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The Effects of Multiple Modalities to Increase Oxygenation of Hypoxic Tumor Cells to

Improve Radiation Therapy Response
Olivia Rozsits
December 7th, 2016

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All life relies on the presence of oxygen to grow, prosper, and reproduce. Oxygen in
cells, however, may increase the formation of free radicals which could lead to the production of
organic peroxide that is damaging to the cells. The purpose of radiation therapy for treatment of
cancer is to damage and kill the malignant cells, while sparing the normal cells as much as
possible. The presence of oxygen increases a cells sensitivity to radiation and may be beneficial
to increasing tumor control response in radiation therapy treatments. The oxygen enhancement
ratio (OER) is the ratio of the biologic response of cells in the absence of oxygen to those in the
presence of oxygen.1 The oxygen effect is greatest for sparsely ionizing radiation such as x-rays
and gamma rays. Oxygen, however, will only increase the cells response to radiation up to a
point when the oxygen tension is between 0 and 20 mmHg. The oxygen must be present within
milliseconds of irradiation for the effects to be successful.1 Many clinicians have begun to
explore this phenomenon for the benefit oxygen may have in increasing the response of tumor
cell kill with radiation therapy treatments. Three different studies are analyzed to determine the
effects of oxygen enhancement in tumor cells for radiation therapy treatments. Each study
evaluated is focused on a different type of cell: breast cells, colon cells, and glioblastoma of the
brain tissue.
Poor tumor oxygenation (hypoxia) can be found in many solid tumor cells and can lead to
tumor resistance to radiation therapy treatments. Almost 40% of locally advanced breast cancers
exhibit tumor regions with oxygen concentrations below what is required for half-maximal
radiosensitization.2 Increasing the dose of radiation may be necessary to overcome the
radioresistant nature of the hypoxic tumor cells. Normal surrounding tissue, however, will thus
become over exposed to radiation and increase side effects and risk of secondary malignancies.

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To avoid this problem, Abassi et al. proposed the use of biocompatible manganese dioxide NPs
(MDNPs) for sustained and localized generation of molecular oxygen in solid tumors to
modulate the tumor microenvironment (TME) and enhance radiation efficacy.2 Tumors were
grown orthotopically by injecting breast tumor cells into the mammary fat pads of 6 to 8 week
old mice.2 Tumor bearing mice were randomized at the same age and divided into four groups:
(i) saline, (ii) saline + radiotherapy, (iii) MDNPs and (iv) MDNPs + radiotherapy.2 Tumor
irradiation was performed using XRAD 225Cx irradiator with photon energy of 225 KVp and to
a dose of 10 Gy.2 Results showed that significant regression up to 87% was observed in the
tumor models treated with MDNPs + radiotherapy at day 5 after treatment compared with the
tumor volume at day zero of the treatment, while radiotherapy alone resulted in tumor growth
delay without regression.2 The results of the study support that MDNP + radiotherapy treatment
of solid breast tumors could allow for equivalent tumor reduction using a lower single dose of
irradiation compared with that of a single high radiotherapy dose alone, thereby reducing the
damage of surrounding healthy tissue while achieving therapeutic benefit.2 While this study
provides sufficient evidence of improved tumor response with MDNPs and radiotherapy, more
research is suggested to provide results from a randomized clinical trial on humans.
The use of nanoparticles has become more prevalent in radiation therapy treatments due
to their ability to cause the absorbed radiation dose to increase. Particularly, gold nanoparticles
(GNPs) increases the production of reactive oxygen species (ROS) when subjected to radiation.3
ROS leads to irreparable DNA damage and eventually cell death, which is desired for tumor
control and treatment3. Gold has a high atomic number which increases the probability of the
photoelectric effect to take place. Due to the photoelectric effect, short-range auger electrons

