In vivo monitoring response to chemotherapy of human diffuse large B-cell lymphoma xenografts in SCID mice by 1H and 31P MRS

Abstract

Rationale and objectives: A reliable noninvasive method for in vivo detection of early therapeutic response of non-Hodgkin's lymphoma (NHL) patients would be of great clinical value. This study evaluates the feasibility of (1)H and (31)P magnetic resonance spectroscopy (MRS) for in vivo detection of response to combination chemotherapy of human diffuse large B-cell lymphoma (DLCL2) xenografts in severe combined immunodeficient (SCID) mice.

Materials and methods: Combination chemotherapy with cyclophosphamide, hydroxy doxorubicin, Oncovin, prednisone, and bryostatin 1 (CHOPB) was administered to tumor-bearing SCID mice weekly for up to four cycles. Spectroscopic studies were performed before the initiation of treatment and after each cycle of the CHOPB. Proton MRS for detection of lactate and total choline was performed using a selective multiple-quantum-coherence-transfer (Sel-MQC) and a spin-echo-enhanced Sel-MQC (SEE-Sel-MQC) pulse sequence, respectively. Phosphorus-31 MRS using a nonlocalized, single-pulse sequence without proton decoupling was also performed on these animals.

Results: Significant decreases in lactate and total choline were detected in the DLCL2 tumors after one cycle of CHOPB chemotherapy. The ratio of phosphomonoesters to beta-nucleoside triphosphate (PME/betaNTP, measured by (31)P MRS) significantly decreased in the CHOPB-treated tumors after two cycles of CHOPB. The control tumors did not exhibit any significant changes in either of these metabolites.

Conclusions: This study demonstrates that (1)H and (31)P MRS can detect in vivo therapeutic response of NHL tumors and that lactate and choline offer a number of advantages over PMEs as markers of early therapeutic response.

Figure 1

Time dependence of DLCL2 tumor volume of the control tumors (dashed line) and CHOPB treated tumors (solid line).

Figure 2

(a) Representative 1H MR spectra of total choline and lactate of the CHOPB treated tumors before the treatment, and after three cycles of CHOPB using the SEE-Sel-MQC sequence. (b) Time course of MR signal intensity of total choline (normalized to water signal then to the first data) in the control tumors (dashed line) and CHOPB treated tumors (solid line).

Figure 3

(a) Representative in vivo lactate-edited 1H MR spectra of the CHOPB treated tumors before treatment, after two cycles of CHOPB using the Sel-MQC pulse sequence. (b) Time course of MR signal intensity of lactate (normalized to water signal then to the first data) in the control tumors (dashed line) and CHOPB treated tumors (solid line).

Figure 4

(a) Representative in vivo ³¹P MR spectra of the CHOPB treated tumors before treatment, and after three cycles of CHOPB using non-decoupled one-pulse sequence. (b) Time courses of PME/βNTP of the control tumors (dashed line) and CHOPB treated tumors (solid line).

Figure 5

Plots of the volumes of the CHOPB treated tumors compared with the MR signal ratio of lactate/water (top), total choline/water (middle) and PME/βNTP (bottom) of the tumors. Each plot displays a correlation line between the tumor volume and the MR signal intensity ratio of lactate/water, total choline/water and PME/βNTP. The square of correlation coefficients (R²) is displayed in each legend.