Summary
The cytostatic agent 5′-deoxy-5-fluorouridine (5′-dFUrd) improves cachexia and prolongs survival, suppressing tumor growth in mice bearing large burdens of colon 26 adenocarcinoma. To investigate the mode of this anticachectic action, we isolated colon 26 variants that were resistant to the anticachectic activity in vivo in tumorbearing mice that initially responded to 5′-dFUrd in terms of tumor growth and cachexia but again became cachectic and refractory to the drug after prolonged treatment. The original line and variants were equally susceptible to the antiproliferative action of 5′-dFUrd, and their growth was stopped. However, 5′-dFUrd given to cachectic mice exhibiting large burdens of these variants could not reverse wasting and only slightly prolonged the survival period. These results indicate that the anticachectic activity of 5′-dFUrd is independent of its antiproliferative action and that the survival of colon 26-bearing mice is shorter when the size of the tumors is not reduced to levels below those that cause cachexia.
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Armstrong RD, Cadman E (1983) 5′-Deoxy-5-fluorouridine selective toxicity for human tumor cells compared to human bone marrow. Cancer Res 43: 2525
Bollag W, Hartmann HR(1980) Tumor inhibitory effects of a new fluorouracil derivative: 5′-deoxy-5-fluorouridine. Eur J Cancer 16: 427
Connolly KM, Diasio RB, Armstrong RD, Kaplan AM (1983) Decreased immunosuppression associated with anticancer activity of 5′-deoxy-5-fluorouridine compared to 5-fluorouracil and 5-fluorouridine. Cancer Res 43: 2529
DeWys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, Cohen MH, Douglass HO Jr, Engstrom PF, Ezdinli EZ, Horton J, Johnson GJ, Moertel CG, Oken MM, Perlia C, Rosenbaum C, Silverstein MN, Skeel RT, Sponzo RW, Tormey DC (1980) Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am J Med 69: 491
Ghezzi P, Saccardo B, Villa P, Bianchi M, Dinarello CA (1986) Role of interleukin-1 in the depression of liver drug metabolism by endotoxin. Infect Immun 54: 837
Ghezzi P, Saccardo B, Bianchi M (1986) Recombinant tumor necrosis factor depresses cytochrome P450-dependent microsomal drug metabolism in mice. Biochem Biophys Res Commun 136: 316
Hyvärien A, Nikkílä EA (1962) Specific determination of blood glucose witho-toluidine. Clin Chim Acta 7: 140
Ishitsuka H, Miwa M, Takemoto K, Fukuoka K, Itoga A, Maruyama HB (1980) Role of uridine phosphorylase for antitumor activity of 5′-deoxy-5-fluorouridine. Gann 71: 112
Kono A, Hara Y, Sugata S, Karube Y, Matsushima Y, Ishitsuka H (1983) Activation of 5′-deoxy-5-fluorouridine by thymidine phosphorylase in human tumors. Chem Pharm Bull (Tokyo) 31: 175
Miwa M, Cook A, Ishitsuka H (1986) Enzymatic cleavage of various fluorinated pyrimidine nucleosides to 5-fluorouracil and their antiproliferative activities in human and murine tumor cells. Chem Pharm Bull (Tokyo) 34: 4225
Ohta Y, Sueki K, Kitta K, Takemoto K, Ishitsuka H, Yagi Y (1980) Comparative studies on the immunosuppressive effect among 5′-deoxy-5-fluorouridine, ftorafur, and 5-fluorouracil. Gann 71: 190
Peters GJ, Braakhuis BJM, Bruijin EA de, Laurensse EJ, Walsum M van, Pinedo HM (1989) Enhanced therapeutic efficacy of 5′-deoxy-5-fluorouridine in 5-fluorouracil-resistant head and neck tumors in relation to 5-fluorouracil-metabolising enzymes. Br J Cancer 59: 327
Tanaka Y, Tanaka T, Ishitsuka H (1989) Antitumor activity of indomethacin in mice bearing advanced colon 26 carcinoma compared with those with early transplants. Cancer Res 49: 5935
Tanaka Y, Eda H, Tanaka T, Udagawa T, Ishikawa T, Horii I, Ishitsuka H, Kataoka T, Taguchi T (1990) Experimental cancer cachexia induced by colon 26 adenocarcinoma in mice. Cancer Res 50: 2290
Tanaka Y, Eda H, Fujimoto K, Tanaka T, Ishitsuka H (1990) Anticachectic activity of 5′-deoxy-5-fluorouridine in a murine tumor cachexia model, colon 26 adenocarcinoma. Cancer Res 50: 4528
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Eda, H., Tanaka, Y. & Ishitsuka, H. 5′-Deoxy-5-fluorouridine improves cachexia by a mechanism independent of its antiproliferative action in colon 26 adenocarcinoma-bearing mice. Cancer Chemother. Pharmacol. 29, 1–6 (1991). https://doi.org/10.1007/BF00686327
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DOI: https://doi.org/10.1007/BF00686327