodecafluoropentane (DDFP), perfluorodecalin (PFD), and perfluoroctylbromide (PFOB) in the facilitation of oxygen exchange. Artif Cells Blood Substit Immobil Biotechnol. Copyright © 2009 Taylor & Francis Ltd. Abbreviations: DDFPe, dodecafluoropentane emulsion; PFOBe, perfluorooctylbromide; PFDe, perfluorodecalin emulsion.
See this image and copyright information in PMC

References

    1. Vaupel P, Mayer A, Höckel M. Tumor hypoxia and malignant progression. Methods Enzymol. 2004;381:335–354. - PubMed
    1. Less JR, Posner MC, Skalak TC, Wolmark N, Jain RK. Geometric resistance and microvascular network architecture of human colorectal carcinoma. Microcirculation. 1997;4(1):25–33. - PubMed
    1. Siemann DW. The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by Tumor-Vascular Disrupting Agents. Cancer Treat Rev. 2011;37(1):63–74. - PMC - PubMed
    1. Vaupel P, Höckel M, Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal. 2007;9(8):1221–1235. - PubMed
    1. Zhu W, Dong Z, Fu T, et al. Modulation of Hypoxia in Solid Tumor Microenvironment with MnO2 Nanoparticles to Enhance Photodynamic Therapy. Adv Funct Mater. 2016;26(30):5490–5498.