Synthetic matrix metalloproteinase inhibitors inhibit growth of established breast cancer osteolytic lesions and prolong survival in mice.
OBJECTIVE
Breast cancer frequently leads to incurable bone metastasis. Essential requirements for the development of bone metastasis are cell-cell and cell-matrix interactions, release of bioactive growth factors and cytokines, and removal of large amounts of bone matrix. Matrix metalloproteinases (MMPs) play an important role in all of these processes, but the possibility of using synthetic MMP inhibitors to decrease bone metastasis has received little attention.


METHODS
In the present study, we tested two general MMP inhibitors, BB-94 and GM6001, in a mouse model of breast cancer-induced bone metastasis.


RESULTS
In a simulation of intervention therapy, mice were inoculated with breast cancer cells, and at the time of diagnosis of osteolytic lesions, the mice were treated for 10 or 15 consecutive days with BB-94 or GM6001, respectively. Both inhibitors reduced the growth of osteolytic lesions by >55% compared with control mice. Next, we simulated prevention therapy by initiating treatment with GM6001 at time of inoculation with cancer cells or 3 days earlier. Assessment of osteolytic lesions 28 days after inoculation showed that, in both cases, the treatment reduced the size of the osteolytic lesions by 60%, compared with that of control mice. Importantly, MMP inhibition also resulted in extension of symptom-free survival in the mice, whether the treatment was initiated at the time of diagnosis of osteolytic lesions or of cancer cell inoculation.


CONCLUSIONS
The present study suggests the potential of synthetic MMP inhibitors as intervention or prevention treatments of breast cancer-induced osteolysis.
Winding
Bent
B
Center for Clinical and Basic Research, Nordic Bioscience, Herlev/Ballerup, Herlev Hovedgade 207, DK-2730 Herlev, Denmark.
NicAmhlaoibh
Róisín
R
Misander
Henriette
H
Høegh-Andersen
Pernille
P
Andersen
Thomas Levin
TL
Holst-Hansen
Claus
C
Heegaard
Anne-Marie
AM
Foged
Niels Taekker
NT
Brünner
Nils
N
Delaissé
Jean-Marie
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control*; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010014:Osteolysis / Q000517:prevention & control*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat