Modulation of 5-fluorouracil-induced toxicity in mice with interferon or with the interferon inducer, polyinosinic-polycytidylic acid.

Partially purified preparations of mouse interferon, administered during the 2-day period following the administration of a toxic dose of 5-fluorouracil (FUra), yielded significant protection from mortality in BALB/c × DBA/2 F1 mice. Protection against FUra-induced toxicity was also observed when the interferon inducer polyinosinic-polycytidylic acid (poly I·poly C) was administered with FUra. The temporal relationship between the administration of poly I·poly C and FUra was found to be a critical determinant of the intensity of toxic manifestations. In relation to FUra alone, poly I·poly C could enhance (when administered 48 hr before FUra), diminish (when administered together with FUra), or not affect (when administered 48 hr after FUra) the degree of resultant toxicity. Cytofluorometric analysis of the DNA content of bone marrow cells indicated a transient period (about 42 hr) of inhibition of cell cycling following the administration of poly I·poly C, followed by reentry into cycle (between 42 and 66 hr) and a return to normal cycle phase distribution by 90 hr. This disturbance of the kinetic pattern of cell cycling in bone marrow would explain the administration time-dependent variability of the effect of poly I·poly C on FUra toxicity, since FUra is known to be a cell cycle-specific cytotoxic drug. Potential practical application of this observation to the clinical use of FUra in cancer therapy is discussed.