Prevention of metastasis by a polyamine synthesis inhibitor in an animal bone metastasis model.
In order to better understand the development of skeletal metastases, we developed an appropriate animal model, as the natural progression of metastases in humans cannot be studied on the cellular level. In this study, we established a new animal model which developed bone metastasis in a bone grafted subcutaneously. C57BL/6 mice, which had received a bone (femur or tibia) transplanted in the dorsal subcutis, were injected with B16 melanoma cells into the left heart ventricle. Metastasis was found in approximately 70% of the extraskeletal bones. Using this model, the antimetastatic effect of a polyamine synthesis inhibitor was investigated. Inhibitors of the polyamine biosynthetic pathway have received considerable attention for their potential use in the treatment of cancer as they are responsible for the greatly increased production of the polyamines putrescine, spermidine, and spermine. A polyamine synthesis inhibitor, methylglyoxal-bis(cyclopentylamidinohydrazone) MGBCP, was investigated for its inhibitory effects on bone metastases. MGBCP (20 mg/kg) was administered intraperitoneally every day for 4 weeks and demonstrated strong inhibitory effects on bone metastases. MGBCP inhibited angiogenesis in the transplanted bone and the growth of B16 melanoma cells, thus suggesting a preventive mechanism in bone metastasis. No remarkable adverse effects of MGBCP were observed in any animal throughout the experimental period. Our results indicate that MGBCP has a strong potential for use as an anti-metastatic drug.
Wakabayashi
H
H
Department of Orthopedic Surgery, Faculty of Medicine, Mie University, Mie, Japan.
Hibasami
H
H
Iida
K
K
Satoh
N
N
Yamazaki
T
T
Sonoda
J
J
Hirata
H
H
Nakashima
K
K
Uchida
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000098:blood supply / Q000517:prevention & control / Q000556:secondary*; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D008545:Melanoma / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008935:Mitoguazone / Q000031:analogs & derivatives / Q000494:pharmacology; D009389:Neovascularization, Pathologic; D011073:Polyamines / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011073:Polyamines; C059234:methylglyoxal bis(cyclopentylamidinohydrazone); D008935:Mitoguazone