In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates.
In a double blind randomized study, the bisphosphonate drug Pamidronate (Aredia) significantly protected Durie-Salmon stage III multiple myeloma patients from osteolytic bone disease. In the patient sub-group on salvage chemotherapy. Pamidronate treatment was also significantly associated with prolonged survival. To test if this drug could induce direct antitumor effects, we exposed myeloma cells to increasing concentrations of Pamidronate or a more potent bisphosphonate, Zoledronate. A concentration- and time-dependent cytotoxic effect was detected on four of five myeloma cell lines as well as three specimens obtained directly from myeloma patients. Zoledronate-induced cytotoxicity was significantly greater than that of Pamidronate. Cytotoxicity could not be explained by bisphosphonate-induced chelation of extracellular calcium or secondary decrease in production of the myeloma growth factor interleukin-6. Morphological examination, DNA electrophoresis and cell cycle analysis indicated that the bisphosphonate-induced cytotoxic effect consisted of a combination of cytostasis and apoptotic myeloma cell death. Enforced expression of BCL-2 protected against the apoptotic death but not against cytostasis. Most cytotoxic effects were seen between 10 and 100 microM of drug. The results suggest a possible direct anti-tumor effect in myeloma patients treated with bisphosphonates which may participate in their significantly increased survival. This hypothesis should now be further tested in clinical trials.
Aparicio
A
A
Department of Medicine, VA West Los Angeles Hospital and UCLA Jonsson Comprehensive Cancer Center, California 90073, USA.
Gardner
A
A
Tu
Y
Y
Savage
A
A
Berenson
J
J
Lichtenstein
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000378:metabolism / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D000077268:Pamidronate; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D000077211:Zoledronic Acid
D000970:Antineoplastic Agents; D002614:Chelating Agents; D004164:Diphosphonates; D007093:Imidazoles; D015850:Interleukin-6; D019253:Proto-Oncogene Proteins c-bcl-2; D000077211:Zoledronic Acid; D000077268:Pamidronate; D002118:Calcium