Abstract
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 anti-tumor 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 μM 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.
Similar content being viewed by others
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Aparicio, A., Gardner, A., Tu, Y. et al. In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia 12, 220–229 (1998). https://doi.org/10.1038/sj.leu.2400892
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2400892
- Springer Nature Limited
Keywords
This article is cited by
-
Unexpected chronic lymphocytic leukemia B cell activation by bisphosphonates
Cancer Immunology, Immunotherapy (2024)
-
Geranylgeranyl diphosphate synthase inhibition induces apoptosis that is dependent upon GGPP depletion, ERK phosphorylation and caspase activation
Cell Death & Disease (2017)
-
Bisphosphonates in Multiple Myeloma: Preclinical and Clinical Data
Clinical Reviews in Bone and Mineral Metabolism (2013)
-
Bisphosphonates induce apoptosis in CLL cells independently of MDR phenotype
Cancer Chemotherapy and Pharmacology (2008)