title: Systemic immunotoxin treatment inhibits formation of human breast cancer metastasis and tumor growth in nude rats.
abstract: 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.
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Oslo, Norway.
authors.forename: O
authors.initials: O
authors.lastname: Engebraaten
authors.forename: G
authors.initials: G
authors.lastname: Sivam
authors.forename: S
authors.initials: S
authors.lastname: Juell
authors.forename: O
authors.initials: O
authors.lastname: Fodstad
mesh_terms: 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
chemical_list: 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