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Anti-epidermal growth factor and growth of human cells
Notes
459
Brain metastases.
Anti-epidermal growth factor and growth of human cells.
The microvasculature of the brain is lined by a continuous nonfenestrated endothelium which limits the entrance of circulating macromolecules (including anticancer drugs) into the brain parenchyma. Although this "blood--brain barrier" protects the brain from microorganisms, it does not stop invasion ~y circulating metastatic cells. Indeed, metastases in the brain develop in as many as 40 % of patients with solid tumors. Because treatment of brain metastases with parenterally administered chemotherapeutic agents has been disappointing, we began a search to identify biological approaches for therapy with emphasis given to monocytes --macrophages. We first studied the nature of the blood--brain barrier in experimental b r a i n metastases produced in mice by injecting ma!ignant cells into the internal carotid artery. Several weeks later when the tumor lesions were established, the mice were injected intravenously with the dye, sodium fluorescein. Detailed microscopic examination revealed that the blood-br~in barrier in the experimental metastases was intact. The tumors, however, were infiltrated by mononuclear phagocytes which were identified by a series of histochemical analyses to be macrophages of blood monocyte origin. Because blood monocytes can cross an intact blood--brain barrier to infiltrate brain metastases, the systemic activation of monocytes to become tumoricidal may be beneficial for treatment of small brain cancer metastases. IJ. Fidler (i) MD Anderson Cancer Center, Houston TX,77030, USA
To investigate the potential utility of anti-epidermal growth factor receptor monoclonal antibodies as therapy for cancer, two monoclanal antibodies to polypeptide components of the receptor were tested for their effects on growth of normal and malignant human cells. Both antibodies showed cytostatic inhibition of epidermoid carcinoma and breast carcinoma cells expressing amplified EGF receptors (approximately 10S/cell). Norton! fibroblasts, normal human bone marrow progenitors, and tumors cells with lesser numbers of EGI ~ receptors were not inhibited. In contrast, monoclonal antibody conjugated to recombinant ricin A chain inhibited the growth of tumor cells with widely varying numbers of EGF receptors. There was a rough correlation between the IC~0 for growth inhibition and the number of EGF receptors/cell. Kinetics of cytotoxicity indicated that one to two days of immunotoxin exposure were required for maximal cell kill, suggesting protracted exposure to such reagents may be required for anti-tumor effects in vivo. Cytotoxicity of the immunotoxin for an ovarian carcinoma cell line with approximately 120,000 receptors per cell was incomplete even at 10 -7 M. These studies suggest that anti-epidermal growth factor receptor antibodies may have anti-proliferative effects on human tumor cells with amplified EGF receptor expression, but immunotoxins prepared with these antibodies are more effective. However, even the immunotoxin may require protracted cell exposure for maximal cell kilting and de no~,o resistant tumor cells may exist. Further studies are needed to determine the mechanisms by which anti-EGF receptor antibodies inhibit cell growth and the mechanisms of anti-EGF receptor-ricin A chain immunotoxin resistance. R.Taetle (2) University of California, San Diego, CA 92103-1990, USA
(1) J. Natl. Cancer Inst. (1988) 80, 1027.
(2) J. Natl. Cancer Inst. (1988) 80, 1053.
459
Brain metastases.
Anti-epidermal growth factor and growth of human cells.
The microvasculature of the brain is lined by a continuous nonfenestrated endothelium which limits the entrance of circulating macromolecules (including anticancer drugs) into the brain parenchyma. Although this "blood--brain barrier" protects the brain from microorganisms, it does not stop invasion ~y circulating metastatic cells. Indeed, metastases in the brain develop in as many as 40 % of patients with solid tumors. Because treatment of brain metastases with parenterally administered chemotherapeutic agents has been disappointing, we began a search to identify biological approaches for therapy with emphasis given to monocytes --macrophages. We first studied the nature of the blood--brain barrier in experimental b r a i n metastases produced in mice by injecting ma!ignant cells into the internal carotid artery. Several weeks later when the tumor lesions were established, the mice were injected intravenously with the dye, sodium fluorescein. Detailed microscopic examination revealed that the blood-br~in barrier in the experimental metastases was intact. The tumors, however, were infiltrated by mononuclear phagocytes which were identified by a series of histochemical analyses to be macrophages of blood monocyte origin. Because blood monocytes can cross an intact blood--brain barrier to infiltrate brain metastases, the systemic activation of monocytes to become tumoricidal may be beneficial for treatment of small brain cancer metastases. IJ. Fidler (i) MD Anderson Cancer Center, Houston TX,77030, USA
To investigate the potential utility of anti-epidermal growth factor receptor monoclonal antibodies as therapy for cancer, two monoclanal antibodies to polypeptide components of the receptor were tested for their effects on growth of normal and malignant human cells. Both antibodies showed cytostatic inhibition of epidermoid carcinoma and breast carcinoma cells expressing amplified EGF receptors (approximately 10S/cell). Norton! fibroblasts, normal human bone marrow progenitors, and tumors cells with lesser numbers of EGI ~ receptors were not inhibited. In contrast, monoclonal antibody conjugated to recombinant ricin A chain inhibited the growth of tumor cells with widely varying numbers of EGF receptors. There was a rough correlation between the IC~0 for growth inhibition and the number of EGF receptors/cell. Kinetics of cytotoxicity indicated that one to two days of immunotoxin exposure were required for maximal cell kill, suggesting protracted exposure to such reagents may be required for anti-tumor effects in vivo. Cytotoxicity of the immunotoxin for an ovarian carcinoma cell line with approximately 120,000 receptors per cell was incomplete even at 10 -7 M. These studies suggest that anti-epidermal growth factor receptor antibodies may have anti-proliferative effects on human tumor cells with amplified EGF receptor expression, but immunotoxins prepared with these antibodies are more effective. However, even the immunotoxin may require protracted cell exposure for maximal cell kilting and de no~,o resistant tumor cells may exist. Further studies are needed to determine the mechanisms by which anti-EGF receptor antibodies inhibit cell growth and the mechanisms of anti-EGF receptor-ricin A chain immunotoxin resistance. R.Taetle (2) University of California, San Diego, CA 92103-1990, USA
(1) J. Natl. Cancer Inst. (1988) 80, 1027.
(2) J. Natl. Cancer Inst. (1988) 80, 1053.