Hypoxia and dysfunctional
tumor vessels represent a prominent feature of
pancreatic cancer, being, at least in part, responsible for
chemotherapy resistance and immune suppression in these
tumors. We tested whether the increase of
oxygen delivery induced in vivo by
myo-inositol trispyrophosphate (ITPP) can reverse
hypoxia, control
tumor growth and improve
chemotherapy response.
Tumor size, metastatic development (microcomputed tomography scan follow-up) and the survival of rats and nude or NOD.SCID mice, (bearing syngenic rat and MiaPaCa2- or patient-derived pancreatic
tumors), were determined on ITPP and/or
gemcitabine treatment. Partial
oxygen pressure, expression of angiogenic factors and
tumor histology were evaluated. Infiltration and oxidative status of immune cells, as well as
chemotherapy penetration in
tumors, were determined by fluorescence-activated cell sorting, fluorometry,
nitric oxide release assays, Western blot and confocal microscopy. Weekly intravenous ITPP application resulted in the inhibition of
metastasis development and restricted primary
tumor growth, showing a superior effect on the rats' survival compared with
gemcitabine. ITPP treatment restored
tumor normoxia and caused a reduction in
hypoxia inducible factor-1α levels, with subsequent
VEGF and Lox downregulation, resulting in improved vessel structure and decreased desmoplasia. The latter effects translated into elevated immune cells influx and improved susceptibility to
gemcitabine treatment. Growth of human pancreatic
tumor xenografts was strongly inhibited by administration of ITPP. ITPP exploits a two-stage mechanism causing rapid, early and sustainable late stage normoxia. This is due to the
angiogenic factor modulation and vascular normalization, leading to enhanced
chemotherapy delivery and synergistic
life prolongation, on combination with low doses of
gemcitabine.