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Preclinical aspects and therapeutic perspectives of acute and chronic leukemias

Increasing understanding of the processes regulating cell growth, differentiation, and the process of malignant transformation as well as the identification of immunologic defense mechanisms against leukemic cells and a better knowledge of the pharmacokinetics of cytostatic drugs, provide the basis for novel therapeutic approaches being explored in preclinical investigations and early clinical trials. These approaches include antileukemic therapy at the molecular level by attempts to block the translation of central oncogenes by antisense oligonucleotides or the interference with abnormal signal transduction by modulation of key enzyme systems, eg, tyrosine kinases or protein kinase C. Reversion of the neoplastic phenotype may be obtained by transfection of tumor cells with wild-type tumor-suppressor genes or restoration of cellular differentiation, ie, by retinoic acid in acute promyelocytic leukemia. Antisense oligonucleotides may also be applied to abrogate abnormal expression of hematopoietic growth factors. Growth factors are also being used clinically to sensitize leukemic cells prior to cytostatic treatment or for a more rapid recovery of normal hematopoiesis after intensive chemotherapy. Immunologic approaches against leukemic cells are based on the identification of disease-specific markers, providing the target for antibody therapy with monoclonal antibodies coupled to immunotoxins or allowing the augmentation of cell-mediated immunity by cytokine stimulation, ie, with interleukin-2 or retroviral transfer of genes, eg, the tumor necrosis factor-α gene into effector cells. New perspectives also arise from a more detailed knowledge of cytostatic drug pharmacokinetics and the detection of metabolic differences between leukemic cells and their normal hematopoietic counterparts, allowing the design of more specific and tumor-directed drug scheduling. This review highlights some examples of recent preclinical findings that may translate into a better understanding of leukemia biology and ultimately improved therapy for these diseases.