Mechanisms of Cell Sensitization to α Radioimmunotherapy by Doxorubicin or Paclitaxel in Multiple Myeloma Cell Lines

Abstract

Purpose: The purpose of this study was to analyze different mechanisms (cell cycle synchronization, DNA damage, and apoptosis) that might underlie potential synergy between chemotherapy (paclitaxel or doxorubicin) and radioimmunotherapy with α radionuclides. Experimental Design: Three multiple myeloma cell lines (LP1, RMI 8226, and U266) were treated with ²¹³Bi-radiolabeled B-B4, a monoclonal antibody that recognizes syndecan-1 (CD138) 24 hours after paclitaxel (1 nmol/L) or doxorubicin (10 nmol/L) treatment. Cell survival was assessed using a clonogenic survival assay. Cell cycle modifications were assessed by propidium iodide staining and DNA strand breaks by the comet assay. Level of apoptosis was determined by Apo 2.7 staining. Results: Radiation enhancement ratio showed that paclitaxel and doxorubicin were synergistic with α radioimmunotherapy. After a 24-hour incubation, paclitaxel and doxorubicin arrested all cell lines in the G₂-M phase of the cell cycle. Doxorubicin combined with α radioimmunotherapy increased tail DNA in the RPMI 8226 cell line but not the LP1 or U266 cell lines compared with doxorubicin alone or α radioimmunotherapy alone. Neither doxorubicin nor paclitaxel combined with α radioimmunotherapy increased the level of apoptosis induced by either drug alone or α radioimmunotherapy alone. Conclusion: Both cell cycle arrest in the G₂-M phase and an increase in DNA double-strand breaks could lead to radiosensitization of cells by doxorubicin or paclitaxel, but apoptosis would not be involved in radiosensitization mechanisms.