Figure 3

The sawtooth pattern of β5 inhibition in vivo and its relationship to the kinetics of cancer cell death. (A) A patient dosed with bortezomib at the beginning of day 1 experiences approximately 65% inhibition of β5 activity (shown as a red trace) in whole blood lysate. β5 activity recovers, and the patient is dosed again on day 4. (B) Zoom-in of (A) to emphasize β5’s pharmacodynamic response to a single dose. In this and the following examples, it is assumed that the kinetics of cancer cell death are a function of cell type and percentage inhibition. The example shown assumes that MM cells commit to cell death within a few hours when the proteasome is inhibited by more than 60% (>60% I), as signified by the time interval denoted by the light gray bar. On the other hand, solid tumor cells require much longer exposure (dark gray bar) to effect cell death at 60% inhibition. (C) Same as (B), except that a greater percentage inhibition of the proteasome is achieved. Even though the rate of recovery is the same as (B), it is suggested that solid tumor cells remain in the `kill zone’ below the dotted line sufficiently long to commit to apoptosis. Note that even though the time required for killing solid tumors (dark gray bar) is drawn the same as in (B), a greater percentage inhibition could reduce the time required to commit to apoptosis. (D) Same as (B), except the recovery curve has a shallower slope due to inhibition of new proteasome synthesis. In this hypothetical example, reducing the rate of recovery maintains proteasome inhibition in the `kill zone’ for a sufficiently long time to kill solid tumor cells.