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 (FUd greater than FUra greater than FdUrd greater than 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 micrograms
RNA and 4.8 pmol FUra per micrograms
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 micrograms
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.