Mardor Y, Kaplan O, Sterin M, Ruiz-Cabello J, Ash E, Roth Y, Ringel I, Cohen J S
Advanced Technology Center, Sheba Medical Center, Tel Hashomer, Israel.
Cancer Res. 2000 Sep 15;60(18):5179-86.
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.
我们已使用扩散加权质子磁共振波谱法（DWMRS）在体外实时非侵入性地选择性观察乳腺癌和黑色素瘤细胞系的细胞内代谢物。选择代表乳腺癌进展不同阶段的乳腺癌细胞系进行研究。获得了在藻酸盐珠中灌注的六种细胞系的细胞内生化图谱。研究了细胞系组之间的光谱差异，包括胆碱、乳酸和苏氨酸峰。我们还监测了灌注癌细胞中抗肿瘤药物氯尼达明（LND）的反应随时间和药物浓度的变化。先前的研究报道，这种药物会诱导细胞内酸化和乳酸积累。扩散加权质子谱显示，在几种癌细胞系中，作为对LND治疗的反应，细胞内乳酸信号增加了2至9倍。这些结果与以下假设一致，即LND在某些癌细胞中的主要机制是显著抑制乳酸转运。此外，我们已经表明，黑色素瘤细胞与某些类型的乳腺癌细胞的反应之间存在两到三倍的差异。如质子DWMRS所预测的，黑色素瘤细胞的更高敏感性与水抑制磁共振谱的变化相关，并通过生物学测定得到证实。这项研究证明了使用DWMRS监测细胞内代谢以及研究抗癌药物的作用效果和作用机制的可行性。我们相信，这种方法可用于非侵入性临床应用，如良性和恶性组织的鉴别、治疗反应的实时监测、剂量反应和毒性作用。
