MODULATION OF 5-FLUOROURACIL-INDUCED TOXICITY IN MICE WITH INTERFERON OR WITH THE INTERFERON INDUCER, POLYINOSINIC-POLYCYTIDYLIC ACID

Abstract

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 .times. DBA/2 F1 mice. Protection against FUra-induced toxicity was also observed when the interferon inducer polyinosinic-polycytidylic acid (poly I.cntdot.poly C) was administered with FUra. The temporal relationship between the administration of poly I.cntdot.poly C and FUra was found to be a critical determinant of the intensity of toxic manifestations. In relation to FUra alone, poly I.cntdot.poly C could enhance (when administered 48 h before FUra), diminish (when administered together with FUra), or not affect (when administered 48 h after FUra) the degree of resultant toxicity. Cytofluorometric analysis of the DNA content of bone marrow cells indicated a transient period (.apprx. 42 h) of inhibition of cell cycling following the administration of poly I.cntdot.poly C, followed by reentry into cycle (between 42 and 66 h) and a return to normal cycle phase distribution by 90 h. 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.cntdot.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.