RATE OF DNA-SYNTHESIS AS AN INDICATION OF DRUG TOXICITY AND AS A GUIDE FOR SCHEDULING CANCER-THERAPY

  • 1 January 1978
    • journal article
    • research article
    • Vol. 62  (5) , 755-769
Abstract
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 [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] and chlorozotocin) that have some clinical activity against cancer were determined and are considered to be indicative of the degree of normalcy of the respective tissues at those times. There are some difference and some similarities in the effects of the agents on 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 extent of inhibition and stimulation differed for the various agents. Except for CCNU, the preceeding description would also apply to effects on liver and lungs, but 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 the other agents. The data obtained with the single agents were used for setting up experiments in which a single dose of 1 agent was followed after selected intervals of time with a single dose of a 2nd agent. The combination of adriamycin plus 5-FU was less toxic when the 2 agents were given simultaneously than when 5-FU was given 24-96 h after adriamycin, while for the combination of adriamycin plus CCNU there was less toxicity if CCNU was administered 24 h after 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, lethality was greater when the 2 agents were administered 120 h apart than when the 2 agents were given simultaneously or were separated by 24 or 48 h. This was true regardless of which agent was administered first. These results are consistent with what might be predicted on the basis of data obtained for the single agents in this study and of what is known about the mechanisms of action of these agents and 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.