Elevated interstitial fluid pressure(IFP), observed in every animal and human tumor, is suggested to be a major impedance to the transport and uptake of therapeutic agents into tumor tissue. Elevated IFP reduces tumor blood flow and results in tumor acidosis, and hypoxia that adversely affects the reaction kinetics of certain drugs, and radiation therapy, respectively. The net impact of elevated IFP is to reduce the quantity and effectiveness of drugs or radiation sensitizing agents that reach the tumor. Tumors lack a functioning lymphatic system. Fluid buildup from leaky tumor capillaries is responsible for elevated IFP. We have developed a mechanical drainage system, the """"""""Artificial Lymphatic System"""""""" (ALS), to reduce elevated IFP by providing an alternative drainage path for the excess fluid. It is inserted into accessible tumors and results in increased blood flow, and tends to normalize the local hypoxia and acidosis. ALS, used as an adjunct to chemotherapy in rat tumor models, reduced IFP, increased blood flow, increased uptake of drugs and shrank tumors faster than no ALS controls. Our proposal seeks to validate the efficacy of an ALS as an adjunct to standard chemo and radiation therapies by treating the dog limb osteogenic sarcoma(OS), a tumor that is very similar to human limb OS. The project, performed in collaboration with the NY Animal Medical Center(AMC), treats dogs that present with the disease.
Our Specific Aims are to 1) characterize the dog OS's IFP and blood flow and 2) Incorporate an appropriate ALS into the AMC's standard chemo/surgery, and radiation therapy protocols to enhance their treatment effects. Dogs will be randomized into """"""""ALS adjunct"""""""" and """"""""No ALS"""""""" control groups for the chemo or radiation protocol; Dog owners will select the treatment protocol. Outcome measures for chemo and radiation protocols are drug uptake/percent necrosis and PO2 levels/time to local recurrence, respectively. We will also monitor pain reduction and tissue reactions from the implant. Our results will be used as preliminary data to file for a Phase 1 clinical trial to treat human limb OS. The MSKCC Therapeutics faculty believes that the ALS, if successful in this model, has promise as an adjunct for limb salvage procedures and in the treatment of many unresectable or disfiguring tumors.
| Diresta, Gene R; Nathan, Saminathan S; Manoso, Mark W et al. (2005) Cell proliferation of cultured human cancer cells are affected by the elevated tumor pressures that exist in vivo. Ann Biomed Eng 33:1270-80 |
| DiResta, Gene R; Aiken, Sean W; Healey, John (2004) Dog osteogenic sarcoma microvasculature observed with a Spalteholz technique. Clin Orthop Relat Res :39-43 |
| Zachos, T A; Aiken, S W; DiResta, G R et al. (2001) Interstitial fluid pressure and blood flow in canine osteosarcoma and other tumors. Clin Orthop Relat Res :230-6 |
| DiResta, G R; Lee, J; Healey, J H et al. (2000) ""Artificial lymphatic system"": a new approach to reduce interstitial hypertension and increase blood flow, pH and pO2 in solid tumors. Ann Biomed Eng 28:543-55 |
| DiResta, G R; Lee, J; Healey, J H et al. (2000) Enhancing the uptake of chemotherapeutic drugs into tumors using an ""artificial lymphatic system"". Ann Biomed Eng 28:556-64 |
