Correlation of ZAP-70 expression in B cell leukemias to the ex vivo response to a combination of fludarabine/genistein.
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.
Mansour
Amal
A
Department of Pathology, New Jersey Medical School, UMDNJ, Newark, NJ 07103, USA.
Chang
Victor T
VT
Srinivas
Shanti
S
Harrison
Jonathan
J
Raveche
Elizabeth
E
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D015448:Leukemia, B-Cell / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000096:biosynthesis* / Q000187:drug effects
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D016753:Interleukin-10; D019833:Genistein; D051746:ZAP-70 Protein-Tyrosine Kinase; D014740:Vidarabine; C024352:fludarabine