CellBiologylnternationalReports, Vol. 5, No. 10, October 7981 991 SELECTIVE KILLING OF TRANSFORMED CELLS IN COMBINATION WITH INHIBITORS OF POLYAMINR BIOSYNTRESIS AND S-PHASE SPECIFIC DRUGS %rasad S. Sunkara, lSusan K. Fowler and 2Kenji Nishioka Departments of lDevelopmenta1 Therapeutics and 'Surgery The University of Texas System Cancer Center M.D. Anderson Hospital and Tumor Institute Houston, Texas 77030 SUMMARY: The objective of this study was to examine the effect of inhibition of polyamine biosynthesis on the cell cycle traverse of normal and transformed cells using a-difluoromethyl ornithine (DFMO), a catalytic Irreversible inhibitor of ornithine decar- boxylase. The results of this study indicate that DFMO brings about a significant decrease in the intracellular levels of putrescine and spermidine followed by an inhibition of cell growth in both the normal and transformed cells. The DFMO treatment re- sults in a differential effect on the cell cycle traverse of nor- 9~1 and transformed cells. A majority of the normal cells were arrested in Gl phase whereas their transformed counterparts were found to be accumulated in S phase of the cell cycle. Further, treatment of both types of cells with an S phase specific drug like Ara-C after polyamine depletion with DPMO resulted in a preferential synergistic killing of the transformed cells while the normal cells were protected from the cytotoxicity of Ara-C. These observations suggest the use of inhibitors like DPMO might help in designing better therapeutic regimens in combination with other cytotoxic drugs. INTRODUCTION The naturally occurring polyamlnes, putrescine, spermidine and spermine seem to play an important role in the proliferation of mammalian cells (1). With the availability of specific inhibi- tors of polyamine biosynthesis, it has been possible to demon- strate that polyamines play important roles in the regulation of * Present and correspondence address: Merrell Research Center Merrell Dow Pharmaceuticals Inc. 2110 East Galbraith Road Cincinnati, Ohio 45215 030%1651/61/100661-06/$02.00/0 @ 1661 Academic Press Inc. (London) Ltd.