Many cancers arise in a tissue stem cell, and cell differentiation is impaired resulting in an accumulation of immature cells. The introduction of all-trans retinoic acid (ATRA) in 1987 to treat acute promyelocytic leukemia (APL), a rare subtype of acute myeloid leukemia (AML), pioneered a new approach to obtain remission in malignancies by restoring the terminal maturation of leukemia cells resulting in these cells having a limited lifespan. Differentiation therapy also offers the prospect of a less aggressive treatment by virtue of attenuated growth of leukemia cells coupled to limited damage to normal cells. The success of ATRA in differentiation therapy of APL is well known. However, ATRA does not work in non-APL AML. Here we examine some of the molecular pathways towards new retinoid-based differentiation therapy of non-APL AML. Prospects include modulation of the epigenetic status of ATRA-insensitive AML cells, agents that influence intracellular signalling events that are provoked by ATRA, and the use of novel synthetic retinoids. 1. Introduction There is an increasing need to devise milder treatments for older patients with cancer. The proportion of older people in the population is steadily increasing, and 23% of the UK population is projected to be aged ≥65 by 2034, with 5% aged ≥85 [1]. More than half of cancer patients are aged ≥65 years, and around 40% of older persons will be diagnosed with some form of cancer. Treatment of these patients poses a real challenge to the health care service, more so as the population as whole ages. For older persons, an immediate resort to eradicating cancer via aggressive chemotherapy is neither well tolerated nor necessary. Differentiation therapy to reduce tumour load followed by milder chemotherapy provides an alternative approach. It is also important to bear in mind that many patients aged ≥65 years are excluded from aggressive trials, by coexisting age-related conditions, for example, declining bone marrow [2, 3] and hepatic function [4]. Trials of new combinations of drugs in leukemia include only younger patients able to tolerate multidrug chemotherapy. For patients in their 80s with malignancies, differentiation therapy that might merely aim to control disease for the patient’s natural lifespan is perhaps a more realistic target. AML, which accounts for ~80% of adult acute leukemias [5], involves the proliferation, abnormal survival, and arrest of cells at a very early stage of myeloid cell differentiation. Alongside this expansion of leukemia cells, the production of normal red cells, platelets,
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