A novel bisphosphonate minodronate (YM529) specifically inhibits osteolytic bone metastasis produced by human small-cell lung cancer cells in NK-cell depleted SCID mice.
In the present study, we examined the effects of a newly developed bisphosphonate, minodronate (YM529), on osteolytic bone metastasis caused by lung cancer. Human small-cell lung cancer (SBC-5) cells, injected intravenously into natural killer cell-depleted SCID mice, produced radiologically detectable bone metastasis by day 18 and macroscopically visible visceral metastases (lung, liver, kidney, systemic lymph node) by day 35. Prophylactic treatment with YM529 on day 1 significantly inhibited the formation of osteolytic bone metastasis evaluated on X-ray photographs in a dose-dependent manner. In addition, treatment with YM529 after establishment of bone metastasis (on day 21) also inhibited bone metastasis, although the treatment was more effective when started earlier. Single administration was as effective as repeated treatment, suggesting a sustained inhibitory effect of YM529 on bone metastasis. YM529 reduced the number of osteoclasts in the bone metastatic lesions in vivo, but had no effect on the proliferation or cytokine production of SBC-5 cells in vitro. These results suggest that YM529 is a potent inhibitor of bone metastasis of human lung cancer, probably by suppressing osteoclastic bone resorption. In contrast, treatment with YM529 had no effect on visceral metastasis, even if started on day 1, and did not prolong the survival of the mice. Therefore, development of a combined modality is necessary for prolonging the survival of small-cell lung cancer patients with multiple-organ metastasis.
Zhang
Helong
H
Department of Internal Medicine and Molecular Therapeutics, University of Tokushima School of Medicine, Tokushima, Japan.
Yano
Seiji
S
Miki
Toyokazu
T
Goto
Hisatsugu
H
Kanematsu
Takanori
T
Muguruma
Hiroaki
H
Uehara
Hisanori
H
Sone
Saburo
S
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary*; D001862:Bone Resorption / Q000188:drug therapy; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004164:Diphosphonates / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000556:secondary; D007694:Killer Cells, Natural / Q000502:physiology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008207:Lymphatic Metastasis / Q000517:prevention & control; D008212:Lymphocyte Depletion; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010014:Osteolysis; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000276:immunology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000970:Antineoplastic Agents; D016207:Cytokines; D004164:Diphosphonates; D016228:Endothelial Growth Factors; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C087958:YM 529