Selective killing of transformed cells by exploitation of their defective cell cycle control by polyamines.

a potent inhibitor of the putrescine-activated S-adenosylrne thionine decarboxylase (44), can specifically block the synthe sis of spermidine and spermine both in vivo (30) and in vitro in tissue-cultured cells (11, 35). This study describes the exten sion of our original studies with normal rat fibroblasts (35) to a detailed comparison of the effects of MGBG on a normal mouse fibroblast cell line and its tumorigenic counterpart. The differ ence in response of such normal and tumor cells to treatment with MGBG can be exploited to selectively kill the tumor cell population. The selective killing of tumor cells with relative sparing of the normal cell population is the much-sought-after goal of the cancer chemotherapist. One particular class of agent used in cancer chemotherapy comprises drugs that kill proliferating cells in only a specific portion of the cell cycle, e.g. , hydrox yurea and arabinosylcytosine in S phase. However, such drugs do not differentiate between normal and tumor cells, and their use therefore results in considerable destruction of rapidly proliferating normal tissues in vivo such as the bone marrow and gut epithelium. The feasibility of selectively protecting normal cells but not tumor cells from the cytotoxic effects of such chemotherapeutic agents was first demonstrated by the studies of Pardee and James (28). These workers showed that inhibitors of protein synthesis and cyclic adenosine 3':5'-mono phosphate metabolism could arrest proliferating normal cells in the G1 phase without significantly affecting the proliferation of transformed cells. Such pretreated transformed cells could be selectively killed by subsequent treatment with drugs cyto toxic for cells in S phase or mitosis. Our studies demonstrate that another class of inhibitor, i.e. , one that interferes with the role played by polyamines, can similarly be used to selectively kill tumor cells.