Radiation enhancement by biochemical modulation and 5-fluorouracil

Purpose: To evaluate the effects of biochemical modulation by N- (phosphonacetyl)-L-aspartate (PALA), 6-methylmercaptopurine riboside (MMPR), and 6-aminonicotinamide (6AN), (PALA + MMPR + 6AN is referred to as PMA) on tumor radiosensitivity, and evaluate the efficacy of the addition of 5-PU to the PMA + XRT regimen for enhancement of tumor response to radiation without exceeding normal tissue tolerance. Methods and Materials: A first generation transplant of the CD8F1 spontaneous murine tumor was studied. 31P nuclear magnetic resonance spectroscopy was used to determine the interval between chemotherapy and radiation based on energy depletion. PMA was administered three times with fractionated XRT (15 Gy x 3 = 45 Gy) on days 1, 10, or 11, and 21. The addition of 5-fluorouracil (5-FU) at maximum tolerated doses was evaluated and intergroup 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, pretreatment with bolus i.p. 5-FU enhanced XRT. In comparison, mice treated with PMA + XRT had a tumor doubling rime (TDT) > 123.2 days (109.4-138.7), (p < 0.0001 compared to 5-FU + XRT). The addition of 5-FU to PMA + XRT induced a doubling time of > 170.8 days (150.7-193.7) (p = 0.0002 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 CR 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). Mortality and local effects induced by radiation in the PMA + XRT group were 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.