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Fluorinated Pyrimidines. XXI. The Tumor-inhibitory Activity of 5-Trifluoromethyl-2'-deoxyuridine^*

Charles Heidelberger and Sandra W. Anderson

( McArdle Memorial Laboratory, Medical School, University of Wisconsin, Madison, Wisconsin)

The tumor-inhibitory activity of 5-trifluoromethyluracil (F₃T) and 5-trifluoromethyl-2'-deoxyuridine (F₃TDR) has been studied in four transplanted mouse neoplasms. The toxicity has been determined in BDF₁ female mice following daily intraperitoneal injection for 7 days, and the LD₅₀'s for F₃T and F₃TDR are 800 mg/kg/day x 7 and 325 mg/kg/day x 7, respectively. F₃TDR is more toxic when given by stomach tube, the LD₅₀ being 225 mg/kg/day x 7. The toxicity is caused by depletion of the bone marrow, depression of the white count, and denudation of the gastrointestinal tract. In Sarcoma 180 and the Ehrlich ascites carcinoma, F₃TDR is less effective than 5-fluoro-2'-deoxyuridine (FUDR). Against L1210 leukemia F₃TDR and FUDR are equally effective, whereas in Adenocarcinoma 755 F₃TDR has a significantly better chemotherapeutic index than does FUDR. F₃T has significant activity only against the Ehrlich ascites carcinoma. Combination chemotherapy of F₃TDR and FUDR shows additive, but not synergistic, effects. A FUDR-resistant line of the Ehrlich ascites carcinoma is cross-resistant to F₃TDR. The mechanism of tumor inhibition appears to be primarily a result of the inhibition of thymidylate synthetase.

^* This work was supported in part by grants C-2832 and CA-07175 from the National Cancer Institute, National Institutes of Health, U. S. Public Health Service. A preliminary report of this work appeared in Proc. Am. Assoc. Cancer Res., 5:26, 1964.

American Cancer Society Professor of Oncology.

Received 6/27/64.