Cytosine arabinoside resistance in childhood leukemia

Resistance to cytosine arabinoside (ara-C) is an important cause of treatment failure in childhood acute leukemias. Resistance is a gradual phenomenon, so its clinical appearance depends on the dose intensity and schedule of ara-C. The chemotherapeutic targets carrying the property of ara-C resistance are the leukemic stem cells. In vitro sensitivity tests, both clonogenic and nonclonogenic, correlate moderately well with clinical responses. However, prospective studies with predefined categories of resistance are still missing. Specific resistance mechanisms have been found in leukemic blast cells, covering all steps of the ara-C metabolism including decreased nucleoside transport through the plasma membrane, impaired phosphorylation by deoxycytidine kinase, increased detoxification by cytidine deaminase, short cytosine arabinoside triphosphate (ara-CTP) half-life, increased dCTP pools and altered sensitivity of DNA polymerase α. These have all been found in cells with spontaneous or artificially induced ara-C resistance. Possible countermeasures for specific resistance mechanisms include optimization of ara-C dosage (intermediate- or high-dose ara-C) and timing (i.e., time sequential therapies), modulators of ara-C cytotoxicity like fludarabine, which increases ara-CTP levels, hydroxyurea, other cytostatics, inhibitors of cytidine deaminase, and hemopoietic growth factors. The role of apoptosis for ara-C induced cytotoxicity for normal and leukemic cells has been elucidated by recent studies. DNA damage by cytosine arabinoside monophosphate incorporation into DNA can be recognized by p53 in a decision phase. This ultimately leads to an execution phase, in which typical apoptotic changes are induced by ICE-like proteinases and endonucleases. High bcl-2 levels suppress apoptosis and comprise another mechanism of resistance, which may be overcome by downregulation of bcl-2 with retinoids. In summary, despite a broad spectrum of resistance mechanisms, a number of strategies have been developed preclinically to overcome ara-C resistance and are available for clinical evaluation.