Abstract
Xenograft tumor models are widely studied in cancer research. Our aim was to establish and apply a model for aggressive CD20-positive B-cell non-Hodgkin lymphomas, enabling us to monitor tumor growth and shrinkage in a noninvasive manner. By stably transfecting a luciferase expression vector, we created two bioluminescent human non-Hodgkin lymphoma cell lines, Jeko1(luci) and OCI-Ly3(luci), that are CD20 positive, a prerequisite to studying rituximab, a chimeric anti-CD20 antibody. To investigate the therapy response in vivo, we established a disseminated xenograft tumor model injecting these cell lines in NOD/SCID mice. We observed a close correlation of bioluminescence intensity and tumor burden, allowing us to monitor therapy response in the living animal. Cyclophosphamide reduced tumor burden in mice injected with either cell line in a dose-dependent manner. Rituximab alone was effective in OCI-Ly3(luci)-injected mice and acted additively in combination with cyclophosphamide. In contrast, it improved the therapeutic outcome of Jeko1(luci)-injected mice only in combination with cyclophosphamide. We conclude that well-established bioluminescence imaging is a valuable tool in disseminated xenograft tumor models. Our model can be translated to other cell lines and used to examine new therapeutic agents and schedules.
Highlights
N ON-HODGKIN LYMPHOMAS (NHLs) are one of the most common hematologic malignancies and represent approximately 3 to 4% of all cancer cases.[1]
Recent clinical trials revealed that combinations of a conventional cytotoxic chemotherapy regimen and rituximab (Rx) immunotherapy resulted in considerable improvement in therapy outcomes for CD20+ B-cell lymphoma.[2,3]
In additional in vitro experiments, we found that the original cell lines Jeko[1] and OCI-Ly3 have different proliferation characteristics after the addition of 4-hydroperoxycyclophosphamide (Figure S1, online version only)
Summary
N ON-HODGKIN LYMPHOMAS (NHLs) are one of the most common hematologic malignancies and represent approximately 3 to 4% of all cancer cases.[1]. The surface marker CD20 is an excellent target for antibody therapy because there is no significant antibody shedding or internalization of CD20 after binding to the specific antibody.[5] The discussed mechanisms of action are antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), cell cycle arrest, apoptosis,[6] and the potential of Rx to sensitize cells to further chemo- and immunotherapy.[7] It is of note that Rx can sensitize chemoresistant tumor cells to chemotherapy through inhibition of p38 mitogen-activated protein kinase, nuclear factor kB, extracellular signal–regulated kinase 1/2, and AKT antiapoptotic survival pathways This results in downregulation of antiapoptotic gene products such as Bcl-2, Bcl-xL, and Mcl-1. One can expect that insights from chemo- and immunotherapy of this model can be better translated to the human situation compared to models based on subcutaneous tumors
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