Changes in the noninvasive, in vivo electrical impedance of three xenografts during the necrotic cell-response sequence

Purpose: To investigate the noninvasive, in vivo use of electrical impedanc e spectroscopy (EIS) as a method for observing the real-time, cellular-leve l responses of a volume of tissue to therapies. Here, we studied the EIS re sponse during the development and progression of hyperthermia-induced coagu lative necrosis in three diverse human xenografts, Methods and Materials: A necrotic cell response sequence was selectively in duced in three types of subcutaneously-grown human tumor xenografts by appl ying hyperthermia at 44.5 degrees C. The electrical impedance of the tumors was measured from 100 Hz to 10 MHZ, noninvasively, in vivo during the trea tments. From the full spectrum EIS, ratios between resistivities at selecte d frequencies (rho-ratios) were used as indicators of the changes in the el ectrical impedance spectra of each tumor's cell population. Results: The rho-ratios consistently demonstrated characteristic, early, ra pid increases which coincided with cell and organelle swelling typical of e arly necrosis, These increases subsequently slowed, but no decrease began b efore the end of treatment, unlike previous, similarly treated, thermo-sens itive EMT6 mouse tumors. This was consistent with the xenograft histology, which revealed ubiquitous, early-stage coagulative necrosis, with no gross plasma membrane damage at the end of treatment. The extent of both the necr osis and rho-ratio changes were similar to those seen early in the EMT6 tum or treatment. Within several days after treatment, the xenograft volumes re gressed nearly completely, suggesting completion of the cell populations' n ecrotic response (lysing) during this period. Consistent with this, extende d EIS measurements over a 24-h posttreatment period allowed tracking of the necrotic response sequence through this lysing phase for one type of xenog raft, Conclusion: The change in the electrical impedance of a volume of tumor tis sue which occurs during and/or after a hyperthermia treatment can be correl ated with the extent of necrosis observed histologically in the cell popula tion. (C) 1999 Elsevier Science Inc.