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

Authors' Affiliations: ¹ Institut National de la Sante et de la Recherche Medicale U601, Moncousu, Nantes, France; ² Centre René Gauducheau, Nantes-St. Herblain, France; and ³ Transuranium Institute, Karlsruhe, Germany

Requests for reprints: Michel Cherel, Institut National de la Sante et de la Recherche Medicale U601, 9 quai Moncousu, 44093 Nantes, France. Phone: 33-2-4008-4747; Fax: 33-3-4035-6697; E-mail: Michel.Cherel{at}univ-nantes.fr.

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 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 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 radioimmunotherapy increased tail DNA in the RPMI 8226 cell line but not the LP1 or U266 cell lines compared with doxorubicin alone or radioimmunotherapy alone. Neither doxorubicin nor paclitaxel combined with radioimmunotherapy increased the level of apoptosis induced by either drug alone or 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.