1H MRS‐visible lipids accumulate during apoptosis of lymphoma cells in vitro and in vivo

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Abstract
Proton MRS detection of cellular lipid accumulation has been suggested as a noninvasive method for detecting apoptosis or programmed cell death (PCD) in vivo. The spectral changes that have been observed in apoptotic cells include a general increase in lipid signals and a specific increase in the ratio of the lipid methylene‐to‐methyl peak intensities. These changes were investigated here following drug‐induced apoptosis, both in vitro with a murine lymphoma cell line (EL‐4) and in vivo following implantation of these cells to form subcutaneous tumors. Fluorescence microscopy and flow cytometric measurements with a lipophilic dye revealed an accumulation of cytoplasmic lipid droplets in isolated EL‐4 cells undergoing etoposide‐induced apoptosis. 1H MR spectra (both diffusion‐weighted (DW) and unweighted) showed an increase in lipid signals. However, the methylene/methyl peak ratio showed only minimal changes. Localized in vivo spectroscopy of EL‐4 tumors also showed an increase in lipid signals, including a signal from polyunsaturated lipid at 2.8 ppm, after 16–24 h of drug treatment. Again there was no significant change in the methylene/methyl peak ratio. This study confirms that MRS‐detectable lipids accumulate in tumor cells undergoing apoptosis, and therefore may be usable as a marker for the noninvasive detection of tumor cell apoptosis in the clinic. Magn Reson Med 54:43–50, 2005.