RADIATION ENHANCEMENT BY BIOCHEMICAL MODULATION AND 5-FLUOROURACIL

Purpose: To evaluate the effects of biochemical modulation by N-(phosp honacetyl)-L-aspartate (PALA), 6-methylmercaptopurine riboside (MMPR), and 6-aminonicotinamide (6AN), (PALA + MMPR + 6AN is referred to as P MA) on tumor radiosensitivity, and evaluate the efficacy of the additi on of 5-FU to the PMA + XRT regimen for enhancement of tumor response to radiation without exceeding normal tissue tolerance. Methods and Ma terials: A first generation transplant of the CD8F1 spontaneous murine tumor was studied, 31P nuclear magnetic resonance spectroscopy was us ed to determine the interval between chemotherapy and radiation based on energy depletion. PMA was administered three times with fractionate d XRT (15 Gy x 3 = 45 Gy) on days 1, 10, or 11, and 21. The addition o f 5-fluorouracil (5-FU) at maximum tolerated doses was evaluated and i ntergroup comparisons were made for tumor growth delay, local control, and disproportionate normal tissue damage,. Results: The combination of 5-FU + XRT induced a tumor doubling time of 75.4 days (67.4-84.4) ( p < 0.0001 compared to XRT), validating that in this tumor model, pret reatment with bolus i.p. 5-FU enhanced XRT. In comparison, mice treate d with PMA + XRT had a tumor doubling time (TDT) > 123.2 days (109.4-1 38.7), (p < 0.0001 compared to 5-FU + XRT). The addition of 5-FU to PM A + XRT induced a doubling time of > 170.8 days (150.7-193.7) (p = 0.0 002 compared to PMA + XRT). The doubling time for the PMA + XRT cohort and the PMA + 5-FU + XRT cohorts are underestimates since some of the tumor bearing mice continue to have a complete regression (CR). The C R rate (measured on day 250) for the PMA + 5-FU + XRT cohort was 31.7% compared to 0% for 5-FU + XRT and 10% for PMA + XRT (p < 0.05), Morta lity and local effects induced by radiation in the PMA + XRT group wer e comparable to the toxicity for the PMA + 5-FU + XRT group indicating that the addition of 5-FU at 75 mg/kg to PMA + XRT was tolerated and induced both greater CR and tumor doubling times than XRT alone, 5-FU (150 mg/kg) + XRT, or PMA + XRT. Conclusions: PMA is superior to 5-FU as a radiosensitizer in the schedule studied. The combination of PMA 5-FU further enhanced XRT without exceeding normal tissue tolerance. (C) 1997 Elsevier Science Inc,.