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

• Published in: Clinical cancer research Vol. 11; no. 19; pp. 7047s - 7052s
• Main Authors: Supiot, Stephane, Gouard, Sebastien, Charrier, Josiane, Apostolidis, Christos, Chatal, Jean-Francois, Barbet, Jacques, Davodeau, François, Cherel, Michel
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.10.2005
• Subjects: Antibiotics, Antineoplastic - pharmacology; Antibodies, Monoclonal - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Cell Cycle; Cell Division; Cell Line, Tumor; Cell Survival; Combined Modality Therapy; Comet Assay; DNA Damage; Dose-Response Relationship, Drug; Doxorubicin - pharmacology; G2 Phase; Humans; Image Processing, Computer-Assisted; M phase; Multiple Myeloma - drug therapy; Multiple Myeloma - radiotherapy; Paclitaxel - pharmacology; Radiation Tolerance; Radioimmunotherapy - methods; Radioisotopes - metabolism; α immunotherapy; α particles
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-1004-0021

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 213 Bi-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 G 2 -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 G 2 -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.