Systemic immunotoxin treatment inhibits formation of human breast cancer metastasis and tumor growth in nude rats.
Adjuvant chemotherapy in breast cancer patients has had limited success, which is possibly because of lack of effect on non-proliferating cells accompanied by the emergence of drug-resistant cell clones. Since immunotoxins (ITs) are known to exert proliferation-independent cytotoxicity, we investigated the efficacy of systemically administered anti-carcinoma ITs in nude rat models, simulating micrometastatic disease. The monoclonal antibodies MOC31, BM7 and 425.3, which recognize epithelial glycoprotein 2, MUC-1 mucin and the epidermal growth factor receptor, chemically conjugated to Pseudomonas exotoxin A (PE), inhibited protein synthesis of the 2 breast cancer cell lines at concentrations of 0.3-0.4 ng/ml, except for BM7-PE, which was less efficacious (65 ng/ml). In the MA-11 model in nude rats, a single i. v. dose of 20 microg MOC31-PE prevented development of metastasis in the spinal cord in 11/19 (58%) of the animals. Similarly, 425.3-PE treatment gave 6/9 (66%) long-term survivors. In rats injected intracardially or intratibially with MT-1 cells, treatment with 425. 3-PE prevented metastasis in 4/10 (40%) and intratibial tumor growth in 17/18 (94%) of the rats. Importantly, an equimolar dose of free 425.3 (antibody) was ineffective, whereas PE alone was toxic. With BM7-PE, 5/17 (29%) cures were obtained in the intratibial model. The results demonstrate that systemic short-term treatment with non-toxic doses of the 3 ITs tested can effectively inhibit the development of experimental breast cancer metastasis and/or local tumor growth in bone. The results support the development of the ITs towards clinical evaluation for possible use as short-term adjuvant therapy in patients at high risk of early relapse.
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Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Oslo, Norway.
Sivam
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Juell
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Fodstad
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D036002:ADP Ribose Transferases; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001427:Bacterial Toxins; D001859:Bone Neoplasms / Q000517:prevention & control / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D002945:Cisplatin / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D066246:ErbB Receptors / Q000276:immunology*; D005098:Exotoxins / Q000627:therapeutic use*; D005260:Female; D000922:Immunotoxins / Q000627:therapeutic use*; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D011923:Rats, Nude; D013047:Specific Pathogen-Free Organisms; D013125:Spinal Neoplasms / Q000517:prevention & control / Q000556:secondary; D013977:Tibia; D014407:Tumor Cells, Cultured; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D002945:Cisplatin; D004317:Doxorubicin; D066246:ErbB Receptors; D005098:Exotoxins; D000922:Immunotoxins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A