Although the use of chemotherapeutics and cytokines is associated with objective tumor regression in some instances, this is rarely complete and almost never translates to cure or significantly prolonged survival. Resistance to the direct toxic effects of chemotherapeutics may be a manifestation of the low intratumoral concentrations associated with their intravenous administration. Higher doses are generally proscribed by systemic toxicity. Dose-limiting systemic toxicity may also serve as an obstacle to the efficacious use of some biological response modifiers. Among the myriad of ways that tumors are able to escape immune recognition, insufficient intratumoral concentrations of immunostimulatory cytokines may be responsible in part for the limited efficacy of these reagents when they are administered systemically. Tumor-targeted therapy represents a rational approach to overcoming resistance to these therapies because it may allow for the delivery of high concentrations of anticancer drugs selectively to tumors that far exceed the concentrations achieved through systemic administration. The resulting high intratumoral concentrations of chemotherapeutics may translate to greater tumor cell kill with less associated systemic toxicity. Alternatively, cytokines delivered in this fashion may create a microenvironment within the tumor that overcomes tolerance, leading first to a local and subsequently a systemic immune response. Over the past year, we have conducted a series of in vitro investigations that have established a rational basis for employing oil-based chemotherapy and immunotherapy in the treatment of cancer. Results of our ongoing clinical protocol demonstrate the safety of this approach and suggest that the delivery of chemotherapeutics using an oil in water emulsion can overcome resistance to conventional therapy with less associated systemic toxicity.
The aims of the proposed research are two-fold. First, we will determine the efficacy and toxicity of a 5-fluoro-2-deoxyuridine (FUdR)-based oil in water emulsion administered locoregionally for the treatment of isolated metastatic or locally recurrent cancer. In addition we will determine the efficacy and characterize the immunological effects of cytokines administered locoregionally in oil.
