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Effects of N-Methylformamide on the Growth, Cell Cycle, and Glutathione Status of Murine TLX5 Lymphoma Cells¹

Cancer Research Campaign Experimental Chemotherapy Group, Pharmaceutical Sciences Institute, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom

The growth of the murine TLX5 lymphoma is inhibited in vivo by administration of N-methylformamide (Gescher, A., et al., Br. J. Cancer, 45: 843–850, 1982). Continuous incubation of TLX5 murine lymphoma cells in vitro with N-methylformamide for 72 h, at concentrations of between 43 and 170 mM (0.25 and 1% v/v), brought about a concentration-dependent decrease in growth rate (50% inhibitory concentration = 68 mM) and viability. Cell replication was decreased by 37% after 48 h exposure to 106 mM N-methylformamide, while viability was maintained at 82%. Analysis of the distribution of these cells in the cell cycle by flow cytofluorimetry showed a 23% increase in the proportion of G₁ cells and a fall in the proportion of cells in the S and G₂/M phases. As the drug concentration and time of exposure to N-methylformamide were increased, with an associated reduction in cell replication and viability, the proportion of G₁ cells rose. When TLX5 cells were washed free of N-methylformamide after an exposure to 106 mM for 48 h and cultured in drug-free medium, the cells returned to exponential growth and to a normal cell cycle distribution. Clonogenic assays showed that the recovery of proliferation, after removal of the drug, was due to that of all those cells which, in a parallel experiment, excluded the dye trypan blue. It is concluded that the cessation of replication and the accumulation of cells in G₁ of the cell cycle, after treatment with N-methylformamide, are probably not events representative of terminal differentiation but rather of cytostasis, which was accompanied by rapid cell death. Coincident with the reduction of TLX5 cell proliferation caused by N-methylformamide and the accumulation of cells in G₁, cellular glutathione concentrations fell by 80%. A similar fall was induced by treatment of the cells with D,L-buthionine[S,R]-sulfoximine (5 µM) for 48 h, but this treatment had no effect on cell growth.

¹ Supported by Grant SP 1518 from the Cancer Research Campaign.

² Recipient of a graduate studentship.

³ To whom requests for reprints should be addressed.

Received 12/10/86. Revised 5/ 4/87. Revised 10/26/87. Revised 2/29/88. Accepted 3/16/88.

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