Interaction between flavone acetic acid (LM-975, NSC 349512) and radiation in Glasgow's osteogenic sarcoma in vivo

Flavone acetic acid (FAA) is a new anticancer agent in Phase II trials in Europe. In preclinical testing FAA showed broad activity against murine solid tumors and minimal activity against murine leukemias. Our interest in studying the combination of FAA and radiation was based on two of its biological effects which might modify radiation damage. First, FAA depletes ATP and inhibits macromolecular synthesis which are needed to repair radiation-induced DNA strand breaks; and second, inhibition of tumor blood flow by FAA could lead to radiobiological hypoxia. Various schedules of FAA (170 mg/kg I.V.) (n = 9, SF = 0.44) and radiation (10 Gy) (n = 9, SF = 0.37) were investigated against s.c. implanted Glasgow osteogenic sarcoma. In the same model we studied both the kinetics of ATP depletion by 31P-Nuclear Magnetic Resonance Spectroscopy and the repair of radiation induced single and double strand breaks by alkaline elution. The combined response was not significantly different from log-additive when radiation was given 24, 5 or 1 hr before FAA. When FAA was given immediately before radiation an increase in tumor response, significantly different from log-additive (p = 0.03) was observed. This enhancement disappeared when radiation was delayed for between 1 and 48 hr after FAA. While decreased ATP levels and increased response to radiation occurred within minutes after FAA administration, no effect of FAA at either 180 or 200 mg/kg was observed on the repair of radiation induced single or double strand breaks (10 and 50 Gy, respectively; 5 hr after FAA) in spite of significant ATP depletion in the tumors.