Myeloid growth factors

Cytokines, eg, interferons, interleukins, tumor necrosis factor (TNF), and certain growth factors, could have antitumor activity directiy, or may modulate cellular mechanisms of antitumor activity (2). Cytokines may be used to influence the proliferation and differentiation of T-ceUs, B-ceUs, macrophage—monocyte, myeloid, or other hematopoietic cells. Alternatively, the induction of interferon release may represent an important approach for synthetic—medicinal chemistry, to search for effective antiinflammatory and antifibrotic agents. Inducers of interferon release may also be useful for lepromatous leprosy and chronic granulomatous disease. The potential cytokine and cytokine-related therapeutic approaches to treatment of disease are summarized in Table 4. A combination of cytokines is a feasible modaUty for treatment of immunologically related diseases however, there are dangers inherent in such an approach, as shown by the induction of lethal disserninated intravascular coagulation in mice adrninistered TNF-a and IFN-y. 

Inhibition of hematopoietic growth factors Imatinib (Glivec ) is applied to treat chronic myeloid leukemia in Philadelphia-chromosome positive patients. In these patients, translocation of parts of chromosomes 9 and 22 results in the expression of a fusion protein with increased tyrosine kinase activity, called Bcr-Abl. Imatinib is a small Mw inhibitor selective for the tyrosine kinase activity of Bcr-Abl. Thereby, it inhibits the Bcr-Abl induced cell cycle progression and the uncontrolled proliferation of tumor cells. 

Broxmeyer HE, Cooper S, Kohli L, et al. Transgenic expression of stromal cell-derived factor-l/CXC chemokine ligand 12 enhances myeloid progenitor cell sur-vival/antiapoptosis in vitro in response to growth factor withdrawal and enhances myelopoiesis in vivo. J Immunol 2003 170(1) 421 429. 

Liu, Q., Sasaki, T., Kozieradzki, I., Wakeham, A., Itie, A., Dumont, D.J., and Penninger, J.M., 1999, SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid ceU survival. Genes Dev 13 786-791. 

The stem cell line Myl-D7 not only expresses differentiation markers of all lineages but is dependent for growth on self-renewing stem cells within the Myl-D7 clone which spontaneously differentiates along the lymphoid, myeloid, or erythroid direction (Itoh et ah, 1996). Supernatant of MS5 induces short term growth of Myl-D7 cells. This may indicate that at least soluble stem cell growth factors are secreted by MSS cells. 

Growth factor potential The possibility that epoetin alfa can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. Hypersensitivity reactions Skin rashes and urticaria are rare, mild, and transient. If an anaphylactoid reaction occurs, immediately discontinue the drug and initiate appropriate therapy. Refer to Management of Acute Hypersensitivity Reactions. Fertility Impairment In female rats treated IV with epoetin alfa, there was a trend for slightly increased fetal wastage at doses of 100 and 500 units/kg. 

Growth factor potential Darbepoetin alfa is a growth factor that primarily stimulates RBC production. The possibility that darbepoetin alfa can act as a growth factor for any tumor type, particularly myeloid malignancies, has not been evaluated. 

Interleukin-11 acts through a specific cell surface cytokine receptor to stimulate the growth of multiple lymphoid and myeloid cells. It acts synergistically with other growth factors to stimulate the growth of primitive megakaryocytic progenitors and, most importantly, increases the number of peripheral platelets and neutrophils. 

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