Mechanisms of cell sensitization to alpha radioimmunotherapy by doxorubicin or paclitaxel in multiple myeloma cell lines.
OBJECTIVE
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 alpha radionuclides.


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


CONCLUSIONS
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.
Supiot
Stephane
S
Institut National de la Sante et de la Recherche Medicale U601, Moncousu, Nantes, France.
Gouard
Sebastien
S
Charrier
Josiane
J
Apostolidis
Christos
C
Chatal
Jean-Francois
JF
Barbet
Jacques
J
Davodeau
François
F
Cherel
Michel
M
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D003131:Combined Modality Therapy; D020552:Comet Assay; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D016195:G2 Phase; D006801:Humans; D007091:Image Processing, Computer-Assisted; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000532:radiotherapy*; D017239:Paclitaxel / Q000494:pharmacology*; D011836:Radiation Tolerance; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D011868:Radioisotopes; D004317:Doxorubicin; D017239:Paclitaxel