We recently postulated that one mechanism by which tumors progress to a heterogeneous malignant state is via undermethylation of DNA. DNA hypomethylation may result in the expression of genes that were previously not expressed. The treatment of tumor cells with 5-azacytidine has resulted in the selection of clones with varying phenotypes including tumor-immunogenic, nonmetastatic clones from metastatic tumors, metastatic clones from nonmetaststic tumors, and TK+ clones from cell populations that are spontaneously TK-. We continue to investigate the role of under methylation in the generation of the malignant phenotype. The second phase of our study is to assess the usefulness of immunogenic variants in the adoptive immunization of animals bearing metastatic tumors. Our current therapeutic protocol includes surgery, elimination of suppressor cells, adoptive transfer with primed spleen cells, and II-2 administration. These protocols have resulted in considerable prolongation of survival of animals challenged with a tumor considered to be the most aggressive murine tumor known. New experiments will utilize both active and adoptive immunization of animals using both the aggressive tumor and some additional less malignant (metastatic) tumors. Finally, we are also undertaking a series of studies to attempt to identify the antigen expressed by the immunogenic variants using antibodies in the hope of eventually using genetic probes to identify the genes responsible for antigen expression. (IP)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039853-02
Application #
3179222
Study Section
Pathology B Study Section (PTHB)
Project Start
1984-08-01
Project End
1986-02-28
Budget Start
1985-03-01
Budget End
1986-02-28
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Hospitals
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Lenzi, R; Frost, P; Abbruzzese, J L (1994) Modulation of cisplatin resistance by 2'-deoxy-5-azacytidine in human ovarian tumor cell lines. Anticancer Res 14:247-51
Ellerhorst, J A; Frost, P; Abbruzzese, J L et al. (1993) 2'-deoxy-5-azacytidine increases binding of cisplatin to DNA by a mechanism independent of DNA hypomethylation. Br J Cancer 67:209-15
Abbruzzese, J L; Frost, P (1992) Studies on the mechanism of the synergistic interaction between 2'-deoxy-5-azacytidine and cisplatin. Cancer Chemother Pharmacol 30:31-6
Anzai, H; Frost, P; Abbruzzese, J L (1992) Synergistic cytotoxicity with 2'-deoxy-5-azacytidine and topotecan in vitro and in vivo. Cancer Res 52:2180-5
Itaya, T; Fearon, E; Fiesinger, T et al. (1991) Immunogenicity of a non-class I MHC expressing murine tumor transfected with the influenza virus hemagglutinin or murine interleukin-2 genes. Cancer Immunol Immunother 33:267-73
Frost, P; Abbruzzese, J L; Hunt, B et al. (1990) Synergistic cytotoxicity using 2'-deoxy-5-azacytidine and cisplatin or 4-hydroperoxycyclophosphamide with human tumor cells. Cancer Res 50:4572-7
Frost, P (1990) Immunogenic variants induced by mutagens: a mechanism for generating autoimmune responses to tumors. Immunol Ser 52:53-64
Judde, J G; Ellis, M; Frost, P (1989) Biochemical analysis of the role of transmethylation in the methionine dependence of tumor cells. Cancer Res 49:4859-65
Itaya, T; Hunt, B; Frost, P (1989) Retention of immunogenicity after X-irradiation of mouse colon tumor cells expressing the transfected influenza virus hemagglutinin gene. Cancer Immunol Immunother 28:248-52
Itaya, T; Judde, J G; Hunt, B et al. (1989) Genotypic and phenotypic evidence of clonal interactions in murine tumor cells. J Natl Cancer Inst 81:664-8

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