Preliminary data are available about bone marrow (BM) changes in patients with chronic myeloid leukemia (CML) who received the molecularly targeted and highly effective tyrosine kinase inhibitor Imatinib mesylate (STI571). This review is focused on a systematic assessment of BM features detectable at different stages of CML (stable, accelerated, blastic) following long-term (more than 10 months) treatment. By applying enzyme- and immunohistochemistry including monoclonal antibodies visualizing proliferating cell nuclear antigen (PCNA) and apoptosis (anti-apostatin), a more elaborate insight into alterations affecting hematopoiesis and the stroma compartment was gained. In patients with stable-phase CML therapy resulted in a significant reduction in cellularity, neutrophil granulopoiesis and number of megakaryocytes, accompanied by a retrieval of erythroid precursors. In patients with Imatinib as the only treatment morphometric analysis of CD61+ megakaryopoiesis was in keeping with a significant decrease in maturation defects implying a lesser amount of atypical micromegakaryocytes almost consistent with normalization. Moreover, a reduction of the initially enhanced (CD34+) microvessel density was detectable associated with a decrease in luminal distension. Regression of marked to moderate myelofibrosis was recognizable in about 70% of patients especially in the accelerated and blastic phases. The amount of myeloblasts, CD34+ progenitor cells and lysozyme-expressing immature myelomonocytic cells declined with treatment, but recurred in about 19% of patients that developed a leukemic relapse after 21+/-6 months of therapy. Data on proliferative activity and apoptosis in general supported in vitro findings concerning the inhibitory effect of this agent on growth associated with a tendency for stimulated apoptosis, at least in responding patients.

Until now, the clinical demise of cancer has relied on surgical resection and the inhibition of tumor cell proliferation using ionizing radiation or chemotherapeutic drugs designed to perturb DNA synthesis or the mitotic event. The development of cytotoxic agents has resulted in improvements in the treatment of leukemia, lymphoma, testicular cancer, and many other solid tumor types. Hormone-based drugs have also been useful for breast and prostate cancers. Although much success has been achieved, cytotoxic modalities walk the therapeutic tightrope of toxicities to normal tissues vs cancer cells, and drug resistance is generally present de novo or develops with treatment. Over the last decade or so, more attention has been focused on different therapeutic approaches. These include the development of monoclonal antibodies (MAbs) to specifically target cancer cells, and small molecule-inhibitors of cell-signaling pathways that have been linked to oncogenesis or maintenance of the malignant phenotype. For example, the former approach has seen the development and licensing of Herceptin(R) (trastuzumab; Genentech/Roche), a humanized MAb that targets erbB2/HER2, a receptor tyrosine kinase that is overexpressed in some 30% of breast cancers and has shown promising clinical activity when used in combination with other drugs for the treatment of metastatic breast cancer. Promising small-molecule inhibitors of cell-signaling pathways include Gleevec trade mark (STI571, imitanib mesylate; Novartis) and Iressa trade mark (ZD1839, gefitinib; AstraZeneca). Gleevec is a small-molecule inhibitor (a phenylaminopyridine) of the tyrosine kinase encoded by the abl gene. In chronic myelogenous leukemia (CML), a chromosomal translocation forms the Philadelphia chromosome that expresses a bcr/abl gene resulting in the expression of a constitutively active Abl tyrosine kinase. Gleevec has shown excellent clinical activity against CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Gleevec is not uniquely selective for inhibition of Abl tyrosine kinase and has additional inhibitory activities against the c-Kit receptor tyrosine kinase and the platelet-derived growth factor receptor tyrosine kinase. Resistance to Gleevec characterized by overexpression or mutations in the bcr/abl gene is now emerging.

The statin family of drugs are well-established inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase and are used clinically in the control of hypercholesterolemia. Recent evidence, from ourselves and others, shows that statins can also trigger tumor-specific apoptosis by blocking protein geranylgeranylation. We and others have proposed that statins disrupt localization and function of geranylgeranylated proteins responsible for activating signal transduction pathways essential for the growth and/or survival of transformed cells. To explore this further, we have investigated whether the mitogen-activated protein kinase (MAPK) signaling cascades play a role in regulating statin-induced apoptosis. Cells derived from acute myelogenous leukemia (AML) are used as our model system. We show that p38 and c-Jun NH(2)-terminal kinase/stress-activated kinase MAPK pathways are not altered during lovastatin-induced apoptosis. By contrast, exposure of primary and established AML cells to statins results in significant disruption of basal extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Addition of geranylgeranyl PP(i) reverses statin-induced loss of ERK1/2 phosphorylation and apoptosis. By establishing and evaluating the inducible Raf-1:ER system in AML cells, we show that constitutive activation of the Raf/MAPK kinase (MEK)/ERK pathway significantly represses but does not completely block lovastatin-induced apoptosis. Our results strongly suggest statins trigger apoptosis by regulating several signaling pathways, including the Raf/MEK/ERK pathway. Indeed, down-regulation of the Raf/MEK/ERK pathway potentiates statin-induced apoptosis because exposure to the MEK1 inhibitor PD98059 sensitizes AML cells to low, physiologically achievable concentrations of lovastatin. Our study suggests that lovastatin, alone or in combination with a MEK1 inhibitor, may represent a new and immediately available therapeutic approach to combat tumors with activated ERK1/2, such as AML.