An obvious feature of malignant cells is their failure to differentiate, and to acquire the histologic, biochemical, and functional features of the mature cells of the tissue from which they arise. Thus, leukemia cells resemble in appearance, surface markers, and molecular profile the more primitive normal progenitors of the myeloid or lymphoid series. Indeed it has been possible to isolate a small fraction of continuously self-renewing cells (called tumor stem cells) from frankly malignant tissues. These tumor cells are able to reproduce multiple differentiated cell lineages when appropriately stimulated by "differentiating" agents such as 5-azacytidine (see Chapter 1) or retinoids. The progression from mature cell phenotype to an undifferentiated malignancy is recapitulated in serial observations of chronic myelogenous leukemia and in experimental models of malignant transformation.
Research efforts have defined pathways responsible for a block in differentiation in malignant cells and have suggested strategies for pharmacologic intervention. Vitamin A and related retinoids were the first compounds to show differentiating effects in cell culture, and all-trans retinoic acid (ATRA) (Figure 9-1) was subsequently found to be highly effective in inducing remission in promyelocytic leukemia, a disease characterized by a translocation involving the retinoic acid receptor, RAR-alpha (1). Subsequently, other pathways have been exploited as targets for development of differentiating agents, including histone deacetylase (HDAC), DNA cytosine methyltransferase (CMT), and vitamin D signaling pathways. CMT is targeted by both 5-azacytidine and decitabine, as discussed in the section on antimetabolites, while HDAC inhibitors and vitamin A analogs are useful agents in peripheral T-cell lymphoma and acute promyelocytic leukemia (APL), respectively. Here we will consider four clinically useful agents that promote differentiation: ATRA and arsenic trioxide (ATO), both of which are effective in APL, and vorinostat and rhombedepsin, which are approved for treatment of cutaneous T-cell lymphoma (CTCL).
Differentiating agents useful in APL therapy. (A) All-trans retinoic acid (ATRA) and (B) arsenic trioxide.
Retinoids (vitamin A and its derivatives) induce differentiation of malignant cells in cell culture systems. Early work showed that retinoids caused promyelocytic leukemia (APL) (HL-60) cells to undergo maturation into granulocytes at drug concentrations easily achievable in humans. In normal cells, RAR-alpha forms homodimers as well as heterodimers with retinoid X receptor, and the dimer in turn complexes with the PML transcription factor. The RAR-alpha homodimer in complex with PML in turn binds ATRA, leading to chromatin modification and transcription of genes that induce differentiation (2). In APL cells, the normal pathway for vitamin A action is disrupted by a translocation fusing portions of the RAR-alpha gene on chromosome 15 and the PML gene on chromosome 17. The fusion protein acts as a repressor of differentiation and, through the FOS gene, promotes proliferation. The RAR-alpha/PML fusion protein has low affinity for ATRA and requires pharmacologic concentrations of ...