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Protection by Cycloheximide against Cytotoxicity Induced by Vincristine, Colchicine, or ¹²-Prostaglandin J₂ on Human Osteosarcoma Cells¹

Department of Preventive Medicine [T. S., A. A., N. M., K. K.], Department of Biochemistry [H. N.], Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602, and Department of Internal Medicine [M. F.], Aichi Cancer Center, Chikusa-ku, Nagoya 464, Japan

We examined the protective effects of cycloheximide against cytotoxicity induced by vincristine, colchicine, ¹²-prostaglandin J₂, or other antitumor agents on the human osteosarcoma cell line, KSu. Vincristine at a concentration of 0.5 µg/ml decreased the initial cell number to 34% during 4 days; however, when cycloheximide (0.5 to 10 µg/ml) was coexistent, the decrease of the cell number was suppressed and 68% of the initial cells remained viable at the maximum. Furthermore, 0.1 µg/ml of cycloheximide also reduced cytotoxicity of colchicine (0.1 to 5 µM) or ¹²-prostaglandin J₂ (1 to 5 µg/ml) and reduced the cytotoxicity of 0.1 µg/ml of doxorubicin or 1 µg/ml of mitomycin C, suggesting that protection by cycloheximide is shown against cytotoxicity of various types of antitumor agents even on human malignant cells. Next, protein synthesis was reduced to 52% of a control at 3 h by 0.1 µg/ml of cycloheximide, suggesting that protein synthesis inhibition precedes the protection. De novo protein synthesis analysis showed that vincristine (0.5 µg/ml) does not induce any specific protein, whereas ¹²-prostaglandin J₂ (3 or 4 µg/ml) induced M_r 70,000 and 90,000 proteins, and these were markedly inhibited by cycloheximide (0.1 µg/ml). In a cell-cycle study, M-phase arrest by vincristine (0.5 µg/ml) was inhibited in the presence of 0.1 µg/ml of cycloheximide, suggesting that cell cycle arrest by cycloheximide may be important for protection. From these data, this protection by cycloheximide seems to be more general than expected before.

¹ This research was supported in part by a Grant-in-Aid for Comprehensive Ten Year Strategy for Cancer Control from the Ministry of Health and Welfare of Japan (M. F.). Presented in part at the 78th Annual Meeting of the American Association for Cancer Research, Atlanta, GA, May 1987 (1).

² Present address: Harvard Medical School, Department of Ophthalmology, c/o Thaddeus P. Dryja, M.D., Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114. To whom requests for reprints should be addressed.

Received 3/23/88. Revised 10/28/88. Accepted 11/28/88.