Modulation of Therapeutic Response

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In the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The major goal of this project continues to define and understand those aspects of unique tumor physiology, anatomy, cellular, and molecular processes that ultimately define the very nature of a tumor such that a particular dose of ionizing radiation, when used will be more effective. One means to that end is to investigate the interaction of ionizing radiation with a variety of chemotherapy agents to assess if tumors can be made more sensitive. We previously demonstrated that treatment of diverse human tumor cell lines with paclitaxel induced a block in G2/M of the cell cycle (radiosensitive phases of the cell cycle) which resulted in significant radiosensitization. As a consequence, translation of this pre-clinical information into a clinical trail combining radiation and paclitaxel in the treatment of head/neck cancer is currently underway in the Radiation Oncology Branch. We have tested other chemotherapeutic agents including camptothecin derivatives, mitoxantrone, and UCN-01. Neither mitoxantrone nor UCN-01 was found to significantly radiosensitize a variety of human tumor cell lines. While camptothecin derivatives were found to radiosensitize, their inherent cytotoxicity alone will most likely prevent them from being used in the clinic with radiation. Recent studies have centered on the agent MGI-114, a new alkylating sesquiterpenoid which has shown cytotoxicity in both in vitro and in vivo models. We have shown that MGI-114 selectively radiosensitizes human breast and colon cell lines to radiation with an indication that the sensitization is related to cell cycle blocks in S phase. We have also initiated studies using two anaplastic thyroid cancer cell lines in an attempt to identify agents that might radiosensitize these cell lines. Of approximately eight different agents evaluated only 5-iododeoxyuridine radiosensitized with a dose-modifying factor of approximately 2.It is well established that hypoxia is a major determinant of radiation sensitivity. Therefore, we are using several murine tumor models to study tumor hypoxia. Our approach is to use current invasive techniques and extend that information to non-invasive methods that are under development, such that patient tumor treatment profiles may be optimized on an individual basis. To that end we are using in vitro and in vivo survival techniques, oxygen probes, nitroimidazole fixation followed by immunohistochemistry, F-18 nitroimidazole PET scanning, blood oxygen level determination (BOLD) NMR, electron paramagnetic resonance (EPR), and Overhauser NMR. Presently we are comparing/contrasting these various techniques with the goal of ultimately bringing non-invasive EPR or Overhauser NMR functional imaging to clinical trial. The information we acquire will teach us how to assess oxygen status in a tumor in a non-invasive manner to effect optimum treatment. Gene expression within a tumor as a function of oxygen status, reperfusion, ionizing radiation exposure and general oxidative stress is being investigated to determine those molecular events that are important in the tumor cell responsiveness and survival to insult by ionizing radiation alone or in combination with pharmacologic agents using cDNA microarray technology. The aim is to extend our knowledge of tumor micro-environment, physiology, and molecular biology and to correlate such knowledge with non-invasive methods of studying tumors so that we design efficient and effective treatment protocols using radiation in combination or tandem with pharmacologic agents. Likewise, we anticipate that studying gene expression profiles following radiation treatment will potentially provide novel molecular targets that may be selectively inhibited and/or enhanced which will modulate the radiation response.