Differentiation therapy

An approach to the treatment of advanced or aggressive malignancies in which the malignant cells are treated so that they can resume the process of maturation and differentiation into mature cells. Differentiation therapy is based on the concept that cancer cells are normal cells that have been arrested at an immature or less differentiated state, lack the ability to control their own growth, and so multiply at an abnormally fast rate. Differentiation therapy aims to force the cancer cell to resume the process of maturation. Although differentiation therapy does not destroy the cancer cells, it restrains their growth and allows the application of more conventional therapies (such as chemotherapy) to eradicate the malignant cells. Differentiation agents tend to have less toxicity than conventional cancer treatments. The first differentiation agent found to be successful was all-trans-retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL). APL is the result of a translocation (an exchange of chromosome material) between chromosomes 15 and 17. There are two chromosome breaks: one in chromosome 15 and the other in chromosome 17. The break in chromosome 15 disrupts the promyelocytic leukemia (PML) gene which encodes a growth suppressing transcription factor. And the break in chromosome 17 interrupts the retinoic acid receptor alpha (RARa) gene which regulates myeloid differentiation. The translocation creates a PML/RARa fusion gene. It produces a chimeric protein that causes an arrest of maturation in myeloid cell maturation at the promyelocytic stage. (It reduces terminal cell differentiation.) And this causes the increased proliferation of promyelocytes. Most APL patients are now treated first with all-trans-retinoic acid (ATRA). It causes the promyeloctes to differentiate (to mature) and so deters them from proliferating. ATRA induces a complete remission in about 70% of cases. ATRA is the prototype of a differentiation therapy agent.