New therapeutic strategies for the treatment of acute lymphoblastic leukaemia

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Abstract
Steady progress in the development of protocol-based therapy has led to a cure rate of more than 80% in children and up to 40% in adults with acute lymphoblastic leukaemia (ALL). However, innovative approaches to therapy are needed to further improve the cure rates and to reduce the toxic side effects of current intensive regimens. Most of the conventional drugs used to treat leukaemia are nonspecific and work either by targeting DNA directly, inhibiting nucleic acid synthesis, blocking protein synthesis or interfering with the mitotic spindle apparatus. These, therefore, have a narrow therapeutic index. Strategies to improve delivery and therapeutic index of conventional drugs include the encapsulation of drugs into liposomes or binding drugs covalently to monomethoxy-polyethylene glycol. Newer antifolates have been designed to improve membrane support, and/or circumvent resistance due to impaired polyglutamation or inability to deplete reduced folate pools. Newer nucleoside analogues have been developed to improve bioavailability and to decrease neurotoxicity. Monoclonal antibodies, targeted towards leukaemia-associated antigens, have been administered in the unconjugated forms or conjugated to antileukaemic drugs, immunotoxins or radioactive molecules. Molecular therapeutic agents have been developed to inhibit certain key enzymes, such as tyrosine kinases, DNA methyltransferases, histone deacetylases, γ-secretase, serine and threonine kinase and proteosomes. As strategies to analyse the molecular genetic and epigenetic aberrations in cancer cells yield ever greater insights into ALL pathogenesis, one can expect an expanding repertoire of targeted therapies. This might result in an era of individualized molecular medicine and lead to more effective and less toxic regimens.