Interstitial fluid pressure (IFP) is elevated in
tumors due to abnormal vasculature, lack of lymphatic drainage, and alterations in the
tumor interstitium.
ZD6126 is a
tubulin-binding agent that selectively disrupts
tumor vasculature resulting in
tumor necrosis. This study examined the effect of
ZD6126 on
tumor IFP and the response of
tumors with different IFP levels to
ZD6126. Pretreatment IFP was measured using the wick-in-needle method in
tumors (murine KHT-C and human CaSki) growing i.m. in the hind legs of mice. Mice were treated i.p. with a single dose of
ZD6126 (100 or 200 mg/kg) and posttreatment IFP measurements were made. Blood flow imaging was conducted using Doppler optical coherence tomography, whereas
oxygen partial pressure was measured using a fiber optic probe. Clonogenic assays were done to determine
tumor cell survival. In KHT-C
tumors, IFP dropped significantly at 1 hour posttreatment, returned to pretreatment values at 3 hours, and then declined to approximately 25% of the pretreatment values by 72 hours. In CaSki
tumors, the IFP decreased progressively, beginning at 1 hour, to approximately 30% of pretreatment values by 72 hours. Clonogenic cell survival data indicated that
ZD6126 was less effective in
tumors with high IFP values (>25 mm Hg). Vascular disrupting agents, such as
ZD6126, can affect IFP levels and initial IFP levels may predict
tumor response to these agents. The higher cell survival in high IFP
tumors may reflect greater microregional blood flow limitations in these
tumors and reduced access of the
drug to the target endothelial cells.