Correlation of ZAP-70 expression in B cell leukemias to the ex vivo response to a combination of fludarabine/genistein.
Cancer Immunol Immunother. 2007 Apr;56(4):501-14. Epub 2006 Oct 19. PMID: 17051411
The role of ZAP-70 expression on the ex vivo response of blood cells from CLL and PLL patients to a combination of fludarabine, a purine analog, and genistein, a tyrosine kinase inhibitor was studied. Patient cells were studied for the expression of ZAP-70 mRNA and its relation to the induction of apoptosis in response to treatment with genistein 15-60 muM and/or fludarabine 3 muM. The combination of genistein and fludarabine resulted in a significantly increased induction of apoptosis relative to the fludarabine alone. The ex vivo patient cells with a high ZAP-70 expression underwent more apoptosis in response to genistein than did patient cells with a low ZAP-70 mRNA expression. In contrast, basal IL-10 mRNA expression correlated negatively with apoptosis induction in response to genistein (P<0.01). These studies suggest that, in malignant B cells that express elevated levels of the ZAP-70 signaling molecule, genistein may inhibit the ZAP-70 tyrosine kinase activity, resulting in cell death. The ZAP-70 may serve as a target for therapy. In addition, these studies suggest that the IL-10 expression by malignant B cells may not only suppress anti-tumor T cell responses in vivo, but also promote the survival of malignant B cells despite treatment with chemotherapeutic agents.