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Background  The combination of rituximab and 2-CdA is an effective therapy for B-cell tumors. However, the molecular mechanisms and enzymatic pathways involved in the interaction between the two agents are not fully understood. In this study, we provide molecular evidence for positive interaction between these two agents with resultant therapeutic benefit.    Methods  Efficacy of the R-2CdA regimen was evaluated in thirteen patients with B-cell tumors (9 CLL; 3 WM and 1 FL), in vitro against 3 lymphoma cell lines and in a xenograft mouse model. Treatment-induced changes involving phenotype, kinase activity and protein expression were assessed in vitro and in the mouse xenograft tumors. The interaction between RTX and 2-CdA was analyzed using the multiple comparison method, Tukey’s honestly significant difference (HSD). For the clinical and animal data, survival functions were estimated using the Kaplan-Meier method and compared by the log-rank test. P-values <0.05 were considered statistically significant. All statistical analyses were evaluated using GraphPad Prism 4 (San Diego, CA).    Results  9 of 12 (75%) evaluable patients responded to the R-2-CdA regimen with median duration of response of 34 months. Median survival of patients from diagnosis and from completion of R-2-CdA treatment was 13.3 and 7.9 years, respectively. In vitro, the combination was effective in all 3 cell lines of lymphomas but with higher sensitivity in the follicular lymphoma cell line. The combination was also effective in the WSU-WM-SCID xenograft model with dose-dependent response and synergistic benefit. All animals were tumor-free for up to 120 days post 2 cycles of this regimen. Rituximab induced activation of deoxycytidine kinase (dCK), p38 mitogen activated protein kinase (p38MAPK) and glycogen synthase kinase-3β (GSK-3β) in the xenograft WSU-WM tumors. Chemical inhibition of p38MAPK led to inhibition of the GSK-3β phosphorylation suggesting that GSK-3β is regulated by p38MAPK in this model.    Conclusion  Collectively, our studies show concordance between the activity of R-2-CdA in vitro, in human and in WSU-WM xenograft model attesting to the validity of this model in predicting clinical response. Modulation of dCK and GSK-3β by rituximab may contribute to the positive therapeutic interaction between rituximab and 2-CdA.

experimental hematology and oncology

Modulation of deoxycytidine kinase (dCK) and glycogen synthase kinase (GSK-3β) by anti-CD20 (rituximab) and 2-chlorodeoxyadenosine (2-CdA) in human lymphoid malignancies