Rate of DNA synthesis as an indication of drug toxicity and as a guide for scheduling cancer therapy.

The rates of incorporation of [C3H3]thymidine into the DNA of tissues of normal mice at various times after single doses of several drugs (adriamycin, vincristine, methotrexate, 5-fluorouracil [5-FU], melphalan, CCNU, and chlorozotocin) that have some clinical activity against cancer have been determined and are considered to be indicative of the "degree of normalcy" of the respective tissues at those times. These experiments show that there are some differences and some similarities in the effects of the agents upon the various tissues of the mouse. Each of the agents caused early inhibition of incorporation of [C3H3]thymidine followed by stimulation of such incorporation by intestinal mucosa and marrow, but the timing and the extents of inhibition and stimulation differed for the various agents. Except for CCNU, the preceding description would also apply to the effects upon liver and lungs, but the stimulation was delayed in comparison to that of intestinal mucosa and marrow. Early inhibition with little subsequent stimulation occurred in the spleen, kidneys, and heart. For all tissues, recovery was slower and less extensive after CCNU than after the other agents. The data obtained with the single agents were used for setting up experiments in which a single dose of one agent was followed after selected intervals of time with a single dose of a second agent. The combination of adriamycin plus 5-FU was less toxic when the two agents were given simultaneously than when the 5-FU was given 24-96 hours after the adriamycin, while for the combination of adriamycin plus CCNU there was less toxicity if the CCNU was administered 24 hours after the adriamycin rather than simultaneously with it. When a combination of a single dose of methotrexate and a single dose of 5-FU was administered to mice, the lethality was greater when the two agents were administered 120 hours apart than when the two agents were given simultaneously or were separated by 24 or 48 hours; this was true regardless of which agent was administered first. These results are consistent with what might be predicted upon the basis of the data obtained for the single agents in this study and of what is known about the mechanisms of action of these agents and of the effects of the agents in relation to cell and tissue kinetics. These results indicate that patterns of thymidine fixation by tissues following single doses of agents might be useful in scheduling multiple-drug therapy to minimize host toxicity.