Increased breast cancer tumor localization and enhanced cytotoxicity of radioimmunotherapy and chemotherapy combinations

Radioimmunotherapy (RAIT) is a promising modalily;RAIT for solid tumors, however, is limited .suboptimal delivery of radiolabeled antibody (ab). Combining RAIT with chemotherapy can yield additive/synergistic antitumor effects. Combining RAIT with Topotecan (TTN) results in prolonged tumor-free survival in a xenograft model. We now examine the biodistribution (BD)of ⁹⁰Y-BrE3 ab in-vivo with in-vitro chemo-RAIT. Methods: Nude mice breast cancer xenografts (MX-1) received 200μCi ⁹⁰Y-BrE3 (1 dose), 1mg/kg/day TTN (14 days via s.c osmotic pumps) or a combination of ⁹⁰Y-BrE3 and TTN. BD in blood(bd), organs and tumor was performed at 1, 2, 3, 7 and 14d. The decay was fit with non-compartmental models. We assessed cytotoxicity of MCF-7 cells (1μCi ⁹⁰Y-BrE3 for 1h, then washed). RAIT combined with taxol, docetaxel, 5-FU, cisplatin, or PS-341 were compared to TTN/RAIT; escalating doses (0.01 to 1μM) were added, incubated for 48h. Results: Tumor growth was retarded after RAIT or chemotherapy alone; marked inhibition of tumors was observed in mice treated with the combination. ⁹⁰Y-BrE3 alone showed T 1/2 β of 2.29 days for bd in animals treated with ⁹⁰Y-BrE3, and 1.51 d for the combination TTN and ⁹⁰Y-BrE3. Tumor bearing animals absorbed more ab with combination TTN/RAIT than ⁹⁰Y-BrE3 alone (AUC =863 & 10⁵ vs. 586 × 105 dpm/mg/d). Other active agents in breast cancer, were evaluated in-vitro with RAIT in MCF-7 cells. The addition of RAIT produced maximal cytotoxic augmentation (20-38%) at low levels (0.001 μM), while smaller increments of cytotoxicity were observed at higher concentrations. RAIT in combination with chemotherapy agents enhanced cytotoxicity by: 5-FU 38%± 0.2%, docetaxol 30%± 3%, cisplatin/TTN/PS341 25%±5% & taxol 20%±4%. Conclusion: We showed significant increases in tumor localization of ⁹⁰Y-BrE3 in-vivo in animals treated with TTN (p<0.01). Other clinically relevant cytotoxic agents showed additive or synergistic effects when combined with RAIT. The in-vivo results suggest that combining the above drugs with RAIT in-vivo will enhance the therapeutic index . Our in-vivo findings with TTN, suggest that adding these chemotherapeutic agents may enhance in-vivo tumor delivery of RAIT. Studies are warranted to evaluate therapeutic RAIT (⁹⁰Y-BrE-3) combined with clinically active chemotherapy drugs in breast cancer.