Overview
Chemoprevention of Radiation Induced Rat Mammary Neoplasms
Principal Investigator:
David L. Huso, D.V.M., Ph.D.
Organization:
Johns Hopkins University School of Medicine
Technical Summary
The major long-term risk associated with radiation exposure during space travel is predicted to be radiation-induced cancer. The cancer-causing effects of low-LET radiations such as x-rays, g-rays, or electrons, typical of environmental earth exposures, have been relatively well-established. However, radiation likely to be encountered in space includes mainly heavy ions and protons along with their secondaries. Much less is known about the biology and risks associated with these types of radiation. The doses of radiation likely to be received even for long missions are probably low, but cover a broad range and are very unpredictable due to solar events. Like other types of radiation, the increased cancer risk associated with proton and heavy ion exposure is troubling because many radiation-induced cancers do not appear until later in life. Therefore, a large amount of uncertainty exists in how best to assess and manage the radiation risks associated with space travel.
Two high priorities in preparation for long missions are 1) providing a better understanding of both the short-term and long-term carcinogenic effects of heavy ion or proton radiation and 2) developing pharmaceutical countermeasures to mitigate the carcinogenic risk associated with low-dose and mid-dose exposures to these types of radiation.
As countermeasures to the cancer risk associated with space travel, chemoprevention offers a particularly promising avenue for investigation because of: 1) the difficulties associated with absolutely blocking radiation-induced mutagenic damage to DNA during prolonged space travel, either with shielding or pharmaceuticals, and 2) the prolonged latency period of most radiation-induced cancers (especially at low doses). This offers a prolonged time period when the most successful chemopreventatives exert their effects. For most cancers, compounds that modulate the regulation of cell growth and apoptosis (rather than blocking mutagenic damage to DNA) have to date shown particular promise in preventing overt cancer from developing in susceptible organs. Current chemoprevention successes against sporadic or familial tumors have identified tamoxifen for prevention of breast cancer, NSAID's (nonsteroidal antiinflamatory drugs) for prevention of colorectal cancer, and retinoids for preventing oropharangeal and other cancers as currently the top candidates for successful chemopreventation of specific tumors in humans.
Organs are not equally sensitive to the carcinogenic effects of radiation. Tissues that appear to be at higher risk for developing radiation-induced neoplasms include the female breast, the gastrointestinal tract (colorectal cancer), the thyroid, the bone marrow/lymphoid system (leukemia), and the lung. The female breast is particularly sensitive to the carcinogenic effects of radiation and therefore a relevant tissue in which to study chemoprevention of radiation-induced cancer. Furthermore, one of the most important advances in the therapy of breast cancer in the past two decades has been the development and use of tamoxifen for breast cancer chemotherapy. Over the past few years, tamoxifen has also emerged as an effective chemopreventative and now is the most widely prescribed anticancer drug in the world. It is prescribed mainly for breast cancer.
The class of compounds that includes tamoxifen, the selective estrogen receptor modulators (SERM's), are thought to have outstanding potential for use in estrogen replacement therapy and as chemopreventive agents. Burgeoning research and development of new SERM compounds has led to many new and improved SERM's undergoing trials. Tamoxifen, however, remains the prototype SERM for breast cancer chemoprevention. Newer SERM's will hopefully further improve on tamoxifen's effects while reducing its side effects. SERM's are ligands for the estrogen receptor (ER) and modify carcinogenesis in breast epithelial cells by antagonizing ER signaling. However, in other tissues SERM's can act as partial ER agonists and promote the beneficial effects of estrogens in, for example, the skeletal and cardiovascular systems. Interestingly, tamoxifen may also affect carcinogenesis in a number of organ systems by disrupting apoptosis regulation in proliferating cells. In spite of the widespread use of tamoxifen, very little is known about its lifetime effectiveness against radiation-induced neoplasms-particularly those induced by radiation likely to be encountered in space such as protons and heavy ions.
