Synergism between gemcitabine and low LET (gamma-rays), but not high-let alpha-particles on multiple myeloma cell lines

Abstract

Purpose/ObjectiveTo study the influence of Linear Energy Transfer (LET) on the radiosensitizing effects of gemcitabine, by comparing low LET (gamma-rays) and high LET particles (alpha-radioimmunotherapy).Materials/MethodsOn 3 multiple myeloma cell lines (LP1, RPMI 8226 and U266), we measured clonogenic survival after gamma-rays irradiation from Cobalt 60 (0 to 4 Gy) alone or combined with 10 nM gemcitabine after a 24h incubation prior to radiation. We also measured survival after alpha-radioimmunotherapy using B-B4 a monoclonal antibody that targets multiple myeloma cells radiolabeled with bismuth 213, alone or combined with 10 nM gemcitabine. Apoptosis was analyzed by apo 2.7 FACS staining.ResultsGemcitabine acted synergistically with gamma-rays on LP1 and U266 cell lines (Radiation Enhancement Ratio : 1.56 and 1.49 respectively), but not on RPMI 8226. Gemcitabine combined with alpha-radioimmunotherapy did not provoke a synergistic effect on all 3 cell lines. In order to explore the mechanisms of synergism we studied apoptosis 24h after irradiation combined with gemcitabine. Gemcitabine combined with gamma-rays increased apoptosis as compared with gemcitabine or gamma-rays alone on LP1 and U266 cell lines, but not on RPMI 8226. Gemcitabine combined with alpha-radioimmunotherapy increased apoptosis as compared with gemcitabine or alpha-radioimmunotherapy alone on U266 but not LP1 or RPMI 8226 cell lines.ConclusionsGemcitabine radiosensitization depended on the kind of radiation, and did not enhance high LET particles cellular effects. Gemcitabine acted synergistically with gamma-rays, but not with alpha-radioimmunotherapy on multiple myeloma cell lines. Gemcitabine enhanced the apoptotic effects of low LET particles, but this cannot be the only explanation of the observed synergistic effects Purpose/ObjectiveTo study the influence of Linear Energy Transfer (LET) on the radiosensitizing effects of gemcitabine, by comparing low LET (gamma-rays) and high LET particles (alpha-radioimmunotherapy). To study the influence of Linear Energy Transfer (LET) on the radiosensitizing effects of gemcitabine, by comparing low LET (gamma-rays) and high LET particles (alpha-radioimmunotherapy). Materials/MethodsOn 3 multiple myeloma cell lines (LP1, RPMI 8226 and U266), we measured clonogenic survival after gamma-rays irradiation from Cobalt 60 (0 to 4 Gy) alone or combined with 10 nM gemcitabine after a 24h incubation prior to radiation. We also measured survival after alpha-radioimmunotherapy using B-B4 a monoclonal antibody that targets multiple myeloma cells radiolabeled with bismuth 213, alone or combined with 10 nM gemcitabine. Apoptosis was analyzed by apo 2.7 FACS staining. On 3 multiple myeloma cell lines (LP1, RPMI 8226 and U266), we measured clonogenic survival after gamma-rays irradiation from Cobalt 60 (0 to 4 Gy) alone or combined with 10 nM gemcitabine after a 24h incubation prior to radiation. We also measured survival after alpha-radioimmunotherapy using B-B4 a monoclonal antibody that targets multiple myeloma cells radiolabeled with bismuth 213, alone or combined with 10 nM gemcitabine. Apoptosis was analyzed by apo 2.7 FACS staining. ResultsGemcitabine acted synergistically with gamma-rays on LP1 and U266 cell lines (Radiation Enhancement Ratio : 1.56 and 1.49 respectively), but not on RPMI 8226. Gemcitabine combined with alpha-radioimmunotherapy did not provoke a synergistic effect on all 3 cell lines. In order to explore the mechanisms of synergism we studied apoptosis 24h after irradiation combined with gemcitabine. Gemcitabine combined with gamma-rays increased apoptosis as compared with gemcitabine or gamma-rays alone on LP1 and U266 cell lines, but not on RPMI 8226. Gemcitabine combined with alpha-radioimmunotherapy increased apoptosis as compared with gemcitabine or alpha-radioimmunotherapy alone on U266 but not LP1 or RPMI 8226 cell lines. Gemcitabine acted synergistically with gamma-rays on LP1 and U266 cell lines (Radiation Enhancement Ratio : 1.56 and 1.49 respectively), but not on RPMI 8226. Gemcitabine combined with alpha-radioimmunotherapy did not provoke a synergistic effect on all 3 cell lines. In order to explore the mechanisms of synergism we studied apoptosis 24h after irradiation combined with gemcitabine. Gemcitabine combined with gamma-rays increased apoptosis as compared with gemcitabine or gamma-rays alone on LP1 and U266 cell lines, but not on RPMI 8226. Gemcitabine combined with alpha-radioimmunotherapy increased apoptosis as compared with gemcitabine or alpha-radioimmunotherapy alone on U266 but not LP1 or RPMI 8226 cell lines. ConclusionsGemcitabine radiosensitization depended on the kind of radiation, and did not enhance high LET particles cellular effects. Gemcitabine acted synergistically with gamma-rays, but not with alpha-radioimmunotherapy on multiple myeloma cell lines. Gemcitabine enhanced the apoptotic effects of low LET particles, but this cannot be the only explanation of the observed synergistic effects Gemcitabine radiosensitization depended on the kind of radiation, and did not enhance high LET particles cellular effects. Gemcitabine acted synergistically with gamma-rays, but not with alpha-radioimmunotherapy on multiple myeloma cell lines. Gemcitabine enhanced the apoptotic effects of low LET particles, but this cannot be the only explanation of the observed synergistic effects