This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Armstrong, R. D. Articles by Cadman, E. Search for Related Content PubMed PubMed Citation Articles by Armstrong, R. D. Articles by Cadman, E.

5'-Deoxy-5-fluorouridine Selective Toxicity for Human Tumor Cells Compared to Human Bone Marrow¹

Departments of Medicine and Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510

Studies were completed to establish the comparative cytotoxicity of 5'-deoxy-5-fluorouridine (5'-dFUrd) and other fluoropyrimidines in human bone marrow stem cells and several cultured human tumor cell lines (i.e., 47-DN and MCF-7 breast carcinomas, MG-63 osteosarcoma, HCT-8 colon tumor, Colo-357 pancreatic tumor, and HL-60 promyelocytic leukemia). In vitro clonogenic assays were used to measure cytotoxicity following a 3-hr drug exposure. 5'-dFUrd was less potent than was 5-fluorouracil or 5-fluoro-2'-deoxyuridine in all cells examined, exhibiting its best activity against the 47-DN [concentration that prevented 50% clonal growth compared to untreated control (LD₅₀) = 32 µM] and MCF-7 (LD₅₀ = 35 µM) breast carcinomas and MG-63 osteosarcoma (LD₅₀ = 41 µM). Intermediate activity was observed against HCT-8 (LD₅₀ = 200 µM) and Colo-357 (LD₅₀ = 150 µM) gastrointestinal tumors. 5'-dFUrd had very poor activity against the HL-60 leukemia (LD₅₀ = 470 µM). The suppression of the clonal growth of human bone marrow stem cells required the greatest amount of 5'-dFUrd (LD₅₀ = 580 µM). With use of these studies, a therapeutic ratio (concentration that prevented 25% clonal growth compared to untreated control of bone marrow divided by LD₅₀ of tumor) was calculated for each drug in each tumor. 5'-dFUrd had values ranging from 1.2 to 7.5 for the solid tumors and 0.5 in HL-60 cells. This was in marked contrast to 5-fluorouracil, or 5-fluoro-2'-deoxyuridine, which failed in all cases to have ratios greater than or equal to one. The results indicate that 5'-dFUrd can exhibit a cytotoxic selectivity for human tumor cells compared to human bone marrow stem cells that does not exist for 5-fluorouracil or 5-fluoro-2'-deoxyuridine. This suggests that 5'-dFUrd may be of greater therapeutic benefit in the treatment of certain human cancers than the fluoropyrimidines used currently.

¹ This work was supported by Grants CA09200 and CA27130 from the National Cancer Institute, Grants In-3142 and CH-145 from the American Cancer Society, and a grant from Hoffmann-La Roche Inc., Nutley, N. J.

² Recipient of a Leukemia Society of America Fellowship Award. To whom requests for reprints should be addressed.

³ Recipient of a Faculty Research Award from the American Cancer Society.

Received 10/20/82. Accepted 2/14/83.