Appropriate animal models provide a powerful means for directly evaluating the effectiveness of particularly promising chemopreventatives against cancers that may occur following radiation exposure. The rat mammary tumor model has been used extensively to analyze the carcinogenic effects of both chemical xenobiotics and physical agents. The Sprague Dawley rat mammary tumor model is particularly well-suited for studies in the low dose range because it is prone to develop mammary neoplasms early in life. Previous studies using the Sprague Dawley model have shown that sublethal doses of radiation (x-rays, gamma rays, neutrons-not particularly relevant to space travel) induced mammary tumors, often within one year, and with a linear dose-effect relationship. Thus the Sprague Dawley rat mammary carcinogensis model not only closely resembles human breast cancer biologically, but it also is a highly sensitive model in which to examine the effects of radiation exposure and for testing pharmaceutical countermeasures against radiation effects. Our initial studies have focused on the effects of whole body, low level heavy ion and proton radiation along with chemoprevention of similarly induced mammary tumors using the female Sprague-Dawley rat mammary tumor model. Our rational approach to chemoprevention (SERM's) is based on one of the few successful emerging chemoprevention strategies used in human cancers to date in regard to sporadic or familial neoplasms. The well-studied, widely prescribed, protoypte SERM, tamoxifen has been effectively and safely used in humans for chemotherapy for almost two decades. These advantages, along with an understanding of its molecular mechanism of action suggests it would be an excellent candidate for successful long-term chemoprevention of specific proton and heavy ion-induced cancers. The prospect for successful long-term chemoprevention of this potentially important, late-appearing cancer relevant to space radiation exposure is indeed an exciting prospect.
Hypothesis
If there is an increased risk for developing cancer due to radiation exposure during prolonged space travel, the increased cancer risk can be mitigated by chemopreventive countermeasures implemented during the long cancer latency period that follows radiation exposure. A logical and relevant area in which to test this hypothesis is in a radiation-induced breast cancer animal model since the female breast is one of the tissues most sensitive to the cancer-inducing effects of radiation and because recent evidence suggests that the compound tamoxifen is an effective breast cancer chemopreventative.
Key Findings
Dr. Huso took over as PI of the chemoprevention studies less than two years ago and since that time considerable progress has been made in this area. Our studies are not complete, but preliminary evidence suggests that tamoxifen will be highly effective in preventing at least the mammary carcinomas that appear early following photon, proton, and heavy ion radiation exposure in the mammary gland. However, it appears there may be some variation in effectiveness depending on the dose and quality of radiation to which the individual is exposed. In addition, it is important to complete these studies and determine the effectiveness of tamoxifen for long-term chemoprevention of radiation-induced mammary cancer.
Although it is still early in the studies, preliminary results from our ongoing tamoxifen studies have pointed to a proof of principle for a strategy in which chemopreventive agents could play an important role in preventing breast cancer following exposure to radiation during space travel. This suggests that new chemopreventatives could be similarly identified that prevent other specific cancers associated with proton and heavy ion radiation exposure relevant to space exploration. Since cancer chemoprevention in general is still in its infancy as an emerging field, chemoprevention based on new targets and emerging compounds, hold considerable promise for continued improvement of strategies to effectively mitigate risks associated with radiation and other predisposing factors for cancers. Further studies are required to confirm the long-term safety and effectiveness of chemoprevention strategies, to identify additional agents that are effective against specific neoplasms, and to continue to improve chemoprevention effectiveness and implementation.
Implications of Findings
The implications are clear. Our results, though preliminary, provide a glimpse of the enormous potential payoff that chemoprevention research could provide in the battle against cancer. Regardless of the reason for an individual to be at increased risk for developing particular cancers, be it radiation exposure as in our studies (relevant to space travel) or genetic and enviornmental factors (relevant to the general population), specific chemopreventive compounds and strategies can be identified and implemented to mitigate risks that predispose individuals to cancer. Much work remains to be done to fully realize the benefits of chemoprevention strategies in the battle against cancer. Support for research into chemoprevention of radiation-induced neoplasms such as that provided by NSBRI therefore benefits not only space exploration efforts, but what is learned in this important area also could provide unique insight into cancer chemoprevention for the general population.