INDUCED-DIFFERENTIATION, THE CELL-CYCLE, AND THE TREATMENT OF CANCER

Hybrid polar compounds, of which hexamethylene bisacetamide (HMBA) is the prototype, have been shown to be potent inducers of differentiatio n of many types of transformed cells, With virus transformed murine er ythroleukemia cells as a model, HMBA was shown to cause these cells to arrest in G(1) phase and express globin genes. HMBA action involves m odulation of factors regulating G(1) to S phase progression, including a decrease in the G(1) cyclin-dependent kinase 4 accumulation of unde rphosphorylated retinoblastoma protein, and an increase in the level o f both retinoblastoma protein and the related protein, p107. In turn, p107 complexes with transcription factors such as E2F and, presumably, inhibits transcriptional activity of these factors for genes whose pr oducts are required for DNA synthesis. This provides a possible mechan ism for HMBA induced terminal cell division of transformed cells. Evid ence that hybrid polar compounds have therapeutic potential for cancer treatment is also reviewed.