Rationale for initial clinical trials and future development of radioprotectors

Over the past two decades a number of chemical radioprotectors have been developed which, although toxic, appear to be usable in clinically relevant doses. Because of differences in blood flow, radiochemical action in hypoxic cells, and active concentration in certain normal tissues, these compounds exhibit differential protection of normal tissue versus tumor. The best, currently available protector, WR-2721, is active in skin, intestine, marrow, mucosa, and salivary glands with lesser activity in kidney and lung and none in brain. Clinical trials have been designed in the Radiation Therapy Oncology Group based on this knowledge. Phase I studies involve patients requiring palliative radiotherapy for tumors located in or adjacent to tissues which are known to be protected. These studies use excalating doses of WR-2721, starting at 50 mg/m2 and will determine the maximum tolerated dose of drug, first as single doses and then as 1X, 3X, and 5X weekly for 3 and 6 weeks. Concomitant radiotherapy is given and normal tissue response at conventionl doses observed. Phase II studies will be site specific based on phase I results and doses. They will be radiation dose ranging studies designed to determine the maximum acceptable radiation dose at each site with WR-2721 protection. These new, higher doses will then be compared to conventional radiotherapy without protector, seeking increased tumor control in phase III studies. WR-2721 is not the ideal sensitizer since it does not protect all normal tissues. It is particularly important to develop compounds which can protect the brain, spinal cord, and lung. A large effort in new drug development will be justified if an improved therapeutic ratio is observed with WR-2721.