Most human acute myeloid leukaemia (AML) cells have limited proliferative capacity, suggesting that the leukaemic clone may be maintained by a rare population of stem cells. This putative leukaemic stem cell has not been characterized because the available in vitro assays can only detect progenitors with limited proliferative and replating potential. We have now identified an AML-initiating cell by transplantation into severe combined immune-deficient (SCID) mice. These cells homed to the bone marrow and proliferated extensively in response to in vivo cytokine treatment, resulting in a pattern of dissemination and leukaemic cell morphology similar to that seen in the original patients. Limiting dilution analysis showed that the frequency of these leukaemia-initiating cells in the peripheral blood of AML patients was one engraftment unit in 250,000 cells. We fractionated AML cells on the basis of cell-surface-marker expression and found that the leukaemia-initiating cells that could engraft SCID mice to produce large numbers of colony-forming progenitors were CD34+ CD38-; however, the CD34+ CD38+ and CD34- fractions contained no cells with these properties. This in vivo model replicates many aspects of human AML and defines a new leukaemia-initiating cell which is less mature than colony-forming cells.

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Proteins with tyrosine kinase activity are recognized as key regulators of cellular processes including growth and differentiation. Tyrosine kinase receptors e.g. EGFR and soluble tyrosine kinase proteins e.g. JAK-2, have emerged as essentials in cell survival for cervical carcinoma and acute myeloblastic leukemia, respectively. These receptors and soluble cytoplasm networks have been studied in detail and finally pharmacological agents, targeted at key molecules, could be produced. Tyrphostins are kinases inhibitors synthesized on the basic structure of erbstatin a natural kinase inhibitor. The JAK-2 specific inhibitor, Tyrphostin AG490 is used to inhibit phosphorylation of EGFR and signal transducer and activator of transcription 3 [STAT-3], and subsequently reduce invasion and adhesion potential of malignant cells. This review summarizes experiments providing a detailed picture of how hematopoietic cancer c-Kit+, Jak-2+ and non hematopoietic tumors c-Kit+, HER-2+, JAK-2+ can be inhibited by the chemosensitizing agent AG490 causing programmed cell death. Furthermore, studies presented herein analyzed several cellular targets that can be modified by the same death effector. The highly conserved JAK-2/STAT-3, c-Kit, and HER-2 signaling pathways play pleiotropic roles during embryonic development and are important for the regulation of self-renewing tissues. The physiological functions of these signaling cascades range from stem cell maintenance and influencing cell fate decisions of progenitor cells, to the induction of terminal differentiation processes, all of which have been found to be recapitulated in different forms of cancers. Inhibiting their action by AG490 represents a therapeutic approach for the treatment of individual types of cancer and several broad-spectrum.

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The HER family receptors have an important role controlling cell growth and differentiation. Although the activity of the HER-2 receptor is strictly controlled in normal cells, its overexpression plays a pivotal role in transformation and tumorigenesis. Constitutive phosphorylation of HER-2 protein has been implicated in conferring uncontrolled growth to mammary cancer cells, and to a lesser extent, with adenocarcinoma of uterus, cervix, fallopian tube, and endometrium. This study addresses the role of HER-2 in cervical carcinoma. Firstly, we demonstrate the presence of HER-2 protein expression by flow cytometry in two new cervical carcinoma cell lines CALO and INBL. Secondly, we use the specific tyrosine kinase inhibitors, Tyrphostins to examine HER-2 regulation by the crystal violet assay. Thirdly, we use western blot analysis to assess the state of HER-2 phosphorylation. The most efficient agent, Tyrphostin B42, known as an inhibitor of epithelial growth factor receptor, arrested cervical carcinoma cell lines growth in vitro at micromolar concentrations within 72 h of application. Tyrphostin B42 inhibited the HER2 signal-regulated kinase pathway, as observed by the reduction in the phosphorylated forms of HER2. The loss of phosphorylated forms of HER2 at early time points after Tyrphostin B42 application was associated with suppression of cell growth. Thus, the inhibition of the proliferation of our cervical carcinoma cell lines by Tyrphostin B42 is associated with inhibition of HER2 protein kinase signal.