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

B. Ng, E. Kramer, R. Ceriani, M. Volm, A. Hamilton, F. Muggia, S. Formenti, P. Furmanski, L. Liebes

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)303
Number of pages1
JournalBreast Cancer Research and Treatment
Issue number3
StatePublished - 2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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