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A novel method for the detection of necrotic lesions in human cancers
A L Epstein1, F M Chen, C R Taylor
1Department of Pathology, University of Southern California, School of Medicine, Los Angeles 90033.
Abstract:
Data are presented in support of the hypothesis that malignant tumors, containing abnormally permeable, degenerating cells, can be selectively detected using monoclonal antibodies to intracellular antigens. Biodistribution, imaging, and autoradiographic studies were performed in nude mice transplanted with four different human tumor cell lines to demonstrate the binding of radiolabeled antinuclear monoclonal antibodies within bulky tumors containing necrotic lesions. For these studies, two monoclonal antibodies, designated TNT-1 (IgG2a) and TNT-2 (IgM) were chosen since they were found to bind to abundant nuclear antigens which are retained in permeable, dying cells. F(ab')2 fragments prepared by pepsin digestion were radiolabeled with iodine-125 or iodine-131 by the iodogen method for i.v. administration. Biodistribution studies in nontumor-bearing BALB/c mice at various time intervals revealed normal patterns of antibody excretion with no accumulation of antibody in healthy organs. In contrast, biodistribution studies performed on Day 3 in tumor-bearing nude mice showed high tumor to organ ratios in those animals bearing necrotic tumors. Necrotic regions dissected at necropsy gave tumor to blood ratios as high as 131:1. Transplants having little demonstrable necrosis were found to have low tumor to blood ratios (0.4:1). Sequential imaging studies confirmed the high tumor-to-organ ratios and showed positive tumor imaging as early as 4 h. Autoradiographic studies of excised tumors showed the presence of label selectively in necrotic areas with preferential labeling over the nuclei of degenerating cells. Because of the universal presence of these nuclear antigens and the known prevalence of necrosis in tumors, this approach may be of value for the imaging and treatment of a wide variety of cancers in humans.
Insights
Monoclonal antibodies targeting intracellular antigens in dying tumor cells enable selective cancer detection. Radiolabeled antibodies show high tumor uptake in necrotic regions, offering potential for improved cancer imaging and treatment.
Area of Science:
- Oncology
- Immunology
- Radiochemistry
Background:
- Malignant tumors often contain permeable, degenerating cells.
- Intracellular antigens are present in dying cells within tumors.
- Selective detection of tumors using antibodies is a promising diagnostic approach.
Purpose of the Study:
- To evaluate the hypothesis that monoclonal antibodies targeting intracellular antigens can selectively detect malignant tumors.
- To demonstrate the binding of radiolabeled antinuclear monoclonal antibodies within necrotic tumor lesions.
- To assess the potential of this approach for cancer imaging and treatment.
Main Methods:
- Biodistribution, imaging, and autoradiographic studies in nude mice xenografted with human tumor cell lines.
- Use of radiolabeled F(ab')2 fragments of antinuclear monoclonal antibodies (TNT-1 and TNT-2).
- Administration of iodine-125 or iodine-131 labeled antibodies via intravenous injection.
Main Results:
- High tumor-to-organ and tumor-to-blood ratios (up to 131:1) were observed in tumors with necrotic lesions.
- Positive tumor imaging was achieved as early as 4 hours post-injection.
- Autoradiography confirmed selective labeling in necrotic areas and over degenerating cell nuclei.
Conclusions:
- Monoclonal antibodies targeting intracellular antigens in degenerating tumor cells allow for selective tumor detection.
- This method shows significant potential for the imaging and treatment of various human cancers.
- The prevalence of necrosis in tumors supports the broad applicability of this technique.