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Schedule-dependent antitumor and toxic effects of thymidine and 5-fluorouracil in AKR and L1210 leukemias

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The effect of thymidine (dThd) on 5-fluorouracil (FUra) toxicity to both leukemia stem cells (LCFU) and hematopoietic stem cells (NCFU) was examined. A dose of 10 mg/mouse of dThd given within 1 h before FUra enhanced FUra cytotoxicity to NCFU by a factor of about 4. This effect was also reflected in the reduction of the LD10. The dose-survival curve of FUra in AKR leukemia was modified by the prior administration of dThd 10 mg/mouse: the cytotoxic effect of FUra was enhanced by a factor of between 100 and 1000 throughout the dose range studied. These findings were reflected in the ILS studies. When given by ‘high dose’ infusion dThd had only a slight antitumor effect on AKR leukemia, and no effect on L1210. When large doses of dThd were infused concomitantly with FUra they ptoentiated its cytotoxicity against NCFU, AKR LCFU, and L1210 LCFU in a dose-dependent manner and by a maximum factor of about 70.

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  1. 1.

    Bruce WR, Meeker BE (1964) Dissemination and growth of transplanted isologous murine lymphoma cells. J Natl Cancer Inst 32: 1145

  2. 2.

    Bruce WR, Van der Gaag H (1963) A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature 199: 79

  3. 3.

    Bruce WR, Meeker BE, Valeriote FA (1967) Survival of mice bearing a transplanted syngeneic lymphoma following treatment with cyclophosphamide, 5-fluorouracil or 1,3-bis (2-chloroethyl)-1-nitrosourea. J Natl Cancer Inst 39: 257

  4. 4.

    Danhauser LL, Rustum YM (1984) Chemotherapeutic efficacy of 5-fluorouracil with concurrent thymidine infusion against transplantable colon tumors in rodents. Cancer Drug Del 1: 269

  5. 5.

    Edelstein M, Valeriote FA, Vietti T (1974) Schedule-dependent synergism for the combination of 1-B-D-arabinofuranosylcytosine and daunorubicin. Cancer Res 34: 293

  6. 6.

    Edelstein M, Valeriote FA, Vietti T (1977) Cellular quantitation of in vivo effects of 1-B-D-arabinofuranosylcytosine on leukemia L1210. J Natl Cancer Inst 58: 941

  7. 7.

    Fisher, Yates F (1963) Statistical tables for biological agricultural and medical research, 6th ed., Table VIII 2. Hafner, Darien, Conn

  8. 8.

    Hewitt HB (1958) Studies of the dissemination and quantitative transplantation of a lymphocytic leukemia of CBA mice. Br J Cancer 12: 378

  9. 9.

    Howell SB, Jenkins RS, Streifel J (1979) Activity of thymidine as a chemotherapeutic agent against human tumor xenografts in nude mice. Cancer Res 39: 3875

  10. 10.

    Kroll M, Brenstein B, Cummings FJ, Calabresi P (1976) Thymidine (Tdr) rescue of myelosuppression induced by 5-fluoro-2′-deoxyuridine (Fudr) and 5-iodo-2′deoxyuridine (Iudr). Proc Am Assoc Cancer Res 17: 162

  11. 11.

    Kufe DW, Major PP, Egan EM, Loh E (1981) 5-fluoro-2′-deoxyuridine incorporation in L1210 DNA. J Biol Chem 256: 8885

  12. 12.

    Lee S, Giovanella BC, Stehlin JS Jr, Brunn JC (1979) Regression of human tumors established in nude mice after continuous infusion of thymidine. Cancer Res 39: 2928

  13. 13.

    Lynch G, Kemeny N, Chun H, et al (1985) Phase I evaluation and pharmacokinetics study of weekly i.v. thymidine and 5-FU in patients with advanced colorectal carcinoma. Cancer Treat Rep 69: 179

  14. 14.

    Oettgen HF, Clifford P, Candler P (1963) Continuous intraarterial or intravenous infusion of 5-fluoro-2′-deoxyuridine: Therapeutic and toxic effects. Cancer Chemother Rep 32: 35

  15. 15.

    Presant CA, Multhauf P, Klein L, et al (1983) Thymidine and 5-FU: a phase II pilot study in colorectal and breast carcinomas. Cancer Treat Rep 67: 735

  16. 16.

    Reynolds EC, Harris AW, Lloyd RF (1979) Deoxyribonucleoside triphosphate pools and differential thymidine sensitivity of cultured mouse lymphoma and myeloma cells. Biochim Biophys Acta 561: 110

  17. 17.

    Santelli G, Valeriote FA (1978) In vivo enhancement of 5-fluorouracil cytotoxicity to AKR leukemia cells by thymidine in mice. J Natl Cancer Inst 61: 843

  18. 18.

    Santelli G, Valeriote FA (1986) Schedule-dependent cytotoxicity of 5-fluorouracil in AKR and L1210 leukemias. J Natl Cancer Inst (in press)

  19. 19.

    Spiegelman S, Nayak R, Sawter R, et al (1980) Potentiation of the anti-tumor activity of 5FU by thymidine and its correlation with the formation of (5FU) RNA. Cancer 45: 1129

  20. 20.

    Sternberg A, Petrelli NJ, Au J, et al (1984) A combination of 5-fluorouracil and thymidine in advanced colorectal carcinoma. Cancer Chemother Pharmacol 13: 218

  21. 21.

    Till JE, McCulloch EA (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14: 213

  22. 22.

    Trader MW, Schabel FM Jr, Carter WR Jr, et al (1979) Comparative therapeutic activity of 5-fluorouracil (FU) alone or thymidine (Tdr) followed by FU against leukemia P388, spontaneous AKR leukemia, and colon carcinoma 26 and 38. Proc Am Assoc Cancer Res 20: 95

  23. 23.

    Valeriote FA, Vietti T, Tolen S (1973) Kinetics of the lethal effect of actinomycin D on normal and leukemic cells. Cancer Res 33: 2658

  24. 24.

    Vietti T, Eggerding F, Valeriote F (1971) Combined effect of X-radiation and 5-fluorouracil on survival of transplanted leukemic cells. J Natl Cancer Inst 47: 865

  25. 25.

    Vietti TJ, Valeriote FA, Kalish R, Coulter D (1978) Kinetics of cytotoxicity of VM-26 and VP-16-213 on L1210 leukemia and hematopoietic stem cells. Cancer Treat Rep 62: 1313

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Author information

Correspondence to Fred Valeriote.

Additional information

This investigation was supported by PHS grant no CA-34144 awarded by the National Cancer Institute, DHSS

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Santelli, G., Valeriote, F. Schedule-dependent antitumor and toxic effects of thymidine and 5-fluorouracil in AKR and L1210 leukemias. Cancer Chemother. Pharmacol. 18, 101–104 (1986). https://doi.org/10.1007/BF00262276

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  • Stem Cell
  • Leukemia
  • Cancer Research
  • Toxic Effect
  • Thymidine