Ample evidence obtained in this laboratory indicates that Doxorubicin (DOX) at moderate doses has immunomodulating effects that can be exploited in cooperation with prolonged treatments with interleukin 2 (IL2) at low doses in inducing cures of EL4 lymphoma and E0771 breast adenocarcinoma in syngeneic C57BL/6 mice. These cures are T cells and/or NK cells dependent in the tumors used (i.e., re. MHC-expression). Evidence obtained at Karolinska Institute and elsewhere indicates that protein-bound polysaccharide K (PSK) has immunomodulating effects that can be exploited therapeutically as well as for prevention of carcinogen-induced tumors. Based on this background, the preventive effects of our DOX plus IL2 regimens will be compared to those of PSK in 2 transgenic mouse tumor models, i.e., the Her2/neu positive FVB/NDL 2-5 breast adenocarcinoma and the TRAMP prostate tumor. In each case, treatments would be started at weaning. Both of these models mimic closely the human disease. The breast tumor develops around 23 weeks after birth and lung metastasis is present at 27-32 weeks. The TRAMP prostate tumor model progresses at well defined stages, from early prostatic intraepithelial neoplasia at around 12 weeks to carcinoma at 18 to 24 weeks and metastasis at 28 weeks or so. Time of tumor onset, incidence and growth rate (grade) of tumors, metastasis and dependence of effects on NK, NKT, T, or LAK cells responses will be evaluated. Although in these models therapy/prevention has been studied by others using vaccines, antibodies and/or interleukin 12, to our knowledge, this is the first time that immunomodulation-determined tumor prevention will be specifically studied in rigorous transgenic models: both innate and adaptive immune responses should be elicited by the treatment tested and should react to cells at very early stages of genetically determined transformation. Methodologies/approaches are well established in this laboratory, except for a new application of MR to evaluate prevention of a visceral tumor like TRAMP. The novel but logical approach of correlating prevention with immunomodulation and determining causal-effects relationships is the subject of this application. The significance of providing information potentially leading to the development of non-toxic immunoaugmenting agents effective in tumor prevention is obvious. It is expected that this R0-3 will be followed by an R0-1 based on the preliminary results obtained herein.
