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Effects of 5-Fluorouracil on 5-Fluorodeoxyuridine 5'-Monophosphate and 2-Deoxyuridine 5'-Monophosphate Pools, and DNA Synthesis in Solid Mouse L1210 and Rat Walker 256 Tumors¹

Department of Pharmacology, The George Washington University Medical Center, Washington, D. C. 20037

We have examined some of the factors determining the action of 5-fluorouracil (FUra) against a responsive and nonresponsive rodent tumor. In mice bearing the FUra-responsive solid L1210 tumor, [³H]deoxyuridine (dUrd) incorporation into tumor DNA ceased promptly after FUra (100 mg/kg i.p.), and recovery was delayed for more than 96 hr. Incorporation of [³H]dUrd into bone marrow and small intestine, which were also strongly inhibited after FUra, recovered well before that of tumor. The levels of acid-soluble 5-fluorodeoxyuridine 5'-monophosphate (FdUMP) behaved in a reciprocal manner to the rate of [³H]dUrd incorporation in the tumor, although in small intestine and bone marrow this relationship was not as evident. Appreciable levels of FdUMP persisted in L1210 tumor for up to 72 hr after FUra. The 2-deoxyuridine 5'-monophosphate pool in the tumor was increased approximately 2-fold.

In rats bearing the relatively FUra-unresponsive solid Walker 256 carcinosarcoma, the incorporation of [³H]dUrd into DNA also promptly ceased after FUra (120 mg/kg s.c.), but then it rapidly resumed its normal rate within 48 hr. The effects of FUra on [³H]dUrd incorporation in rat bone marrow and duodenum were similar to those in the tumor except that recovery of [³H]dUrd incorporation was somewhat slower than that in the tumor. The levels of acid-soluble FdUMP increased and then decreased but not in precise association with inhibition and recovery of [³H]dUrd incorporation, respectively, in all tissues studied. Although initial levels of FdUMP in tumor were high, the anabolite was no longer measurable after 48 hr. The 2-deoxyuridine 5'-monophosphate pool in tumor was increased approximately 2-fold.

The prolonged inhibition of [³H]dUrd incorporation into DNA in the responsive L1210 tumor and the more rapid recovery in the relatively insensitive Walker 256 tumor correlated with the persistence of FdUMP in the L1210 tumor and its rapid disappearance in the Walker 256 tumor, but peak levels of FdUMP did not relate to tumor susceptibility to FUra.

¹ This work was supported by Grants CA 02978 and CA 17601, awarded by the National Cancer Institute, Department of Health, Education, and Welfare, Bethesda, Md., and by American Cancer Society Grant CI-110.

Received 2/ 2/78. Accepted 5/ 8/78.

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