Assessment of bisphosphonate activity in vitro.
Bisphosphonates are a class of drugs developed over the past three decades for the treatment of metabolic bone diseases with high bone turnover, such as Paget's disease, tumor associated osteolysis and osteoporosis. The exceptional pharmacokinetic profile of bisphosphonates makes them very suitable and safe drugs for the treatment of bone diseases, because, by conventional administration, osseous tissue and bone resorbing osteoclasts are the targets for these drugs as a result of the very high affinity of bisphosphonates for bone mineral. Several recent studies have demonstrated, however, that bisphosphonates decrease tumor burden in bone in rodent models of myeloma and metastatic bone disease, with suggestions of antitumor effects also in patients. Although decreased tumor burden could be a consequence of inhibition of bone resorption, there is increasing evidence that bisphosphonates might also have direct effects on tumor cell in vivo, since effects on tumors outside of skeleton or at doses not inhibiting bone resorption have been reported. Recent studies also suggest that bisphosphonates have inhibitory effect also on endothelial cell function and angiogenesis in tumor tissue. These findings suggest that the target cells for bisphosphonates as well as their molecular mechanism of action may be more diverse and complex than realized so far. This review highlights the main methodologies used to monitor the action of BPs in vitro cell models, with a special emphasis on the detection of BP-induced ATP-analoques by mass spectrometry. In addition, cell death monitoring, immunomodulatory effects and inhibition of growth/proliferation are described.
Mitrofan
L M
LM
Laboratoire INSERM U908, Université des Sciences et Technologies de Lille 1, Villeneuve d'Ascq, France. laura_mitrofan@yahoo.com
Auriola
S
S
Mönkkönen
H
H
Mönkkönen
J
J
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007155:Immunologic Factors; D009943:Organophosphorus Compounds; D000255:Adenosine Triphosphate