Comparison of 5-fluorouracil and ftorafur. II. Therapeutic response and development of resistance in murine tumors.
The therapeutic activity of ftorafur was compared to that of 5-fluorouracil (5-FU) in a number of tumor systems. The drugs were active against ip L1210 leukemia when administered ip, sc, or orally. Administration every fourth day x 3 proved to be the most effective treatment schedule for both drugs, although significant activity was seen on all treatment schedules tested. Both congeners had activity against sc implanted L1210 leukemia as well as a limited effect on the ic implanted tumor. 5-FU produced greater increases in lifespan of mice bearing L1210 leukemia than did ftorafur. 5-FU was also more effective against ip B16 melanoma and ip Gardner 6C3HED lymphosarcoma. Ftorafur was ineffective in the treatment of mice bearing ip P388 leukemia, a tumor which is quite sensitive to 5-FU. At approximately equimolar doses both drugs produced a persistent inhibition of 2'-deoxyuridine incorporation into DNA of L1210 cells in vivo. Ftorafur produced a greater inhibition of uridine incorporation into RNA than did 5-FU, which may account for the lower therapeutic activity of ftorafur. In combination chemotherapy of L1210 leukemia 5-FU plus ftorafur was no more effective than 5-FU alone, neither of the congeners was synergistic with either adriamycin or actinomycin D, and in combination with methotrexate therapeutic synergism was observed with 5-FU but not with ftorafur. After eight transplant generations of exposure to ftorafur, a subline of L1210 leukemia became totally resistant to ftorafur and simultaneously cross-resistant to 5-FU. Doses of ftorafur and 5-FU which were optimally effective in mice bearing the parental L1210 line were lethal to mice implanted with the ftorafur-resistant subline. When treatment of the resistant subline was discontinued after nine transplant generations of exposure to ftorafur, sensitivity to 5-FU returned after three transplant generations without ftorafur. The subline retained its resistance to ftorafur until eight transplant generations after cessation of ftorafur treatment. Another subline of L1210 leukemia exposed to 5-fU for 20 transplant generations proved to be completely resistant to 5-fu and cross-resistant to ftorafur. The mutual cross-resistance between ftorafur and 5-FU supports the contention that ftorafur acts primarily as a depot form of 5-FU.
D000818:Animals; D002277:Carcinoma / Q000188:drug therapy; D002460:Cell Line; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use*; D007939:Leukemia L1210 / Q000188:drug therapy; D007942:Leukemia, Experimental / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D008727:Methotrexate / Q000627:therapeutic use; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D005641:Tegafur / Q000627:therapeutic use
D005641:Tegafur; D005472:Fluorouracil; D008727:Methotrexate