PubMed · 5849912
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1965-09-25. [Helpful notes no. 39].. https://pubmed.ncbi.nlm.nih.gov/5849912/
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Fluoropyrimidines, 5-fluorouracil (5-FU), and 5-fluorodeoxyuridine (FdUrd) are effective inhibitors of DNA synthesis. Inhibitory action is potentiated both in vitro and in vivo by the addition of leucovorin (LV; either the natural [6S] isomer or the mixture of the unnatural and natural [6R,S] isomers). The inhibition of DNA is subsequent to thymidylate synthase inhibition mediated by the formation of a covalently bound ternary complex consisting of 5-fluorodeoxyuridine monophosphate, 5,10-methylenetetrahydrofolate, and thymidylate synthase. In vitro exposure of cells to varying concentrations of [6R,S]LV or [6S]LV increases intracellular pools of the reduced folate cofactor. The effect of [6S]LV is both dose and time dependent. The in vitro effective concentration of [6S]LV is approximately 1 to 10 mumol/L, depending on cell type. While HCT-8 cells demonstrated optimal modulation of 5-FU and FdUrd cytotoxicity with 1 mumol/L of [6S]LV for 5 hours, the SE cells required higher doses of LV and longer exposure time. Thus, dependent on the cell type, higher concentration (10 mumol/L) and duration of exposure (greater than 5 hours) may be essential for an effective modulation of fluoropyrimidine action. Clinically, to achieve the concentration and conditions found optimal in an in vitro system, a dose of 500 mg/m2 by 5-hour infusion appears to be the present optimal dose and schedule of [6R,S]LV administration in combination with 5-FU.
The fluoropyrimidines fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd) have shown activity in a variety of malignancies. Nevertheless, even in initially responsive tumors, the development of resistance is a frequent problem. To understand the biochemical basis for acquired resistance, two pairs of cell lines were investigated. MCF7/Adr cells were obtained from the breast cancer cell line MCF7 by incubation with increasing concentrations of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH). These cells are resistant to Adriamycin (200- to 600-fold) and cross-resistant to 5-FU (25-fold) and FdUrd (67-fold). The resistant cells showed significantly increased levels of thymidylate synthase, the target enzyme of the fluoropyrimidines' active metabolite, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP). Other biochemical characteristics, including folate pools, drug uptake, metabolism, and retention, were unchanged. Fd9XR cells have been selected from a human colon cancer cell line (HCT-8) by exposure to FdUrd. These cells are resistant to FdUrd (1,000-fold) but not 5-FU. Biochemical evaluations show that the resistant cells are deficient of thymidine kinase and are thus unable to convert FdUrd to FdUMP. This understanding of the various biochemical mechanisms is essential for the design of specific modulations to overcome resistance to fluoropyrimidines.
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