Noninvasive real-time monitoring of intracellular cancer cell metabolism and response to lonidamine treatment using diffusion weighted proton magnetic resonance spectroscopy

We have used diffusion-weighted proton magnetic resonance spectroscopy (DWM RS) to noninvasively selectively observe only the intracellular metabolites of breast cancer and melanoma cell lines irt vitro in real time. Breast ca ncer 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 gro ups of cell lines, including choline, lactate, and threonine peaks, were in vestigated, We also monitored response to the antineoplastic agent, lonidam ine (LND), as a function of time and drug concentration in perfused cancer cells. Previous studies reported that this drug induced intracellular acidi fication and lactate accumulation. Diffusion weighted proton spectra demons trated a 2- to 9-fold increase in the intracellular lactate signal as a res ponse to LND treatment in several cancer cell lines. These results are cons istent,vith the hypothesis that the principal mechanism of LM) in some canc er 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 ce lls and that of some types of breast cancer cells. The higher sensitivity o f the melanoma cells, as predicted by proton DWMRS, was correlated with cha nges in water-suppressed magnetic resonance spectra and confirmed by a biol ogical assay. This study demonstrates the feasibility of using DWMRS for mo nitoring intracellular metabolism and for studying the effects and mechanis ms of action of anticancer drugs, We believe that this method can be used f or noninvasive clinical applications, such as the differentiation between b enign and malignant tissue, real-time monitoring of response to therapy, do se response, and toxicity effects.