Chlorophenoxy acetic acid derivatives as hemoglobin modifiers and tumor radiosensitizers

We have studied the influence of the antilipidemia drug, clofibrate, and several structurally related analogs on the binding affinity of hemoglobin for oxygen and the radiation sensitivity of the SCCVII/St carcinoma in the mouse. Several compounds in this class reduced hemoglobin affinity in vivo; and two of these, ML1024 (etophyline clofibrate) and ML1037, were at least as effective as clofibrate at reducing hemoglobin affinity and much less toxic. When given orally at a dose of 4.1 m mole/Kg, 1/2-2 hrs before 20 Gy X rays, clofibrate gave radiosensitization in the SCCVII/St tumor equivalent to a 40-fold reduction in hypoxic fraction. ML1024 and ML1037 at a dose (3.0 m mole/Kg), which had a similar effect on hemoglobin, gave much less sensitization of the tumor. Only ML1024 produced a statistically significant effect, equivalent to a four-fold reduction in hypoxic fraction. We conclude that there are several clofibrate analogs which in relation to their toxicity are much better hemoglobin modifiers than the parent compound. They do not, however, show the same radiosensitizing effects, leading us to believe that mechanisms other than changes in hemoglobin/oxygen binding must also be involved.