In my last post on the science behind radiation therapy, I talked about the therapeutic ratio. This is the ratio of probability of killing a tumor versus probability of normal tissue complications. I also talked about some ways to improve the therapeutic ratio such as fractionating the dose or planning the treatment so that the normal tissue dose is lower. One additional way is to protect normal tissue from radiation by using one of a class of chemicals called radioprotectors. A research group at the Vanderbilt-Ingram Cancer Center has found that lithium may function as a radioprotector for normal tissue during radiation therapy of the brain.
As discussed before, radiation can damage DNA by directly interacting with it or by creating free radicals which chemically react with DNA. Although the science behind them is not fully understood, radioprotectors are generally believed to function by “scavenging”, or reacting with and making inert, these free radicals. The most famous radioprotector drugs were created in a US Army program at Walter Reed Hospital starting in 1959. From that program, the most successful drug was amifostine. Amifostine is in widespread use in radiation therapy clinics these days to protect the parotid glands while treating head and neck tumors.
In order for a radioprotector to be useful, it must protect normal tissue more than tumor cells. In the case of amifostine, normal tissue absorbs amifostine faster than tumors do. Also, amifostine must be converted to its active form by cells to work. Tumors perform this conversion more slowly than normal tissue. If the radiation is given quickly enough after administration of the amifostine, then normal tissue cells will be more protected.
According to the research performed by Dr. Fen Xia at Vanderbilt, lithium protects against radiation in a different manner. As I discussed before, the most lethal damage is done to cells when both of the helical strands of DNA are broken. One method of repairing a double strand break is called non-homologous end joining. This is the predominant mechanism of DNA repair in normal neuron cells. Dr. Xia’s group found that lithium allows normal brain tissue cells to apply this mechanism with greater efficiency. However, cancer cells apparently do not use this mechanism of repairing double strand breaks. Therefore, lithium has no effect on DNA repair in tumors. These findings were confirmed in mice treated with cranial irradiation.
If applicable to humans, this research would have a profound effect on the treatment of cancer in the brain. The brain is one of the most difficult organs to treat effectively with radiation, primarily because the dose tolerance of normal brain tissue is too low to give a curative dose to the tumor and also because the tumors tend to be resistant to radiation. For primary brain tumors, using techniques like IMRT or Stereotactic Radiosurgery can help, but for most brain tumors the prognosis is still grim. Lesions that are a result of metastasis from another tumor are often treated by giving dose to the entire brain since the presence of one lesion can signal the existence of others too small to detect with CT or MRI. However, the dose that one can give to the whole brain is too small to completely kill all of these lesions. They will often regrow later, and when the dose tolerance of the whole brain is reached, further treatment becomes extremely difficult.
Being able to protect normal brain tissue from radiation would allow us to give a higher dose to the tumor without increasing the probability of complications. This would possibly allow us to achieve longer survival times for patients with primary brain tumors or metastatic lesions. Hopefully, the results will hold up in humans and clinical trials will start soon.
