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Noninvasive Real-Time Monitoring of Intracellular Cancer Cell Metabolism and Response to Lonidamine Treatment Using Diffusion Weighted Proton Magnetic Resonance Spectroscopy¹

Advanced Technology Center, Sheba Medical Center, Tel Hashomer 52621, Israel [Y. M., Y. R., J. S. C.]; The Hebrew University, Jerusalem 91120, Israel [M. S., I. R.]; Complutense University, Madrid 28040, Spain [J. R-C.]; Tufts University, Boston, Massachusetts 02111 [E. A.]; and Tel-Aviv Medical Center, Tel-Aviv 64239, Israel [O. K.]

We have used diffusion-weighted proton magnetic resonance spectroscopy (DWMRS) to noninvasively selectively observe only the intracellular metabolites of breast cancer and melanoma cell lines in vitro in real time. Breast cancer cell lines representing different stages in breast cancer progression were chosen for study. Intracellular biochemical profiles of six cell lines perfused in alginate beads were obtained. Spectral differences between groups of cell lines, including choline, lactate, and threonine peaks, were investigated. We also monitored response to the antineoplastic agent, lonidamine (LND), as a function of time and drug concentration in perfused cancer cells. Previous studies reported that this drug induced intracellular acidification and lactate accumulation. Diffusion weighted proton spectra demonstrated a 2- to 9-fold increase in the intracellular lactate signal as a response to LND treatment in several cancer cell lines. These results are consistent with the hypothesis that the principal mechanism of LND in some cancer cells is marked inhibition of lactate transport. Moreover, we have shown that there is a factor of two to three between the response of melanoma cells and that of some types of breast cancer cells. The higher sensitivity of the melanoma cells, as predicted by proton DWMRS, was correlated with changes in water-suppressed magnetic resonance spectra and confirmed by a biological assay. This study demonstrates the feasibility of using DWMRS for monitoring intracellular metabolism and for studying the effects and mechanisms of action of anticancer drugs. We believe that this method can be used for noninvasive clinical applications, such as the differentiation between benign and malignant tissue, real-time monitoring of response to therapy, dose response, and toxicity effects.

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