Previous studies from our laboratory have shown that administration of adoptive chemoimmunotherapy (ACIT) consisting of doxorubicin hydrochloride (DOX) and lymphokine activated killer (LAK) cells plus IL2 cured 60-80% of mice bearing established murine renal cancer (Renca). Further studies have shown that LAK cells can be fractionated on Percoll density gradients such that less than 85% of the total cytolytic activity can be enriched in approximately 20% of the cells in fraction 2 (F2). These F2 cells, when labelled with 111-Indium, do not distribute widely or localize to a significant extent in tumor tissue following intravenous administration, suggesting that the mechanism of in vivo antitumor effects by LAK cells may be largely indirect. Additional studies have shown that the investigational drug Flavone acetic acid (FAA) augments NK activity in normal and tumor-bearing mice and synergizes with rIL2 for the treatment of Renca; FAA + rIL2 is an effective treatment for minimal residual disease, intrarenal primary tumors, and for experimentally established pulmonary metastases. The mechanism by which FAA synergizes with rIL2 involves the induction of IFNalpha by FAA, requires both asialo- GM1+ and T lymphocytes. Additional experiments involving the potential role of cytokines in cancer treatment have utilized the retrovirus induced GG2EE myelomonocytic tumor cell model shown to be partially growth inhibited by IFNgamma, ILl, TNFalpha, and TGFbeta. Very low doses of these cytokines exhibit synergistic antiproliferative effects in vitro Studies have also been performed which demonstrate that large granular lymphocytes (LGL) can respond chemotactically to activators of protein kinase C. These results suggest that BRM may induce the localization of LGL in vivo partially through the induction of chemotactic factors.
