batimastat and Prostatic-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

Increased concentrations of metalloproteinases are associated with the invasive and metastatic behavior of several human malignant tumors. Normally, enzymatic activity is tightly regulated by nonspecific mechanisms and specific inhibitors. The aim of the study was to determine the potential of a synthetic metalloproteinase inhibitor, batimastat, to show its in vitro effect on MatLyLu cancer cells and its in vivo effect on tumor growth in orthotopic cancer (R3327 Dunning tumor) in rats.. In vitro, a dose response curve of batimastat was generated over 4 days using the MTT assay. Prostate cancer was injected in vivo in male Copenhagen rats by inoculating R3327 Dunning tumor cells (MatLyLu) into the ventral prostatic lobe of 30 rats. Each of 10 rats received batimastat (30 mg/kg body weight) or vehicle administered once a day by i.p. application beginning the day of cell inoculation. Ten rats remained untreated. The effect on local tumor growth was evaluated by measuring tumor weights 20 days after tumor cell inoculation.. Significant inhibition of tumor cell proliferation in vitro occurred at 400 and 4,000 ng/ml batimastat. After orthotopic cell inoculation, tumors grew to mean weights of 18.9 g in the control group without treatment, to 22.3 g in the vehicle group, and to 11.1 g in the treated group. In comparison to the control group and to the vehicle group, tumor weights increased significantly less under treatment with batimastat.. Batimastat is able to reduce tumor growth in the standard prostate cancer model. Using this model, activity against cancer progression of future inhibitory agents can be reliably assessed.

Topics: Animals; Antineoplastic Agents; Cell Division; Dose-Response Relationship, Drug; Male; Neoplasm Transplantation; Phenylalanine; Prostatic Neoplasms; Rats; Thiophenes; Tumor Cells, Cultured

It has been suggested that increased metalloproteinase activity is a critical event in neoplastic progression leading to the initiation of local invasion and ultimately to the dissemination of neoplastic cells. This has led to an interest in testing the ability of metalloproteinase inhibitors to prevent the progression of carcinoma in situ into invasive and, therefore, more malignant tumors. One such agent is the synthetic matrix metalloproteinase inhibitor, BB-94.. The effect of BB-94 on the intrinsic invasive potential of matrilysin-transfected Du-145 cells was evaluated by an in vitro invasion assay. In addition a diaphragm invasion model, which provides an easily oriented structure in which the earliest penetration of the basal lamina can be observed, was used to investigate the effect of BB-94 on the invasion and growth of tumors formed by these cells when injected into S.C.I.D. mice.. The synthetic matrix metalloproteinase inhibitor, BB-94, was shown to effectively inhibit the invasion of matrigel and murine diaphragm.. Metalloproteinase inhibitors, such as BB-94, that are able to limit tumor growth, and local invasion, may decrease the invasion of invasive carcinomas.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Carcinoma in Situ; Humans; Male; Metalloendopeptidases; Mice; Mice, SCID; Neoplasm Invasiveness; Phenylalanine; Prostatic Neoplasms; Protease Inhibitors; Thiophenes; Transplantation, Heterologous; Tumor Cells, Cultured