batimastat and Bone-Neoplasms

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Disease Models, Animal; Humans; Male; Matrix Metalloproteinase Inhibitors; Neoplasm Metastasis; Phenylalanine; Prostatic Neoplasms; Thiophenes

The metastasis of prostate cancer to bone is associated with a substantial increase in bone matrix turnover. Matrix metalloproteinases (MMPs) play roles in both normal bone remodeling and invasion and metastasis of prostate cancer. This study was designed to determine the role of MMP activity in prostate cancer that has metastasized to bone.. Single human fetal bone fragments were implanted subcutaneously in immunodeficient mice. Four weeks later, PC3 human prostate cancer cells were injected directly into some of the implants, and daily treatment was begun with batimastat (a broad-spectrum MMP inhibitor). There were six mice (i.e., six implants) in each of four experimental arms: bone alone with and without batimastat and bone injected with PC3 cells with and without batimastat. Bone implants were harvested after 14 days of treatment and analyzed for MMP expression, bone histomorphometry, osteoclast counts, blood vessel density, and tumor cell proliferation and apoptosis. Complementary data were obtained from bone biopsy samples from patients and a bone organ coculture system. All statistical tests were two-sided.. MMPs were detected in tumor and stromal cells of clinical specimens and experimental bone implants. In vivo, MMP inhibition reduced the number of osteoclasts per millimeter in PC3-injected implants-from 8.2 (95% confidence interval [CI] = 7.9 to 8.5) to 3.0 (95% CI = 2.3 to 3.7) (P =.006). In addition, it prevented degradation of marrow trabeculae within the bone implants (cross-sectional area of implant occupied by mineralized trabeculae: untreated implant = 29.1% [95% CI = 27.1% to 31.1%], PC3-injected implant = 14.0% [95% CI = 10.9% to 17.1%] [P =.005 versus untreated], and batimastat-treated PC3-injected implant = 27.2% [95% CI = 22.4% to 32.0%] [P =.03 versus PC3 injected alone]). MMP inhibition reduced proliferating tumor cells from 20.8% (95% CI = 19.9% to 21.7%) to 7.4% (95% CI = 5.2% to 9.6%) (P =.006), without affecting angiogenesis or apoptosis. In vitro, MMP inhibition had no toxic effect on PC3 cells but prevented calcium release from bone fragments cocultured with PC3 cells.. MMP activity appears to play an important role in bone matrix turnover when prostate cancer cells are present in bone. Bone matrix turnover and metastatic tumor growth appear to be involved in a mutually supportive cycle that is disrupted by MMP inhibition.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bone Neoplasms; Bone Remodeling; Bone Transplantation; Calcium; Disease Models, Animal; Fetal Tissue Transplantation; Humans; Immunohistochemistry; In Situ Hybridization; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, SCID; Neoplasm Metastasis; Oligonucleotide Probes; Osteoclasts; Phenylalanine; Prostatic Neoplasms; RNA, Messenger; Thiophenes; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

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.. In the present study, we tested two general MMP inhibitors, BB-94 and GM6001, in a mouse model of breast cancer-induced bone metastasis.. 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.. The present study suggests the potential of synthetic MMP inhibitors as intervention or prevention treatments of breast cancer-induced osteolysis.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Cell Survival; Dipeptides; Female; Genetic Therapy; Humans; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Osteolysis; Phenylalanine; Protease Inhibitors; Thiophenes; Transfection; Transplantation, Heterologous; Tumor Cells, Cultured

Bone resorption is a dominant feature of many bone metastases and releases factors from the bone matrix that can promote the expression of the metastatic phenotype in cancer cells. Since proteolytic enzymes, including matrix metalloproteinases (MMPs) contribute to bone destruction by metastatic tumour cells and host cells, we have examined the effect of a MMP inhibitor, batimastat, on the ability of MDA-MB-231 cells to degrade bone in vitro and to form bone metastases in BalbC nu/nu mice. In vitro, the neoplastic cells produced MMP-2 and MMP-9, degraded [3H]-proline-labelled osteoblast matrices, and formed resorption pits in cortical bone. These phenomena were inhibited by < or = 20 microM batimastat. To induce vertebral and long bone metastases in vivo, 1x10(5) MDA-MB-231 cells were injected into the arterial circulation of BalbC nu/nu mice. Test groups were also given 30 mg/kg batimastat intraperitoneally (i.p.). After 21 days, the long bone metastases were characterised by a 67% reduction of metaphyseal medullary bone and complete replacement of marrow by tumour. In tumour-bearing mice that had been treated with 30 mg/kg batimastat i.p., the tumour volume decreased 8-fold, osteolysis was inhibited by 35%, and replacement of the bone marrow by tumour was inhibited by 65%. Similar effects were observed in the vertebral metastases. These data provide evidence that MDA-MB-231 cells can degrade osteoblast matrices and mineralised bone in vitro and support the hypothesis that MMPs are involved in the pathogenesis of osteolytic bone metastases in vivo. They demonstrate that an agent which inhibits proteolysis can retard the development of osteolytic bone metastases in this model.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Humans; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred BALB C; Phenylalanine; Thiophenes; Tumor Cells, Cultured