Effective future use of cytokines such as interleukin-2 (IL-2) and interleukin-6 (IL-6) as anti-neoplastic agents may require: 1) innovations in the delivery to sites of action, and 2) less toxic routes, schedules or formulations. This is particularly true for cancer involving the lung-whether primary or metastatic. Because of lymphatic uptake and distribution to the mononuclear system, liposomes may be a more effective formulation of IL-2 or IL-6 for some applications against pulmonary cancer. The anti-tumor efficacy of regionally administered IL-2 and IL-6 liposomes will be tested against pulmonary metastases in mice. Methods to efficiently monitor the synthesis and the pharmacokinetics of uptake, distribution, and metabolism of cytokine liposomes will be developed. Mechanisms of anti-tumor action will be investigated by analysis of uptake of IL-2 liposomes by immune cells in vivo as well as testing of humoral and cellular immune function in mice treated with IL-2 liposomes. The toxicity of effective routes and schedules will be measured by extravasation of radioisotopes and fluorescent markers through 'leaky' pulmonary endothelium. Thus, preclinical studies of pharmacodynamics and mechanisms of cytokine liposome action against cancer involving the lung will investigate and evaluate: 1)Anti-tumor effects of IL-2 and IL-6 liposomes as related to stimulation of humoral and cellular immunity. The development of anti-tumor antibodies, macrophage activation, DTH, specific cytotoxic cells, and LAK activity will be assessed in relation to IL-2 and IL-6 liposome administration. 2)The most effective routes and schedules of regional delivery of cytokine liposomes to the lung will be determined. 3)Toxicity of IL-2 liposomes including quantitation of pulmonary capillary leak will be compared to IL-6 liposomes.
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