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, wh ich is possibly because of lack of effect on non-proliferating cells accomp anied by the emergence of drug-resistant cell clones. Since immunotoxins (I Ts) are known to exert proliferation-independent cytotoxicity, we investiga ted the efficacy of systemically administered anticarcinoma 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, chemi cally conjugated to Pseudomonas exotoxin A (PE), inhibited protein synthesi s of the 2 breast cancer cell lines at concentrations of 0.3-0.4 ng/ml, exc ept for BM7-PE, which was less efficacious (65 ng/ml). In the MA-11 model i n nude rats, a single i.v, dose of 20 mug MOC31-PE prevented development of metastasis in the spinal cord in 11/19 (58%) of the animals. Similarly, 42 5/3-PE treatment gave 6/9 (66%) long-term survivors. In rats injected intra cardially or intratibially with MT-1 cells, treatment with 425.3-PE prevent ed 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 ineff ective, whereas PE alone was toxic. With BM7-PE, 5/17 (29%) cures were obta ined in the intratibial model. The results demonstrate that systemic short- term treatment with non-toxic doses of the 3 ITs tested can effectively inh ibit the development of experimental breast cancer metastasis and/or local tumor growth in bone. The results support the development of the ITs toward s clinical evaluation for possible use as short-term adjuvant therapy in pa tients at high risk of early relapse. Int. J. Cancer 88:970-976, 2000, (C) 2000 Wiley-Liss, Inc.