1. The incorporation of differentiation induction into the design of cancer therapy

Initiation of maximal tumor cell reduction necessitates the use of high-dose conventional cytotoxic agents that cause lethal antiproliferative death of tumor cells. These agents will also cause nonlethal growth arrest in some tumor cells (dependent on the stage of the cell cycle), which may result in differentiation induction with or without terminal cell division, terminal cell division without differentiation, or proliferation without differentiation. These biologic effects of high-dose cytotoxic agents may be amplified by using lower (noncytotoxic) concentrations of the same or similar type agents in combination with agents designed to induce differentiation. This combination of differentiation therapy is given at optimal synergistic levels scheduled in between high-dose cytotoxic therapy at a time when ordinarily, treatment is not administered. One goal of this treatment is to commit a population of tumor cells to terminal cell division. For example, the combination of cytotoxic agents (mitomycin, radiation) to disturb DNA synthesis with a chemical differentiation inducer (HMBA) is synergistic for the induction of differentiation and terminal cell division of some leukemia cells. The work of Oishi and co-workers, who have identified two cytoplasmic differentiation factors, provides the biochemical basis for this observation.