Early increases in breast tumor xenograft water mobility in response to paclitaxel therapy detected by non-invasive diffusion magnetic resonance imaging

Abstract

An important goal in cancer chemotherapy is to sensitively and quantitatively monitor the response of individual patients' tumors to successful, or unsuccessful, therapy so that regimens can be altered iteratively. Currently, tumor response is monitored by frank changes in tumor morphology, yet these markers take long to manifest and are not quantitative. Recent studies suggest that the apparent diffusion coefficient of water (ADCw), measured noninvasively with magnetic resonance imaging, is sensitively and reliably increased in response to successful CTx. In the present study, we investigate the combination chemotherapy response of human breast cancer tumor xenografts sensitive or resistant to Paclitaxel by monitoring changes in the ADCw. Our results indicate that there is a clear, substantial, and early increase in the ADCw after successful therapy in drug sensitive tumors and that there is no change in the ADCw in p-glycoprotein-positive tumors, which are resistant to Paclitaxel. The mechanism underlying these changes is unknown yet is consistent with apoptotic cell shrinkage and a concomitant increase in the extracellular water fraction.

Figure 1

Tumor volume-based response indexes to Paclitaxel for MCF7/S and MCF7/D40 tumors. In these experiments, the response indexes for the MCF7/D40 and MCF7/S tumors were calculated over a 7-day treatment regime.

Figure 2

DWI obtained from a 12-day-old tumor at different values of the diffusion-weighting factor, b. A. b = 0.027 x 10⁹ s/m², B. b = 0.249 x 10⁹ s/m², C. b = 0.442 x 10⁹ s/m². D. ADC_W map calculated from the images shown in A through C. Final ADC_W values were obtained by summing 3 ADC_W maps obtained with diffusion weighting in 3 orthogonal directions (see Materials and Methods).

Figure 3

(A,B) Effect of Paclitaxel on the distribution of ADC_W values in MCF7/S and MCF7/D40 tumors compared to untreated tumors. ADCw values were obtained 48 hours after the beginning of CTx. To allow for a direct comparison, the number of pixels in each tumor was normalized to a value of 1000 and the data averaged for each group (treated and control mice). (C,D) Effect of Paclitaxel on the growth of MCF7/S and MCF7/D40 tumors compared to untreated tumors.