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Incorporation of 5-Fluorouracil into Murine Bone Marrow DNA in Vivo¹

Institute of Cancer Research, Columbia University, New York 10033 [R. C. S., R. L. S., D. S. M., S. S.]; Memorial Sloan-Kettering Cancer Center, New York 10021 [D. S. M.]; and Catholic Medical Center, New York 11421 [R. C. S., R. L. S., D. S. M.], New York

Although 5-fluorouracil (FUra) is readily incorporated into RNA, the possibility of its being incorporated into DNA in substantial amounts has only recently been recognized. Examination of nucleic acids prepared from tumor-bearing BALB/c x DBA/8 F₁ mice labeled with [³H]FUra in vivo revealed very little alkali-stable, acid-precipitable radioactivity in tumor and only small amounts in intestine. However, substantial amounts were detected in bone marrow. Pretreatment of mice with low-dose thymidine (500 mg/kg) increased the incorporation of FUra into RNA but did not change the amount incorporated into alkali-stable material. The net result was a reduction in the fraction of the total in an alkali-stable form. Formation of DNA containing FUra residues is substantially reduced if the mice receive very high doses of thymidine along with the labeled FUra, presumably through competition from an expanded deoxythymidine triphosphate pool. Bone marrow nucleic acids labeled with ³²P and [³H]FUra were analyzed by cesium sulfate gradients. Two distinct peaks of tritium radioactivity were observed that band with ³²P radioactivity at the densities of RNA and DNA. Pretreatment with alkali destroyed the (³²P/³H)RNA peak, but not the DNA peak. Cesium sulfate-purified DNA containing FUra residues was digested with pancreatic DNase and venom phosphodiesterase. The resulting nucleotides were analyzed by high-pressure liquid chromatography. The majority of the radioactivity cochromatographed with 5-fluorodeoxyuridine monophosphate marker. No radioactivity was detected in the regions corresponding to fluorouridine monophosphate or deoxyuridine monophosphate, although radioactivity was detected cochromatographing with deoxythymidine monophosphate. After digestion with alkaline phosphatase, the majority of the radioactivity cochromatographed with fluorodeoxyuridine (and some thymidine). These results confirm previous observations of FUra incorporation into DNA of tissue culture cells.

¹ This investigation was supported by USPHS Grant 2 PO1 CA 25842-03, awarded by the National Cancer Institute, Department of Health and Human Services, and in part by the Chemotherapy Foundation, New York, NY 10028.

² To whom requests for reprints should be addressed, at St. Anthony's Cancer Research Center, 89-15 Woodhaven Boulevard, Woodhaven, NY 11421.

Received 3/22/83. Accepted 1/26/84.

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