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

The effects of methylglyoxal bis(guanylhydrazone) (MGBG) upon the proliferation of normal, nontumorigenic 3T3 fibroblasts and their SV40 virus-transformed counterparts (SV-3T3) were studied. MGBG is a potent inhibitor of the synthesis of the polyamines spermidine and spermine; in addition, it interferes with the intracellular functioning of polyamines by virtue of its being a structural analog of spermidine. Treatment of proliferating 3T3 and SV-3T3 fibroblasts with MGBG resulted in fundamentally different responses in these model normal and tumorigenic cell lines. Proliferating 3T3 cells were reversibly arrested at some point in G1 by MGBG treatment; in contrast, the proliferation of SV-3T3 cells was little affected by MGBG, such that these tumor cells continued to progress through the cell cycle at an appreciable rate. Neoplastic transformation therefore appears to be associated with the loss of a polyamine-sensitive growth regulatory or “restriction” point in G1. The loss of this control process is considered to be analogous to the loss of other growth regulatory mechanisms observed upon transformation. By pretreating proliferating cultures of 3T3 and SV-3T3 cells with MGBG and subsequently treating such cultures with hydroxyurea, a cytotoxic drug that kills cells only in the S phase of the cell cycle, a highly selective killing of the still cycling tumorigenic SV-3T3 cells was obtained. In contrast, normal 3T3 cells were protected from the cytotoxic effects of hydroxyurea by virtue of their MGBG-induced growth arrest in the insensitive G1 phase. These studies demonstrate the feasibility of selectively killing transformed cells by exploiting the biochemical basis underlying a difference in the regulation of growth between normal and transformed cells.