Inhibitory effects of a new bisphosphonate, minodronate, on proliferation and invasion of a variety of malignant bone tumor cells.
Little is known about the biological effects of bisphosphonates on primary malignant bone tumors. The purpose of this study was to investigate the antitumor effects of newly developed minodronate (MIN) on a variety of human malignant bone tumors. We examined the effects of MIN and clinically relevant incadronate (INC) on the proliferation, apoptosis, and cell cycle of two osteosarcoma (Saos-2, MG-63), two chondrosarcoma (SW1353, OUMS27), and two Ewing's sarcoma (RD-ES, SK-ES-1) cell lines. Furthermore, we investigated the anti-invasion effects of MIN on sarcoma cells and the effects of MIN on tumor growth in nude mice. MIN inhibited the viability of all six cell lines in a dose-dependent manner with IC50 values of 2.7 to 5.0 microM, which were significantly lower than those of INC. Importantly, both bisphosphonates affected the viability of normal bone marrow stromal cells much less than sarcoma cells. Both bisphosphonates induced cell cycle perturbation in all sarcoma cells tested and apoptosis in Saos-2 and SW1353 cells, although they failed to induce apoptosis in RD-ES and SK-ES-1 cells. MIN significantly suppressed invasion, even at a low concentration of 1 microM (p < 0.01). Daily injection of 5 microg of MIN inhibited the growth of SK-ES-1 xenograft sarcoma in nude mice without loss of body weight. These findings suggest that MIN may have a beneficial adjuvant role in the treatment of patients with malignant bone tumors.
Kubo
Tadahiko
T
Department of Orthopaedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Hiroshima 734-8551, Japan. kubot@hiroshima-u.ac.jp
Shimose
Shoji
S
Matsuo
Toshihiro
T
Tanaka
Kumi
K
Yasunaga
Yuji
Y
Sakai
Akira
A
Ochi
Mitsuo
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; C087958:YM 529; C071542:cimadronate