Detecting early response to cyclophosphamide treatment of RIF-1 tumors using selective multiple quantum spectroscopy...

The purpose of this study was to develop a reliable, noninvasive method for early detection of tumor response to therapy that would facilitate optimization of treatment regimens to the needs of the individual patient. In the present study, the effects of cyclophosphamide (Cp, a widely used alkylating agent) were monitored in a murine radiation induced fibrosarcoma (RIF-1) using in vivo (1)H NMR spectroscopy and imaging to evaluate the potential of these techniques towards early detection of treatment response. Steady-state lactate levels and Gd-DTPA uptake kinetics were measured using selective multiple quantum coherence (Sel-MQC) transfer spectroscopy and dynamic contrast enhanced imaging, respectively in RIF-1 tumors before, 24 and 72 h after 300 mg/kg of Cp administration. High-resolution (1)H NMR spectra of perchloric acid extracts of the tumor were correlated with lactate and glucose concentrations determined enzymatically. In vivo NMR experiments showed a decrease in steady-state lactate to water ratios (5.4 +/- 1.6 to 0.6 +/- 0.5, p < 0.05) and an increase in Gd-DTPA uptake kinetics following treatment response. The data indicate that decreases in lactate result from decreased glycolytic metabolism and an increase in tumor perfusion/permeability. Perchloric acid extracts confirmed the lower lactate levels seen in vivo in treated tumors and also indicated a higher glycerophosphocholine/phosphocholine (GPC/PC) integrated intensity ratio (1.39 +/- 0.09 vs 0.97 +/- 0.04, p < 0.01), indicative of increased membrane degradation following Cp treatment. Steady-state lactate levels provide metabolic information that correlates with changes in tumor physiology measured by Gd-DTPA uptake kinetics with high spatial and temporal resolution. Both of these parameters may be useful for monitoring early tumor response to therapy.