This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Grant, S. Articles by Cadman, E. Search for Related Content PubMed PubMed Citation Articles by Grant, S. Articles by Cadman, E.

Modulation of 1-ß-D-Arabinofuranosylcytosine Metabolism and Cytotoxicity in L1210 Cells by Fluoropyrimidine Pretreatment¹

Departments of Medicine and Pharmacology, Yale School of Medicine, New Haven, Connecticut 06510 [E. C.], and Department of Medicine, Columbia University School of Medicine, New York, New York 10021 [S. G.]

The effect of pretreatment with the fluoropyrimidines 5-fluorouracil (FUra), 5-fluorouridine (FUrd), 5-fluoro-2'-deoxyuridine (FdUrd), and 5'-deoxy-5-fluorouridine (5'-dFUrd) on the intracellular metabolism and in vitro cytotoxicity of 1-ß-D-arabinofuranosylcytosine (ara-C) was explored in L1210 cells. A 4-hr exposure to 100 µM FUra, FUrd, or FdUrd produced greater than 3-fold increments in the intracellular accumulation of [³H]deoxycytidine, and 2-fold increments in the intracellular accumulation of [³H]ara-C were produced over a 1-hr exposure. Intracellular 1-ß-D-arabinofuranosylcytosine 5'-triphosphate levels in cells exposed to these 3 agents were also increased over 2-fold. L1210 cells exposed sequentially to 1 µM FUra, FUrd, or FdUrd followed by 5 µM ara-C for 1 hr resulted in synergistic cell killing measured by soft-agar cloning. Although intracellular 2'-deoxycytidine 5'-triphosphate levels were reduced in cells treated for 4 hr with FUra and FUrd, this was not associated directly with the maximum accumulation of ara-C. FdUrd treatment was as effective as FUra and FUrd at enhancing ara-C accumulation and 1-ß-D-arabinofuranosylcytosine 5'-triphosphate formation and producing synergistic cytotoxicity; however, the 2'-deoxycytidine 5'-triphosphate pools were minimally affected. 5'-Deoxy-5-fluorouridine did not increase intracellular ara-C accumulation, reduce intracellular 2'-deoxycytidine 5'-triphosphate levels, or enhance ara-C cytotoxicity. This sequential drug interaction is similar to that which we have observed when methotrexate precedes ara-C and provides a rational basis from which further in vivo studies can be designed.

¹ Supported by Young Investigator Award CA-24187 from the National Cancer Institute, Grants CA-08341 and CA-27130 from the National Cancer Institute, Grant CH-145 from the American Cancer Society, and a Swebelius Award from the Yale Comprehensive Cancer Center.

² Fellow of the Leukemia Society.

³ Recipient of a Faculty Research Award from the American Cancer Society. To whom requests for reprints should be addressed.

Received 4/19/82. Accepted 6/ 8/82.