Recent clinical trials showed that certain human malignancies can respond to such biological response modifier as nuclease resistant complex of polyriboinosinic acidpolyrobocytidylic acid with poly-1-lysine and carboxymethylcellulose - poly(ICLC). The response, however was relatively short lasting, particularly when large tumor burden was present. To improve the tumor curability we propose to use poly(ICLC) in combination with ionising radiation. During preliminary studies in mice and nonhuman primates, exposed to total body irradiation no substantial reduction in interferon levels, induced by poly(ICLC) was seen. In irradiated animals an increase in hematopoietic stem cells-CFU-S was also documented. The endogenous interferon, induced by the drug, has the potential of preventing the repair processes in irradiated tumor cells and to augment the natural killer cells and macrophages activity. In this preclinical study in mice we will use poly(ICLC) in combination with local fractionated irradiation to treat solid transplantable tumors of spontaneous origin with well known propensity to form lung metastases (Lewis lung carcinoma in C57 black mice and M109 alveolar carinoma in Balb/c mice). To administer the drug intraperitoneal and topical routes will be used, which were associated with minimal toxicities in preliminary studies. During initial experiments dose-response curves will be obtained for both modalities to assess the sensitivity of the tumors. Optimal doses of poly(ICLC) and local irradiation, leading to maximum tumor response if used as single modalities, will be combined for further use against established tumors. Changes in tumor volume, in the number and sizes of lung metastases, survival of the animals, normal tissue(skin) reaction and the activity of natural killer cells and macrophages will be quantitatively evaluated by direct measurements and statistically analyzed. The levels of serum interferon and drug will be determined and compared with observed antitumor effects. If positive, the data obtained in this study will be used as reference points in the development of protocols for clinical trials, aimed to improve the treatment of such common human malignancy as lung cancer. As to the experimental model, used in this study, it will be used further to evaluate other biological response modifiers with a potential to interact faivorably with local irradiation, fractionated in a manner, typical for modern radiation treatment of human cancer.
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