Combined Anti-Angiogenic Therapy Targeting PDGF and VEGF Receptors Lowers the Interstitial Fluid Pressure in a Murine Experimental Carcinoma

Abstract

Elevation of the interstitial fluid pressure (IFP) of carcinoma is an obstacle in treatment of tumors by chemotherapy and correlates with poor drug uptake. Previous studies have shown that treatment with inhibitors of platelet-derived growth factor (PDGF) or vascular endothelial growth factor (VEGF) signaling lowers the IFP of tumors and improve chemotherapy. In this study, we investigated whether the combination of PDGFR and VEGFR inhibitors could further reduce the IFP of KAT-4 human carcinoma tumors. The tumor IFP was measured using the wick-in-needle technique. The combination of STI571 and PTK/ZK gave an additive effect on the lowering of the IFP of KAT-4 tumors, but the timing of the treatment was crucial. The lowering of IFP following combination therapy was accompanied by vascular remodeling and decreased vascular leakiness. The effects of the inhibitors on the therapeutic efficiency of Taxol were investigated. Whereas the anti-PDGF and anti-VEGF treatment did not significantly inhibit tumor growth, the inhibitors enhanced the effect of chemotherapy. Despite having an additive effect in decreasing tumor IFP, the combination therapy did not further enhance the effect of chemotherapy. Simultaneous targeting of VEGFR and PDGFR kinase activity may be a useful strategy to decrease tumor IFP, but the timing of the inhibitors should be carefully determined.

The Tyrosine Kinase Inhibitor Imatinib Augments Extracellular Fluid Exchange and Reduces Average Collagen Fibril Diameter in Experimental Carcinoma

“…STI571 had no effect on the density of CD31-positive vessels in KAT-4/HT-29 carcinoma, consistent with our earlier findings (19). Furthermore, our data show that the pericyte coverage of CD31-positive vessels was not affected by STI571 treatment.…”

“…Collagenous fibers and the GAG/ proteoglycan ground substance constitute the two major macromolecular complexes in any connective tissue and play a decisive role in the efficacy of fluid and solute transport through tissues (12,39). The finding that the amounts of hyaluronan, chondroitin/dermatan sulfate, and heparan sulfate per unit carcinoma dry weight were unaffected by STI571 treatment, together with the data on an expanded interstitial fluid volume (19), suggest that the GAG/proteoglycan ground substance was diluted by taking up fluid. The collagen content, measured as the total amount of hydroxyproline per unit carcinoma wet weight was not significantly affected by STI571 but the marginal decrease that was recorded fits well with an increase in the interstitial fluid volume.…”

“…STI571 reduces IFP and increases the interstitial fluid volume in KAT-4/HT-29 carcinomas (18,19). A potential mechanism could involve a reduction of fibroblast tensile forces applied on the collagen/microfibrillar network (1,18).…”

“…The KAT-4/HT-29 carcinoma is rich in ECM and has a welldeveloped stromal compartment (8,19,32). Treatment with STI571 had no discernable effect on the gross appearance of the collagenous matrix as judged from stainings with Sirius red Table S1).…”

“…Furthermore, STI571 treatment of the ECM-rich KAT-4/HT-29 carcinoma model increases the extracellular fluid (ECV) volume from 34% to 42% of total tissue water (TTW), without significantly altering plasma volume (about 0.9% of the TTW; ref. 19). TTW is the sum of intracellular, ECV, and plasma.…”