Serotherapy of non-Hodgkin's lymphoma (NHL) using rituximab has revolutionized the use of naked antibodies in thetreatment of cancer. Yet even with this success, there are still many questions about its mechanism of action that, if morewere known, could aid in the improvement of or the development of similar relatively non-toxic approaches for treating thisand other B-cell malignancies with rituximab or other antibodies. In this regard, we hypothesize that the anti-tumor activityof target-specific naked MAbs can be enhanced by one or more of the following means: (a) Stimulation of mononuclearcells and neutrophils using G-GSF or GM-CSF; (b) Natural killer (NK) cell activation via the concomitant use ofimmunomodulatory drugs (DvliDs); (c) Inhibition of the proteasome-ubiquitin system by PS341 (bortezimib); (d)Decreasing expression of Bcl-2 anti-apoptotic protein using antisense oligonucleotides (ASO). In addition, we hypothesizethat the acquirement of resistant to rituximab is associated with: a) common gene expression profile changes betweendifferent rituximab-resistant cell lines and on primary lymphoma cells from patients demonstrating clinical rituximabresistance;b) structural changes in CD20 structure leads to abnormalities in CD20 antigen redistribution into lipid rafts anddownstream signaling. These hypotheses serve as a basis for this project. An investigation of the mechanism of action ofrituximab will be aided in part by the development of several rituximab-resistant cell lines. This undertaking is possibleprimarily because of the cooperation and collaboration of several investigators within this Program Project, includingRoswell Park Cancer Center and at Fox Chase Cancer Center. Thus, this project is uniquely positioned to evaluate all ofthese issues with the intent to ultimately use the insights gained in this research to develop better treatment strategies that canbe tested clinically, and which could lead to important changes in the way B-cell malignancies will be treated in the future.
Showing the most recent 10 out of 43 publications
