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5-Fluorouracil Plus Thymidine or Leucovorin by Continuous I.V. Infusion in the Treatment of Advanced Colorectal Carcinoma

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Clinical Applications of Continuous Infusion Chemotherapy and Concomitant Radiation Therapy

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Abstract

5-Fluorouracil (FUra) has been the drug of choice in the treatment of colorectal cancers (1,2), and it is widely utilized in a variety of other malignancies (3). FUra exerts its antiproliferative effect following metabolic activation to various nucleotides (Chart 1). 5-Fluorouridine triphosphate (FUTP), due to its resemblance with uridine triphosphate (UTP), is incorporated into RNA (4–7); the consequence of this incorporation is the production of fraudulent mRNA, rRNA and tRNA which can ultimately cause cell death. The other proposed mechanism for FUra cytotoxicity is the inhibition of thymidylate synthetase (dTMP-S) by 5-fluorodeoxyuridine monophosphate (FdUMP) (8–11), leading to decreased thymidine triphosphate (dTTP) pools and to inhibition of DNA synthesis. The biochemical mechanism by which FdUMP binds to the dTMP-S involves a cofactor, N5,10methylene tetrahydrofolic acid (N5,10CH2FH4). Santi et al. have calculated that the dissociation constant (Kd) of the ternary complex FdUMP-dTMP-SN5,10CH2FH4, is of the order of 5×10-11M. In absence of the reduced folate cofactor, FdUMP binding to dTMP-S is relatively weak, with a Kd of about 10-5M (9). An additional proposed mechanism of cytotoxicity of FUra is its incorporation into DNA (12–15). To date, little is known about the biological significance of this finding.

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Authors and Affiliations

  1. Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo, NY, 14263, USA

    Fabio Trave & Youcef M. Rustum

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  1. Fabio Trave
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Editors and Affiliations

  1. Division of Medical Oncology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York, USA

    C. Julian Rosenthal M.D. (Associate Professor of Medicine, Director) (Associate Professor of Medicine, Director)

  2. Department of Radiation Oncology, State University of New York Health Science Center of Brooklyn, Brooklyn, New York, USA

    Marvin Rotman M.D. (Professor and Chairman) (Professor and Chairman)

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© 1986 Plenum Press, New York

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Trave, F., Rustum, Y.M. (1986). 5-Fluorouracil Plus Thymidine or Leucovorin by Continuous I.V. Infusion in the Treatment of Advanced Colorectal Carcinoma. In: Rosenthal, C.J., Rotman, M. (eds) Clinical Applications of Continuous Infusion Chemotherapy and Concomitant Radiation Therapy. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-2197-2_4

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  • DOI: https://doi.org/10.1007/978-1-4613-2197-2_4

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4612-9291-3

  • Online ISBN: 978-1-4613-2197-2

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