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Effects of 1,3-Bis(2-chloroethyl)-1-nitrosourea and Some Chemically Related Compounds upon the Progression of Cultured H.Ep. No. 2 Cells through the Cell Cycle¹

Kettering-Meyer Laboratory,² Southern Research Institute, Birmingham, Alabama 35205

The Colcemid block method with some modifications has been used to determine the effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and some chemically related compounds upon the progression of cultured H.Ep. No. 2 cells through the cell cycle. The results and conclusions were as follows.

Survival of cells of glass-attached cultures following exposure to BCNU was dependent upon the duration of exposure to the agent; the rate of killing was approximately first order.

The progression to metaphase of cells initially in the last half of G₂ when exposed to BCNU at a concentration of 25 µg/ml was not inhibited, but the progression to metaphase of cells initially in the first part of G₂, in S, and in G₁ was delayed or prevented. The labeling of cells initially in S at the time of exposure to BCNU was partially inhibited, and the progression into S of cells initially in the first half of G₁ was inhibited or delayed.

Following extended exposure to BCNU, there were slightly more large cells in treated cultures than in control cultures.

A large portion of the effects of BCNU upon progression of the cells through the cycle was probably due to the effects of 2-chloroethylamine, which was derived from the BCNU. However, the 2-chloroethyl-1-nitroso portion of the BCNU also contributed to these effects.

There is a good correlation between the magnitudes of the effects upon progression through the cell cycle and upon the toxicities of BCNU and compounds chemically related to it. Although the effects of these compounds upon the progression of H.Ep. No. 2 cells through the cycle might be more closely related to the toxicity for these cultured cells than to the in vivo antitumor activity, consideration of several kinds of data makes it appear likely that similar effects upon progression through the cycle contribute to the anticancer activities.

¹ This investigation was supported by Contract PH43-66-29, Chemotherapy, National Cancer Institute, NIH, and by grants from the Charles F. Kettering Foundation and the Alfred P. Sloan Foundation, Inc.

² Affiliated with the Sloan-Kettering Institute for Cancer Research, New York, N. Y.

Received 11/10/69. Accepted 2/25/70.