Of five BRMs examined, three (poly ICLC, MVE-2, Picibanil) significantly augmented NK cell and macrophage (MPhi) cytotoxic activity. In vitro and in vivo studies indicate that the tumor cell antiproliferative effects of these BRMs are not direct but mediated through effector cells. Augmented NK activity varied in different tissues (peritoneal greater than blood greater than spleen) and according to treatment route (i.p. greater than i.v. greater than s.c.). NK and MPhi cytotoxic activity was maintained over 7 days folowing single injection. Multiple treatment with MVE-2 and poly ICLC resulted in hypo-responsiveness (HRP) of NK but not MPhi. PGE2 induction by BRM-activated Mphi was one reason for the development of HRP. In vitro incubation of normal MPhi with the BRMs poly ICLC, MVE-2 or Alpha Beta IFN resulted in increased PGE2 secretion; poly ICLC and Alpha Beta IFN increased CSF secretion; and ploy ICLC increased IFN secretion. Poly ICLC, MVE-2 and Picibanil reduced metastatic lung tumor development possibly by augmenting peripheral blood (PB) NK activity. These BRMs reconstituted PB NK activity in mice treated with a selective NK-depressing antibody. Treatment of established B16 melanoma and M109 lung carcinoma, by Cytoxan chemotherapy followed by either poly ICLC, MVE-2 or Picibanil resulted in a significant reduction of lung tumors and increase in survival time. The combined treatment was more effective than with Cytoxan or BRM alone. Surgical debulking of 16/C mammary adenocarcinoma followed by poly ICLC or MVE-2 treatment resulted in decreased metastatic lung tumors. Azimexon reconstituted nucleated bone marrow cells in irradiated mice through CSF-enhanced myeloid stem cell proliferation. Poly ICLC, BM 41.332, and murine alphaBetaIFN also stimulate the production and secretion of CSF capable of forming myeloid colonies from stem cells in vitro.