Can the selective PDGF-receptor antagonist STI571 reduce hypoxia in solid tumors, and enhance drug uptake of Taxol, by lowering the interstitial fluid pressure in stroma rich breast carcinoma, BT-474

Abstract: Background Solid tumors have high interstitial fluid pressure, IFP. This cause a dramatic loss in uptake of anti cancer drugs with poor clinical outcome as result. Treatment with PDGF-receptor antagonist STI-571 lowers tumor IFP and enhances uptake of small compounds. Elevated transvascular transport as result of a lowering in IFP thereby predicts less hypoxia intratumoral. Elevated oxygen levels in tumors enhances further therapeutic outcome from radiation therapy and treatment with Radio labeled antibodies.The Purpose was to investigate if treatment with STI-571 a high Mw compound, cytotoxic antibody Herceptin. Further aim was to investigate the use HIF-1α as a marker for hypoxia in solid KAT-4 tumors. A functional hypoxia marker can further be used in other IFP and cancer research fields.Methods Fox chase SCID mice were injected with BT-474. STI-571 was administrated 3 days prior 3H-Taxol injection, 3H-Taxol was measured in tumor and blood after 24 hours. Hypoxia was measured and compared by immunohistochemistry with HIF-1α monoclonal antibody on KAT-4 tumors treated with STI-571and untreated controls. IFP was measured in STI-571 treated animals.Results STI-571increases uptake of 3H-Taxol in BT-474 breast carcinomas. HIF-1α expression is slightly decreased in STI-571 treated KAT-4 tumors.Conclusions Measuring hypoxia through HIF-1α expression in tumor sections can be applied, but further optimization of protocol is needed. IFP lowering treatment with STI-571 probably affects the uptake of 3H-Taxol in BT-474. These minor experiments confirm the theory of elevated uptake and support the suggestions that combination treatment with STI-571and 3H-Taxol improves clinical outcome in tumor therapy.