Intratumor mapping of intracellular water lifetime: metabolic images of breast cancer?

Shutter-speed pharmacokinetic analysis of dynamic-contrast-enhanced (DCE)-MRI data allows evaluation of equilibrium inter-compartmental water interchange kinetics. The process measured here – transcytolemmal water exchange – is characterized by the mean intracellular water molecule lifetime (τ(i)). The τ(i) biomarker is a true intensive property not accessible by any formulation of the tracer pharmacokinetic paradigm, which inherently assumes it is effectively zero when applied to DCE-MRI. We present population-averaged in vivo human breast whole tumor τ(i) changes induced by therapy, along with those of other pharmacokinetic parameters. In responding patients, the DCE parameters change significantly after only one neoadjuvant chemotherapy cycle: while K(trans) (measuring mostly contrast agent (CA) extravasation) and k(ep) (CA intravasation rate constant) decrease, τ(i) increases. However, high-resolution, (1 mm)(2), parametric maps exhibit significant intratumor heterogeneity, which is lost by averaging. A typical 400 ms τ(i) value means a trans-membrane water cycling flux of 10(13) H(2)O molecules s(−1)/cell for a 12 µm diameter cell. Analyses of intratumor variations (and therapy-induced changes) of τ(i) in combination with concomitant changes of v(e) (extracellular volume fraction) indicate that the former are dominated by alterations of the equilibrium cell membrane water permeability coefficient, P(W), not of cell size. These can be interpreted in light of literature results showing that τ(i) changes are dominated by a P(W)(active) component that reciprocally reflects the membrane driving P-type ATPase ion pump turnover. For mammalian cells, this is the Na(+),K(+)-ATPase pump. These results promise the potential to discriminate metabolic and microenvironmental states of regions within tumors in vivo, and their changes with therapy.