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emitted from the GNPs boost the tumor area while sparing the adjacent normal tissue.3 In this
study, mouse colon cancer cells were used for all in vitro experiments.3 Randomly selected cells
were treated with GNP for 24 hours followed by 8 Gy of irradiation and compared to cells
treated with only 8 Gy of radiation.3 The results showed a significant increase in cell apoptosis
of those cells treated with GNP and irradiation compared to those cells only treated with
radiation.3 This study provides increasing evidence that the combination of nanoparticles in
treatment with radiation therapy can overcome the radioresistant nature of hypoxic tumor cells,
however more clinical research on humans is necessary prior to clinical use.
Hyperbaric Oxygen therapy (HBO) has been indicated in previous studies to enhance the
antitumor effect of radiation therapy due to increased supply of oxygen to hypoxic tumor cells.
High grade gliomas commonly show an extremely low oxygen tension.4 This study combines
the administration of radiation therapy boosts after HBO therapy with chemotherapy.4 24
patients with newly diagnosed glioblastoma and treated with chemotherapy, radiation therapy
boosts, and HBO therapy were retrospectively evaluated.4 Patients underwent eight HBO
treatments each for 60-90 minutes in a monoplace HBO chamber pressurized with 100% oxygen
to 2.0 atmospheres absolute.4 Within 15 minutes after each HBO session, the patient was
promptly treated with a radiation therapy boost.4 The results lead to minimal severe toxicities
and proved to be a promising modality with longer overall survival rates.4 However, there was
local disease progression in more than half the patients, indicating more research is required to
further evaluate the combination of these treatments for patients with high grade glioblastoma.
Utilizing different modalities, all three articles evaluate the effects of hypoxic tumor cells
in radiation therapy treatments. While each study provides significant evidence to the effects of

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radiosensitizing hypoxic tumor cells, each study requires additional research to further explore
side effects and outcomes of the treatments. The MDNP combined with radiation therapy study
was performed only on mice, therefore additional research would need to be conducted in a
randomized clinical study to better understand the effects and outcomes on humans. The GNP
study, however, was conducted with in vitro studies and provided no way to determine how
much GNP was uptaken by the tumor cells. This study would require more research first on
animals to determine systemic effects on an entire organism. The MDNP study had this benefit
of exploring the overall effect on the entire organism and what side effects were possible, but the
GNP study had no way of evaluating if any acute or late side effects would occur on the
organism as a whole. The HBO study provides more sufficient evidence of the effects on actual
humans suffering from glioblastoma, however, as a retrospective study, many of the variables
could not be controlled. For example, the chemotherapy agents used by patients in the HBO
study differed from patient to patient based on toxicity effects of chemotherapy. The
introduction of multiple variables in the study limits the validity of the results and may suggest
that the results are not based solely on the impact of HBO in the treatment course. Therefore,
further research would need to be conducted with more control variables to limit the variability
between patients receiving treatments. This is not always feasible, however, as the physicians
are required to deliver treatments that are best for the sake of the patient even if it may vary from
the controls of the study. Overall, the information from these studies can be used and applied for
further research on the effects of oxygen enhancement to hypoxic tumor cells.

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References
1. Hackworth R. Oxygen Enhancement Ratio. October 2016.
2. Abbasi AZ, Gordijo CR, Amini MA, et al. Hybrid Manganese Dioxide Nanoparticles
Potentiate Radiation Therapy by Modulating Tumor Hypoxia. Cancer Research.
2016;76(22):6643-6656. doi:10.1158/0008-5472.can-15-3475.
3.

Kim MS, Lee E-J, Kim J-W, et al. Gold nanoparticles enhance anti-tumor effect of
radiotherapy to hypoxic tumor. Radiation Oncology Journal. 2016;34(3):230-238.
doi:10.3857/roj.2016.01788.

4.

Yahara K, Ohguri T, Udono H, et al. Radiotherapy using IMRT boosts after hyperbaric
oxygen therapy with chemotherapy for glioblastoma. Journal of Radiation Research.
2016. doi:10.1093/jrr/rrw105.