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Selective Activation of 5'-Deoxy-5-fluorouridine by Tumor Cells as a Basis for an Improved Therapeutic Index¹

Departments of Pharmacology [R.D.A., R.B.D.] and Medicine [R.B.D.], Medical College of Virginia, Richmond, Virginia 23298

The intracellular metabolism of a new fluoropyrimidine, 5'-deoxy-5-fluorouridine (5'-dFUrd), was compared with the metabolism of 5-fluorouracil (FUra), 5-fluorouridine (FUrd), and 5-fluoro-2'-deoxyuridine (FdUrd) in freshly isolated bone marrow cells and Ehrlich ascites tumor cells. Following exposure to tumor cells, all four fluoropyrimidines were metabolized to identical products (i.e., FUra, 5-fluorouridine 5'-monophosphate, 5-fluorouridine 5'-diphosphate, 5-fluorouridine 5'-triphosphate, and 5-fluoro-2'-deoxyuridine 5'-monophosphate), all produced an incorporation of FUra into RNA (FUrd > FUra > FdUrd > 5'-dFUrd), and all completely inhibited thymidylate synthetase activity by 1 hr. However, in bone marrow cells, very different patterns were observed. 5'-dFUrd accumulated in the cells, but there were no measurable metabolism, no incorporation of FUra into RNA, and no inhibition of thymidylate synthetase activity. In contrast, both FUra and FUrd were metabolized and produced an incorporation of FUra into RNA (2.7 pmol FUra per µg RNA and 4.8 pmol FUra per µg RNA at 2 hr, respectively) in bone marrow. Only a minor inhibition of thymidylate synthetase activity was detected. FdUrd also was metabolized by bone marrow cells, produced a low level of FUra incorporation into RNA (0.23 pmol FUra per µg RNA at 2 hr), and produced a complete inhibition of thymidylate synthetase activity. Since 5'-dFUrd is not directly cytotoxic itself, its superior therapeutic index compared to other fluoropyrimidines may largely reflect the selective activation of 5'-dFUrd by sensitive tumor cells as opposed to bone marrow cells, which can activate FUra, FUrd, and FdUrd.

¹ Supported by USPHS Grant CA 23412.

² To whom requests for reprints should be addressed, at Box 540, MCV Station, Richmond, Va. 23298.

Received 4/24/81. Accepted 8/19/81.