Kinetic alterations induced by 5-fluorouracil in bone marrow, intestinal mucosa, and tumor.
In order to provide a more rational approach to the design of chemotherapeutic programs involving 5-fluorouracil (5-FU), the kinetic effect of this drug on bone marrow, gastrointestinal epithelium, and tumorous tissues in mice was monitored by determining the rate of incorporation of labeled deoxyuridine (UdR) into DNA following doses of 15, 50, and 100 mg/kg i.p: In BALB/c x DBA/2 F1 (hereafter called CD2F1) mice bearing P1534 ascites tumor, the magnitude and duration of suppression of [3H]UdR incorporation into DNA were directly related to drug dose for both the normal and tumorous tissues. However, the impact of 5-FU was clearly greater upon the P1534 ascites tumor than on either normal tissue, so that, after a dose of 100 mg/kg, the tumor did not initiate recovery until Day 5, while duodenal mucosa and bone marrow returned to 50% of control levels of UdR incorporation at 2 and 3 days, respectively. In order to determine whether the duration of suppression of [3H]UdR incorporation, such as observed in the P1534 ascites tumor, correlated with sensitivity of Ehrlich ascites tumor to 5-FU, the effect of 50 and 100 mg/kg of 5-FU i.p. on this less 5-FU-sensitive tumor was determined. No difference was observed in the time course of suppression and recovery between Ehrlich ascites tumor and the duodenal mucosa and bone marrow of the G.P. Swiss host. In non-tumor-bearing CD2F1 mice, the toxicity of a 2nd dose of 100 mg/kg 5-FU i.p. was found to be predictably related to the kinetic effect of a 1st dose of 100 mg/kg on [3H]UdR incorporation in the bone marrow and duodenal mucosa. In the time period from 12 hr through Day 6, when [3H]UdR incorporation into DNA rose to a maximum, administration of a 2nd dose of 5-FU was associated with 95% lethality. In contrast, during the period between 0 and 12 hr that preceded recovery of UdR incorporation, a 2nd dose resulted in less than 40% lethality, and, in the period from Day 6 through Day 8, when UdR incorporation was declining, lethality of a 2nd dose also declined to less than 25% lethality. In addition, the antitumor effectiveness of a 2nd dose of 5-FU, 100 mg/kg i.p., was predictably related to the differential effect of the 1st dose of 100 mg/kg on [3H]UdR incorporation in the P1534 tumor as compared to the host bone marrow and duodenal mucosa. Administration of a 2nd dose of 5-FU was maximally effective on Day 7, at a time when [3H]UdR incorporation was declining in the host target tissues and increasing to a maximum in the P1534 ascites tumor. Thus, the present study has demonstrated that [3H]UdR incorporation into DNA may be used to monitor the differential effect of 5-FU on tumor versus normal proliferating host tissues and, where such differences exist, to provide an in vivo method of value in designing a schedule of optimum therapeutic benefit.
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D004247:DNA / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003857:Deoxyuridine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000494:pharmacology* / Q000633:toxicity; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013936:Thymidine / Q000378:metabolism
D004273:DNA, Neoplasm; D004247:DNA; D005472:Fluorouracil; D013936:Thymidine; D003857:Deoxyuridine