Effect of FMdC on the cell cycle of some leukemia cell lines.

Abstract

BACKGROUND:

(E)-2'-deoxy-2'-(fluoromethylene)-cytidine (FMdC), an irreversible inhibitor of ribonucleotide reductase, displays a strong toxicity towards many cell lines derived from human solid tumors, while its activity on leukemia lines is less well-known. The aim of this study was to assess the effect of FMdC on the cell cycle and cell death of human leukemia lines HL-60 and MOLT-4, and murine leukemia L-1210 in vitro. It has been assumed that a prerequisite of FMdC cytotoxicity is intracellular phosphorylation by deoxycytidine kinase (dCK).

METHODS:

Cell cultures in the exponential phase of growth were exposed to different concentrations of FMdC (10 nM to 10 microM) for 6 and 24 hours. In a parallel set of experiments 1 mM deoxycytidine was added to prevent phosphorylation of the drug by dCK. The DNA and protein content in the cells, as well as Annexin V/PI binding were assessed by flow cytometry. The cell cycle was analyzed by the MacCycle software.

RESULTS:

The cytotoxic effects of FMdC, i.e., G(1)/S block and cell death were observed, associated with pronounced changes in the protein content. These effects were of variable intensity among the cell lines studied (HL-60 being the most susceptible), and in some cases, were not completely reversed by deoxycytidine excess.

CONCLUSIONS:

FMdC is a potent cytotoxic/cytostatic agent against human leukemia cell lines in vitro. It also changes the cellular protein content. Unphosphorylated FMdC may slightly influence the cell cycle of some leukemic lines.

• Authors: J S Skierski, M Koronkiewicz, P Grieb
• Journal: Cytometry (Cytometry) Vol. 37 Issue 4 Pg. 302-7 (Dec 01 1999) ISSN: 0196-4763 [Print] United States
• PMID: 10547615 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 1999 Wiley-Liss, Inc.

Chemical References

• Annexin A5
• Antineoplastic Agents
• DNA, Neoplasm
• Neoplasm Proteins
• Deoxycytidine
• tezacitabine

Topics

• Animals
• Annexin A5 (analysis)
• Antineoplastic Agents (metabolism, pharmacology)
• Cell Death (drug effects)
• DNA, Neoplasm (analysis)
• Deoxycytidine (analogs & derivatives, metabolism, pharmacology)
• Flow Cytometry
• G1 Phase (drug effects)
• HL-60 Cells (chemistry, cytology)
• Humans
• Leukemia, Lymphoid
• Mice
• Neoplasm Proteins (analysis)
• Phosphorylation