Abstract
Both leucovorin (LV) and cisplatin (cis-dichlorodiammine platinum II, CDDP) act as modulators of 5-fluorouracil (5-FUra) by increasing the intracellular concentration of reduced folate. We measured intracellular folate levels following the administration of LV or cisplatin in tumor-bearing rats to determine the optimal schedules for their use as 5-FUra modulators. Donryu rats were inoculated with Yoshida sarcoma cells on the right flank. Seven days after tumor inoculation, the animals were injected with LV or CDDP. The kinetic and dose-related changes in intracellular folate concentration were analyzed by means of a binding assay. Folate levels in the tumor tissues were significantly higher than baseline 1 and 2 h after administration of LV and remained significantly high until 8 h after administration. Folate levels in the tumor tissues were significantly higher than baseline 1 and 2 h after cisplatin administration, then decreased to a rather low level 8 h after, and to a significantly lower level than baseline 24 h after administration. The folate levels in the tumor tissue increased in proportion to the dose of LV, but did not increase when the dose of cisplatin was increased from 1 mg/kg to 8 mg/kg. Repeat high-dose administration of LV and repeat low-dose administration of cisplatin are advocated when they are used as modulators of 5-FUra.
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Spears CP, Gustavsson BG, Berne M, Frösing R, Bernstein L, Hayes AA (1988) Mechanism of innate resistance to thymidylate synthase inhibition after 5-fluorouracil. Cancer Res 48: 5894
Omura K, Kawakami K, Ishida F, Hashimoto T, Matsu T, Adachi I, Watanabe Y (1993) Changes of the number of FdUMP binding sites of thymidylate synthase and folate pools in human colorectal carcinomas following the administration of tegafur and uracil: preliminary report. Nippon Geka Gakkai Zasshi 94: 193
Scanlon KJ, Newman EM, Lu Y, Priest DG (1986) Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. Proc Natl Acad Sci USA 83: 8923
Rustum YM, Trave F, Zakrzewski SF, Petrelli N, Herrera L, Mittelman A, Arbuck SG, Creaven PJ (1987) Biochemical and pharmacologic basis for potentiation of 5-fluorouracil action by leucovorin. NCI Monogr 5: 165
Mini E, Mazzei T, Coronnello M, Criscuoli L, Gualtieri M, Periti P, Bertino JR (1987) Effect of 5-methyltetrahydrofolate on the activity of fluoropyrimidines against human leukemia (CCRF-CEM) cells. Biochem Pharmacol 36: 2905
Dohden K, Ohmura K, Watanabe Y (1993) Ternery complex formation and reduced folate in surgical specimens of human adenocarcinoma tissues. Cancer 71: 471
Kemeny N, Lokich JJ, Anderson N, Ahlgrem JD (1993) Recent advances in the treatment of advanced colorectal cancer. Cancer 71: 9
Martin DS (1987) Biochemical modulation: perspective and objectives In: Harrap K, Connors T (ed) New avenues in developmental chemotherapy. Academic Press, London, p 113
Omura K, Doden K, Munemoto Y, Kawakami K, Miyanaga T, Hashimoto T, Ishida F, Watanabe Y (1992) Treatment of advanced cancer of the alimentary tract with cisplatin and 5-fluorouracil. Jpn J Cancer Chemother 19: 723
Fujii S, Ikenaka K, Shirasaka T (1978) Effect of uracil and its derivatives on antitumor activity of 5-fluorouracil and 1-(2-tetrahydrofuryl)-5-fluorouracil. Gann 69: 763
Panasci L, Ford J, Margolese R (1985) A phase II study of sequential methotrexate and fluorouracil in advanced colorectal cancer. Cancer Chemother Pharmacol 15: 164
Ajani JA, Kanojia MD, Bedikian AY, Korinek JK, Stein SH, Espinosa EG, Bodey GP (1985) Sequential methotrexate and 5-fluorouracil in advanced colorectal carcinoma. Am J Clin Oncol 8: 69
Walder S, Schwartz EL, Goldman M, Lyver A, Rader M, Zimmerman M, Itri L, Weinberg V, Wiernik PH (1989) Fluorouracil and recombinant alpha-2a-interferon: an active regimen against advanced colorectal carcinoma. J Clin Oncol 7: 1769
Kemeny N, Younes A, Seiter K, Kammarco P, Adams L, Derby S, Murray P, Houston C (1990) Interferon alpha-2a and 5-fluorouracil for advanced colorectal carcinoma; assessment of activity and toxicity. Cancer 66: 2470
Pazdur R, Ajani JA, Winn R, Bearden J, Belt RJ, Pilat S, Hallinan R, Levin B (1992) A phase II trial of 5-fluorouracil and recombinant alpha-2a-interferon in previously untreated metastatic gastric carcinoma. Cancer 69: 878
O'Connell MJ (1989) A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer. Cancer 63: 1026
Laufman LR, Brenckman WD Jr, Stydnicki KA, Morgan ED, Collier M, Knick VB, Duch DS, Mullin R, Ferone R (1989) Clinical experience with leucovorin and 5-fluorouracil. Cancer 63: 1031
Doroshow JH, Multhauf P, Leong L, Margolin K, Litchfield T, Akman S, Carr B, Bertrand M, Goldberg D, Blayney D, Odujinrin O, Delap R, Shuster J, Newman E (1990) Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol 8: 491
Petrelli N, Douglass HO, Herrera L, Russell D, Stablein DM, Bruckner HW, Mayer RJ, Schinella R, Green MD, Muggia FM, Megibow A, Greenwald ES, Bukowski RM, Harris J, Levin B, Gaynor E, Loutfi A, Kalser MH, Barkin JS, Benedetto P, Woolley PV, Nauta R, Weaver DW, Leichman LP (1989) The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III Trial. J Clin Oncol 7: 1419
Scanlon KJ, Newman EM, Lu Y, Priest DG (1986) Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. Proc Natl Acad Sci USA 83: 8923
Shirasaka T, Shimamoto Y, Ohshimo H, Saito H, Fukushima M (1993) Metabolic basis of the synergistic antitumor activities of 5-fluorouracil and cisplatin in rodent tumor models in vivo. Cancer Chemother Pharmacol 32: 167
Scanlon KJ, Safirstein R, Guttenplan JB, Thies HL, Waxman S (1982) Inhibition of the ACS amino acid transport system by cisplatin. Proc AACR 23: 167
Jeske J, Hansen RM, Libnoch JA, Anderson T (1990) 5-fluorouracil infusion and low-dose weekly cisplatin: an analysis of increased toxicity. Am J Clin Oncol 13: 485
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Omura, K., Misaki, T., Hashimoto, T. et al. Changes in folate concentration in Yoshida sarcoma after administration of leucovorin or cisplatin. Cancer Chemother. Pharmacol. 35, 183–187 (1995). https://doi.org/10.1007/BF00686545
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DOI: https://doi.org/10.1007/BF00686545