Effects of methylacetylenic putrescine, an ornithine decarboxylase inhibitor and potential novel anticancer agent, on human and mouse cancer cell lines

Sensitivity of several human and mouse cancer cell lines to methylacetyleni c putrescine (MAP) was evaluated using clonogenic, sulforhodamine B and cel l counting assays. The effects of MAP on cell morphology, cell cycle phase distribution and changes in polyamine metabolism of xenografted MCF-7 and M DA-MB-231 human mammary tumor cells were also investigated. On the basis of IC50 values, BHT-101 human thyroid carcinoma cells were the most sensitive (9 mu/ml), followed by P388 mouse lymphoma (32 mu g/ml), MCF-7 (48 mu g/ml ) and MDA-MB-231 (110 mu g/ml) human breast carcinoma cell lines. MAP treat ment led to accumulation of P388 cells in G(1) phase. At higher doses, the cytoplasm of the cells became vacuolated followed by apoptosis. The foamy c ytoplasm may suggest a rare type of cell death (Clarke III type) called non -apoptotic programmed cell death. MAP treatment resulted in a total inhibit ion of ornithine decarboxylase (ODC) activity with a concomitant decrease o f intracellular polyamine (mostly putrescine and spermidine) content in the breast cancer cells, whilst the spermine concentration was shown to increa se. MAP proved at least 10 times more potent than the formerly studied DL-a lpha-difluoromethylornithine making it an attractive candidate for clinical testing. [(C) 1999 Lippincott Williams & Wilkins.]