This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, Z.-G. Articles by Rustum, Y. M. Search for Related Content PubMed PubMed Citation Articles by Zhang, Z.-G. Articles by Rustum, Y. M.

Effects of Diastereoisomers of 5-Formyltetrahydrofolate on Cellular Growth, Sensitivity to 5-Fluoro-2'-deoxyuridine, and Methylenetetrahydrofolate Polyglutamate Levels in HCT-8 Cells¹

Department of Experimental Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263

We investigated the biological activities of the natural and unnatural diastereoisomers of 5-formyltetrahydrofolate [(6S)- and (6R)-5-HCO-H₄PteGlu, respectively, both 99.99% pure], using a human ileocecal carcinoma cell line (HCT-8). Optimal cell growth could be supported by (6S)-5-HCO-H₄PteGlu at concentrations as low as 1 nM. (6R)-5-HCO-H₄PteGlu did not support growth. Modulation of the in vitro cytotoxicity of 5-fluoro-2'-deoxyuridine (FdUrd) and intracellular (6R)-5,10-methylenetetrahydrofolates [(6R)-CH₂H₄PteGlu_n] pools by (6S)- and (6R)-5-HCO-H₄PteGlu was determined with cells growing in 1 nM (6S)-5-HCO-H₄PteGlu. For the control cells, the concentration of FdUrd inhibiting growth by 50% was 179 nM and the total (6R)-CH₂H₄PteGlu_n was 2.3 pmol/10⁶ cells. When cells were treated with (6S)-5-HCO-H₄PteGlu for 24 h, the 50% inhibition concentration of FdUrd decreased with increasing concentrations of (6S)-5-HCO-H₄PteGlu, and reached a plateau of 36 nM when (6S)-5-HCO-H₄PteGlu was 1 µM. The total (6R)-CH₂H₄PteGlu_n pools were augmented by (6S)-5-HCO-H₄PteGlu dose dependently up to 6.8 pmol/10⁶ cells at 1 µM (6S)-5-HCO-H₄PteGlu. (6S)-5-HCO-H₄PteGlu at 10 µM did not further increase the total (6R)-CH₂H₄PteGlu_n, but induced a marked shift in the polyglutamate chain length distribution, with an increase in tri- and tetra-, and a decrease in penta-, hexa-, and heptaglutamate. The down-shift of (6R)-CH₂H₄-PteGlu_n polyglutamate chain length observed after (6S)-5-HCO-H₄PteGlu treatment did not impair the modulation of FdUrd cytotoxicity. Thus shorter chain (6R)-CH₂H₄PteGlu_n (n = 3–4) function as well as longer ones (n = 5–7). (6R)-5-HCO-H₄PteGlu, at 200 µM, had no effect on the cytotoxicity of FdUrd, the total (6R)-CH₂H₄PteGlu_n level, or chain length distribution in the presence or absence of additional (6S)-5-HCO-H₄PteGlu. These results suggest that the high plasma (6R)-5-HCO-H₄PteGlu concentrations (up to 200 µM) achieved in patients following i.v. administration of high doses of (6R,S)-5-HCO-H₄PteGlu probably do not have adverse effects on the modulation of antitumor activity of FdUrd or 5-fluorouracil. Since the optimal dose and schedule of (6S)-5-HCO-H₄PteGlu for modulation of fluoropyrimidines may vary from one cell type to another, introducing high doses of (6R,S)-5-HCO-H₄PteGlu in patients so that the plasma concentration of the natural isomer reaches 10 µM is still recommended.

¹ Supported by Program Grant CA21071 and Cancer Center Core Grant CA16056 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263.

Received 1/22/91. Accepted 4/18/91.

This article has been cited by other articles:

				J. Jolivet, A. Dayan, M. Beauchemin, D. Chahla, A. Mamo, and R. Bertrand Biochemical and Molecular Studies of Human Methenyltetrahydrofolate Synthetase Oncologist, August 1, 1996; 1(4): 248 - 253. [Abstract] [Full Text] [PDF]

				L. Chen, H. Qi, J. Korenberg, T. A. Garrow, Y.-J. Choi, and B. Shane Purification and Properties of Human Cytosolic Folylpoly-gamma -glutamate Synthetase and Organization, Localization, and Differential Splicing of Its Gene J. Biol. Chem., May 31, 1996; 271(22): 13077 - 13087. [Abstract] [Full Text] [PDF]

				J Jolivet, A Dayan, M Beauchemin, D Chahla, A Mamo, and R Bertrand Biochemical and molecular studies of human methenyltetrahydrofolate synthetase Stem Cells, January 1, 1996; 14(1): 33 - 40. [Abstract]