RADIO AND CHEMO SENSITIZATION DEPENDENCE ON OXYGEN

The possibility that hypoxic cells limit the successful control of solid tumors by x-rays has been recognized by radiation oncologists for more than 25 years. The realization that hypoxia may be a limiting factor in chemotherapy is much more recent. Attempts to overcome the resistance of hypoxic cells to radiotherapy have led to the development of "hypoxic cell sensitizers", drugs that mimic oxygen and interact with radiation to specifically increase the sensitivity of hypoxic cells. These sensitizers preferentially kill hypoxic cells with a time-dependent cytotoxicity. This cytotoxicity is the basis of the "preincubation effect" where prolonged exposure of hypoxic cells to sensitizing drugs enhances their killing by radiation and cancer chemotherapeutic agents. Exploitation of the preincubation effect of these agents can be clinically advantageous where lower doses of sensitizer can be used systemically to enhance the action of radiation and chemotherapy drugs. The role of oxygen in this potentiation is important because it may help to explain differences found between animal and cell culture systems, and may mimic the intermediate levels of oxygen expected to be found in solid tumors. Determination of the K factor for radio- and chemo- sensitization would be of practical value in evaluating the most effective use of these sensitizing compounds. Experiments with mammalian cells of hamster and human origin are planned to investigate and compare what levels of oxygen in a preincubation exposure result in radio- and chemo- sensitization. Cells pretreated with several 2 and 4-nitroimidazoles will be subsequently exposed to increasing doses of x-rays or Bleomycin, Cis-DDP, L-PAM, PALA, and BCNU. The plasma cell membrane will also be analyzed as a target of the preincubation effect by assaying for levels of Na, Kg Mg, and Ca-ATPase in pretreated cells. Use of the preincubation effect, to enhance the killing of hypoxic cells resistant to drug and radiation therapy, can make a significant contribution in the treatment of solid tumors.