Improved experimental radioimmunotherapy of colon xenografts by combining 131I-CC49 and interferon-gamma.
OBJECTIVE
This study was designed to determine whether the ability of interferon-gamma to upregulate the expression of a human tumor antigen improved the therapeutic efficacy of a radionuclide-conjugated monoclonal antibody.


METHODS
Tumor xenografts of the moderately differentiated human colon tumor cell line HT-29 were grown in athymic mice. Constitutive levels of the human tumor antigen, tumor-associated glycoprotein-72, were measured before and after treatment with interferon-gamma. Antitumor effects of an 131I-labeled antitumor-associated glycoprotein-72 monoclonal antibody, CC49, were determined by measuring changes in tumor volumes in the respective groups of athymic mice.


RESULTS
Interferon-gamma induced a time-dependent and dose-dependent increase in tumor-associated glycoprotein-72 expression in the HT-29 tumors. Immunohistochemical staining revealed a more homogeneous tumor-associated glycoprotein-72-positive tumor cell population in tumors isolated from mice treated for eight days with interferon-gamma, which accounted for the enhanced tumor localization of 131I-CC49 in mice. That experimental model was used to examine the antitumor effects of combining interferon-gamma with 131I-CC49. Administration of 300 microCi of 131I-CC49 to mice bearing HT-29 tumors induced a transient suppression of tumor growth. Conversely, a long-term, sustained HT-29 tumor growth suppression was achieved in mice given 300 microCi of 131I-CC49 and interferon-gamma. In fact, the cytokine/radioimmunoconjugate combination eradicated any evidence of tumor in approximately 30 percent of the mice.


CONCLUSIONS
The ability of interferon-gamma to enhance tumor-associated glycoprotein-72 expression substantially augmented the antitumor effects of the radioimmunoconjugate. Those observations provide additional argument for use of a radioimmunoconjugate in combination with a cytokine to improve tumor diagnosis and therapy.
Greiner
J W
JW
Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Guadagni
F
F
Roselli
M
M
Ullmann
C D
CD
Nieroda
C
C
Schlom
J
J
D000818:Animals; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D006023:Glycoproteins; D011994:Recombinant Proteins; C047052:tumor-associated antigen 72; D007371:Interferon-gamma