In vivo¹H MRS of WSU‐DLCL2 human non‐Hodgkin's lymphoma xenografts: response to rituximab and rituximab plus CHOP

Abstract

In order to identify early (1)H MRS metabolic markers of response to rituximab immunotherapy and to rituximab plus CHOP (cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone) combination therapy, we performed an in vivo MRS investigation of a non-Hodgkin's lymphoma (NHL) xenograft model. Human WSU-DLCL2 NHL cells were subcutaneously implanted into flanks of female severe combined immunodeficient mice. When tumor volumes reached approximately 600 mm(3), rituximab was administered for three weekly cycles at a dose of 25 mg/kg per cycle with or without CHOP. Before and after treatment, tumor lactate (Lac) and total choline (tCho) were detected using the selective multiple quantum coherence sequence and the stimulated echo acquisition mode sequence, respectively. Rituximab produced a small tumor growth delay ( approximately 5 days), whereas treatment with rituximab plus CHOP (RCHOP) led to approximately 20% tumor regression after three cycles of therapy. After one cycle of rituximab, the tCho/H(2)O ratio had decreased significantly (5%, P = 0.003), whereas the Lac/H(2)O ratio had not changed (P = 0.58). Both Lac/H(2)O and tCho/H(2)O had decreased after one cycle of RCHOP treatment (26%, P = 0.001; 10%, P = 0.016, respectively). After two cycles of RCHOP, Ki67 assay of histological tumor specimens indicated approximately 40% decrease in proliferation (P < 0.001) in the RCHOP-treated tumors; no change was detected after treatment with rituximab alone. This study suggests that decreases in tCho/H(2)O are more sensitive indices of response to rituximab, whereas decreases in Lac/H(2)O are more sensitive to response to CHOP combination therapy.

Magnetic Resonance Spectroscopy for Detection of Choline Kinase Inhibition in the Treatment of Brain Tumors

“…Increased fatty acyl chain resonances in MR-visible lipids have been correlated with malignancy and necrosis in human brain tumors (33-35) and an increase in polyunsaturated fatty acids (PUFA) (36, 37), along with a decrease in lactate (38, 39), is typically observed in tumors after treatment. We observed an increase in the 1.3 ppm resonance in both untreated and treated tumors compared to baseline but increased PUFA resonance at 2.8 ppm was observed only in treated tumors.…”

Changes in 2-fluoro-2-deoxy-d-glucose incorporation, hexokinase activity and lactate production by breast cancer cells responding to treatment with the anti-HER-2 antibody trastuzumab

“…The product of glycolysis, pyruvate, can either be converted to acetyl-CoA and enter the tricarboxylic acid cycle or be converted to lactic acid. Lactate levels in * * * tumors can be monitored using 1 H NMR imaging, and studies have shown using this technique that response to therapy can be accompanied by decreased levels of lactic acid [27]. Thus, Lee et al [27] showed that response to treatment of xenografts derived from WSU-DLCL2 nonHodgkin's lymphoma cells with a combination of rituximab, cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone exhibited decreased lactate levels.…”

“…Lactate levels in * * * tumors can be monitored using 1 H NMR imaging, and studies have shown using this technique that response to therapy can be accompanied by decreased levels of lactic acid [27]. Thus, Lee et al [27] showed that response to treatment of xenografts derived from WSU-DLCL2 nonHodgkin's lymphoma cells with a combination of rituximab, cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone exhibited decreased lactate levels. On the other hand, the use of hyperpolarized 13 C-labeled pyruvate utilization [28] has shown decreased flux of the hyperpolarized 13 C label between pyruvate and lactate, corresponding with decreased FDG uptake by murine lymphoma cells after treatment for 24 h with the topoisomerase II inhibitor, etoposide.…”

Predicting tumour response to anti-HER1 therapy using medical imaging: a literature review andin vitrostudy of [18F]-FDG incorporation by breast cancer cells responding to cetuximab

“…49 Decreased lactate levels in tumours during therapy, compared with pretreatment levels, have been shown to be a useful indicator of response to therapy. 50 However, treatment of MDA-MB-468 cells with cetuximab, which was associated with decreased FDG incorporation, did not result in decreased lactate production, which suggests that monitoring tumour lactate levels is not useful for predicting response to cetuximab. As pyruvate production from glucose via glycolysis is not the only source of lactate in tumour cells, the absence of a correlation between lactate production and FDG utilisation is not unexpected.…”

“…The IC 50 dose for MDA-MB-468 cells and the IC 10 (maximum achievable inhibition) doses for MDA-MB-543 and SKBr3 treated with cetuximab for six days were 2.6, 5 and 148 µg/mL, respectively. Incorporation of FDG by SKBr3 and MDA-MB-453 cells was found to be decreased by MDA-MB468 cells using IC 50 and IC 20 doses of cetuximab for six days. Lactate production was found to be increased by MDA-MB-468 cells responding to cetuximab.…”