| Abstract: |
Advanced ovarian cancer is largely incurable, but initially it is frequently confined to the i.p. space. We explored i.p. radioimmunotherapy in a mouse model of human ovarian cancer. Use of a targeted actinium-225 ( 225Ac) in vivo generator of α particles exploits the extreme, selective cytotoxicity of α particles, while providing a feasible half-life to enable delivery to tumor. 225Ac chelated with 2-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid was conjugated to trastuzumab, an anti-HER-2/neu antibody. The radioimmunoconjugate was tested for immunoreactivity, internalization, and cytotoxicity using a human ovarian carcinoma cell line, SKOV3. 225Ac-labeled trastuzumab retained immunoreactivity (50-90%), rapidly internalized into cells (50% at 2 h), and had an ED50 of 1.3 nCi/ml after 4 days of incubation in vitro. i.p. administered 225Ac- or 111In-labeled trastuzumab behaved similarly with high tumor uptake [56-60% injected dose per gram (% ID/g) at 4 h, which increased to 65-70% ID/g at 24 h]. Tumor uptake was 3-5-fold higher than liver and spleen, the normal organs with the highest uptake. i.v. administration of 111In-labeled trastuzumab produced slightly higher normal organ uptake compared with i.p.-administered 111In-labeled trastuzumab. However, tumor uptake was low, 5%-26% ID/g. Therapy was examined with native trastuzumab and 220, 330, and 450 nCi of 225Ac-labeled trastuzumab or 225Ac-labeled control antibody at different dosing schedules. Therapy was initiated 9 days after tumor seeding. Groups of control mice and those administered native trastuzumab had median survivals of 33 and 37 or 44 days, respectively. Median survival was 52-126 days with 225Ac-labeled trastuzumab at various doses and schedules, and 48-64 days for 225Ac-labeled control the same schedules. Deaths from toxicity occurred with the highest activity levels. In conclusion, i.p. administration with a 225Ac-labeled internalizing anti-HER-2/neu antibody can extend survival significantly in a nude mouse model of human ovarian cancer at levels that produce no apparent gross toxicity. |
| Keywords: |
cancer survival; controlled study; unclassified drug; human cell; nonhuman; ovarian neoplasms; mouse; animals; mice; ovary cancer; animal experiment; animal model; cancer cell culture; cytotoxicity; tumor cells, cultured; antibodies, monoclonal; indium radioisotopes; drug uptake; isotope labeling; tissue distribution; transplantation, heterologous; dimerization; neoplasm transplantation; trastuzumab; radioimmunotherapy; indium 111; drug conjugation; actinium; actinium 225; isothiocyanic acid derivative; 2 (4 isothiocyanatobenzyl) 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid; humans; human; female; priority journal; article
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