In vivo MRS markers of response to CHOP chemotherapy in the WSU-DLCL2 human diffuse large B-cell lymphoma xenograft

To identify 1H-MRS molecular biomarkers of early clinical therapeutic response in non-Hodgkin's lymphoma, an in vivo longitudinal study was performed on human non-Hodgkin's diffuse large B-cell lymphoma xenografts (WSU-DLCL2) grown in the flanks of female SCID mice. 31P-MRS measurements, which have been demonstrated to be prognostic clinical indices of response (Arias-Mendoza et al. Acad. Radiol. 2004; 11: 368-376) but which provide lower spatial resolution, were included for comparison. The animals received CHOP (cyclophosphamide, hydroxydoxorubicin, oncovin and prednisone) chemotherapy for three 1-week cycles, resulting in stable disease based on tumor volume. Localization of total choline and phosphorus metabolites in vivo was achieved with stimulated echo acquisition mode and image selected in vivo spectroscopy sequences, respectively. Significant decreases in lactate were detected by the selective multiple quantum coherence spectral editing technique after the first cycle of CHOP, whereas total choline and the phosphomonoester/nucleoside triphosphate ratio did not change until the third cycle. Ex vivo extract MRS of tumors corroborated the in vivo results. Histological staining with antibodies to Ki67 revealed a decrease in proliferation rate in CHOP-treated tumors that coincided with the decrease in lactate. This study demonstrates the utility of lactate as an early proliferation-sensitive indicator of therapeutic response in a mouse model of non-Hodgkin's lymphoma and serves as a basis for future clinical implementation of these methods.