Targeted Alpha Therapy Using Components of the Plasminogen Activation System for the Control of Micrometastatic Breast Cancer

Abstract : We have developed a new adjuvant therapy for the control of metastatic breast cancer. This therapy exploits the involvement of cell-surface receptor bound urokinase plasminogen activator (uPA) in the metastatic spread of breast cancer cells. Once bound to specific cell-surface receptors, uPA efficiently activates plasminogen to the broad- spectrum protease, plasmin. We have successfully labeled and tested recombinant human PAI2 with the alpha radioisotope 213Bi to produce alpha-PAI2. Low doses of alpha-PAI2 are highly cytotoxic towards breast cancer cell lines in vitro, whereas non-specific alpha-BSA bad no cytotoxic effect. In vivo toxicity studies in nude mice show that up to 6 mCi/kg of alpha-PA12 (ip) is well tolerated; in vivo efficacy experiments demonstrate in mice that a local injection of alpha-PAI2 can completely inhibit the growth of tumour at 2 days post-cell inoculation. At this time, only cell clusters are present. Further, a single systemic (iv) administration of alpha-PAI2 at 2 days post-inoculation can also inhibit tumour growth in a dose dependent manner, with 3/5 tumours uncontrolled at 1.5 mCi/kg, 2/5 at 3 mCi/kg and 1/5 at 6 mCi/kg. Clear evidence of tumour growth inhibition is established at 5 mCi/kg. Thus alpha-PAI2 is successful in targeting and killing isolated cells and preangiogenic cell clusters. These results indicate the promising potential of alpha-PAI2 as a novel therapeutic agent for micrometastatic breast cancer.