The Combination of Conventional Chemotherapy with New Targeted Therapy in Hematologic Malignancies: The Safety and Efficiency of Low- Dose Cytarabine Supports its Combination with New Therapeutic Agents in Early Clinical Trials

Cytarabine (cytosine arabinoside) is commonly used in the treatment of hematologic malignancies, including both myeloid and lymphoid disorders. The cytotoxic effect of the drug depends on conversion to its triphosphate form in the targeted cells, and the intracellular levels of this active form depend on the balance between phosphorylating and dephosphorylating enzymes. The sensitivity to cytarabine-triphosphate induced cytotoxicity is in addition dependent on the balance between pro- and antiapoptotic signalling in the malignant cells, especially the balance between various members of the bcl-2 family. Even though differentiation induction has been claimed to be important in low-dose cytarabine, most clinical studies suggest that the cytotoxic affect is most important even in this therapeutic strategy. The clinical experience with the low-dose therapy is based on studies in hematological malignancies, mainly acute myeloid leukemia and myelodysplastic syndromes. These studies clearly document the clinical efficiency of low-dose therapy. However, even this low-dose strategy has a risk of severe hematological toxicity and eventually serious or fatal infections especially in elderly patients. Our understanding of the molecular mechanisms behind chemoresistance and chemosensitivity to cytarabine thereby forms the scientific basis for the design of future clinical studies where cytarabine can be combined with new targeted therapy. Low-dose cytarabine may then represent an efficient alternative with an acceptable toxicity even when combined with new anticancer agents in early clinical studies. However, the possibility of pharmacological interactions with the intracellular metabolism of cytarabine by these new agents has to be considered when combination regimens are designed.