Figure 6

Oxygen and active TH-302 distribution in simulated MiaPaCa-2 tissue extracellular space. (a) A ROI of MiaPaCa-2 xenograft tissue stained with CD-31 (i) was selected (ii) for segmentation (iii), and used as a domain for in-silico simulations of the interstitial transport of oxygen (IV). (b,c) Temporal and spatial distributions of oxygen (1st column), pyruvate (2nd column), inactive TH-302 (3rd column) and active TH-302 (4th column). The bar graphs show averaged amounts of the compound across the tissue slice. The vertical lines in oxygen bar graphs show the border between the normoxic (left) and hypoxic (right) regions of the tissue. Black dots in the active TH-302 tissue graph represent dead cells. (b) Initial distribution of oxygen before the treatment is applied. Pyruvate, inactive and active TH-302 are all absent. (c) Distributions of chemical compounds 10 min after applying TH-302. In the bottom-row simulation pyruvate was applied 30 min before TH-302 (second column) which resulted in decreased pO2 due to increased oxygen uptake by the cells exposed to pyruvate (first column), and in expanded region of TH-302 activation (last column). (d) Distributions of chemical compounds 30 min after applying TH-302. In the bottom-row simulation, pyruvate was applied 30 min before TH-302 (second column). The region of TH-302 activation in two-fold larger (yellow region in the last column), and the number of death cells is 88% larger (black dots in the last column) when compared to simulation with TH-302 only.