What sort of research are you conducting?

Figure 1  Induction of apoptosis by radiation exposure
  Top: Unexposed cancer cells
  Bottom: Cancer cells exposed to X-rays

I am conducting research with the purpose of developing new cancer treatment using radiation. Today, half the population will be affected by cancer and one third will die by cancer. Ionizing radiation has become an invaluable tool for the medical sector in the treatment of cancer. Radiation therapy is widely used along with surgery and chemotherapy as an effective treatment of cancer, but many types of cancer have developed a resistance to radiation or cancer drugs. For example, it is known that if there is a living cancer cell in a location far from blood vessels in an extreme hypoxic state, this cell, when compared with normal cells, is more resistant to the lethal DNA damage from radiation and cancer drugs. It is also known that a high expression of HIF-1α, which gives cells resistance to apoptosis (Figure 1), occurs in hypoxic cells, and many cancer cells show an abnormality in their mitochondria, the subcellular organelle involved with the induction of apoptosis, as well as a high expression of apoptosis resistant factors. Currently, such factors are widely accepted as a major reason for resistant properties of cancer cells against the treatment such as radiation and chemotherapy. At our laboratory, we are working together with the Faculty of Pharmaceutical Sciences, the Graduate School of Medicine, the Graduate School of Information Science and Technology, and with pharmaceutical companies to develop novel drugs that act in a similar way to the oxygen that regulates radiation sensitivity in cancer cells, the drug to inhibit the suppressing factors for apoptosis, and the drug that target mitochondria. We are also investigating the effects of the combined application of these drugs and radiation on cancer cell lines or tumor tissues in mice, rats, and other lab animals.

 

What sort of experiments are you conducting?

Figure 2 X-ray exposure experiment on cell cultures
By placing petri dishes with cell cultures in the hypoxic chamber and ventilating with pure nitrogen gas, it is possible to expose in a hypoxic state.


Figure 3  MRI evaluation of sensitizer effect of doranidazole and radiation on implanted rat glioma cells

First, regarding the combined application of novel radiosensitizing drug and radiation, we initially use various human or rodent cencer cell lines, and utilize cellular biology methods to determine the degree of concentration that will not have toxicity for not only cancer cells but also normal cells by the treatment of the drug alone. We then implant the cancer cells into the mouse or rat tissue, and evaluate the effect of the drug and radiation on the development process of the implanted cancer cells, as well as assess the mechanism from multiple angles with tests on cell cultures and implanted tumors. As an example of a collaborative research with a phamecautical company, I'd like to talk about the effects of a new drug called doranidazole that exhibits behaviors similar to oxygen. The cells of cancer tissue in a hypoxic state becomes 2 to 3 times as resistant to radiation as compared to that in an oxygen-sufficient state, but when this drug is present, they become as suceptible as when in an oxygen-sufficient state. This drug also has virtually no toxicity. This experiment was evaluated by using a special chamber that creates a hypoxic state and irradiates the cancer cells under hypoxia with an X-ray generator, as shown in Figure 2. We discovered that this drug has an effect on a brain tumor model of a rat. Figure 3 shows the magnetic resonance imaging (MRI) results of this drug on a rat's brain implated with a rat glioma cells. You can see from the cross-section image of the brain that after 7 days without treatment, the tumor has grown significantly. Using X-ray exposre or doranidazole has little effect, respectively, but with the combination treatment, the growth is remarkably slowed and the tumor size remains small. These results show that this drug is highly effective against glioma, which has many hypoxic cells. To evaluate the effect of the drug and radiation on the implanted tumor, we used X-ray CT, PET-CT with ¹⁸F−FMISO and ¹⁸F−FDG as hypoxic and metabolic imaging-agents, as well as electron spin resonance (ESR) and other methods to detect the function of oxygen concentration in tissue.
 Until now, we have been observing not only the radiation sensitizer effect of the hypoxic-targeting drug introduced here, but also the effect of drugs that target apoptosis-suppressing proteins and mitochondria energy metabolization, and currently we are researching to understand those mechanisms behind those effects.

 

What's next?

Our next objective in basic research is to understand why drugs that activate mitochondria metabolization increase sensitivity to radiation, and applied research, to develop new radiation sensitizing reagents combined with proton beams that have better dose-distribution than linac X-rays that are widely used in radiation therapy. Through such research, we are hoping to contribute to development of new cancer treatments for not only the veterinary field but the medical field as well