title: Pamidronate causes apoptosis of plasma cells in vivo in patients with multiple myeloma.
abstract: Anti-resorptive bisphosphonates, such as pamidronate, are an effective treatment for osteolytic disease and hypercalcaemia in patients with multiple myeloma, but have also been shown to cause apoptosis of myeloma cell lines in vitro. In this study, we found that a single infusion of pamidronate, in 16 newly diagnosed patients with multiple myeloma, caused a marked increase in apoptosis of plasma cells in vivo in 10 patients and a minimal increase in four patients (P < 0.05). The nitrogen-containing bisphosphonates pamidronate and zoledronic acid also induced apoptosis of authentic, human bone marrow-derived plasma cells in vitro. Apoptosis of plasma cells in vitro was probably caused by inhibition of the mevalonate pathway and loss of prenylated small GTPases, as even low concentrations (>or= 1 micro mol/l) of zoledronic acid caused accumulation of unprenylated Rap1A in cultures of bone marrow mononuclear cells in vitro. GGTI-298, a specific inhibitor of geranylgeranyl transferase I, also induced apoptosis in human plasma cells in vitro, suggesting that geranylgeranylated proteins play a role in signalling pathways that prevent plasma cell death. Our results suggest that pamidronate may have direct and/or indirect anti-tumour effects in patients with multiple myeloma, which has important implications for the further development of the more potent nitrogen-containing bisphosphonates, such as zoledronic acid, in the treatment of myeloma.
authors.affiliation: Department of Medicine and Therapeutics, University of Aberdeen Medical School, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Gordon
authors.forename: Miep H
authors.initials: MH
authors.lastname: Helfrich
authors.forename: Hamdi I A
authors.initials: HI
authors.lastname: Sati
authors.forename: Michael
authors.initials: M
authors.lastname: Greaves
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Culligan
authors.forename: Richard L
authors.initials: RL
authors.lastname: Soutar
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rogers
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077268:Pamidronate; D010950:Plasma Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017368:Protein Prenylation; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D000077268:Pamidronate