batimastat and Ovarian-Neoplasms

Matrix metalloproteinases (MMPs) are a homologous family of enzymes that are involved in tissue remodeling and morphogenesis. Collectively, these enzymes are capable of degrading all components of the extracellular matrix, and they play an important role in normal physiologic conditions, such as wound healing and other processes involving tissue remodeling. However, increased activity of these enzymes now has been observed in a number of different pathological conditions, and it has been hypothesized that such increased activity of MMPs might play a role in the pathogenesis of these conditions. Cancer is one such condition; extracellular matrices constitute the principal barrier to tumor growth and spread, and there is growing experimental evidence that malignant tumors utilize MMPs to overcome these barriers. Consequently, inhibitors of MMPs represent an attractive target for a new class of anticancer agents. Marimastat and batimastat are potent broad-spectrum inhibitors of all major MMPs and have been shown to prevent or reduce spread and growth of a number of different malignant tumors in numerous animal models. Both agents are now in advanced clinical testing in a number of different solid tumors in North America and Europe. The purpose of this paper is to review available preclinical and emerging clinical data, using batimastat and marimastat as prototype MMP inhibitors in the cancer area.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Colorectal Neoplasms; Enzyme Inhibitors; Female; Hemangioma; Humans; Hydroxamic Acids; Melanoma; Metalloendopeptidases; Mice; Ovarian Neoplasms; Pancreatic Neoplasms; Phenylalanine; Protease Inhibitors; Skin Neoplasms; Thiophenes

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Colorectal Neoplasms; Female; Humans; Metalloendopeptidases; Mice; Mice, Nude; Ovarian Neoplasms; Phenylalanine; Thiophenes; Transplantation, Heterologous

This study investigated the functional interplay between vascular endothelial growth factor (VEGF) and metalloproteinases (MMPs) in ovarian carcinomas. Levels of MMP9 (pro and activated form) and proMMP2 in ascites correlated with VEGF and with the ascitic volume in nude mice bearing human ovarian carcinoma xenografts (HOC22 and HOC8). The MMP inhibitor batimastat (BB-94) reduced VEGF release and ascitic fluid formation. Exogenous, activated MMP9, and, to a lesser extent, MMP2, increased VEGF release by SKOV3 and OVCAR3 ovarian carcinoma cells. The effect was dose and time dependent and inhibited by BB-94. MMP9-released VEGF was biologically active, because it induced endothelial cell motility, and its activity was prevented by the VEGF inhibitor SU5416. Our results indicate that MMPs, mainly MMP9, play a role in the release of biologically active VEGF and consequently in the formation of ascites.

Topics: Animals; Ascites; Cell Movement; Culture Media, Conditioned; Endothelial Growth Factors; Enzyme Activation; Female; Humans; Intercellular Signaling Peptides and Proteins; Lymphokines; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Nude; Ovarian Neoplasms; Peritoneal Cavity; Phenylalanine; Thiophenes; Transplantation, Heterologous; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Antineoplastic Agents; Bromodeoxyuridine; Cell Cycle; Female; Humans; Metalloendopeptidases; Ovarian Neoplasms; Phenylalanine; Protease Inhibitors; Thiophenes

Batimastat (also known as BB-94) is a synthetic matrix metalloproteinase inhibitor that has shown antineoplastic and antiangiogenic activity in various tumor models. In this study, two human ovarian carcinoma (HOC) xenografts (HOC22 and HOC8) were used to investigate the effect of batimastat on the antineoplastic activity of cisplatin. Both xenografts produced ascites and solid lesions in the peritoneal cavity of nude mice. HOC cells were inoculated i.p. in nude mice, and treatment was started at different stages of the disease. Batimastat was administered alone or concurrently with or subsequent to cisplatin therapy. In all of the protocols, the response of HOC xenografts was confirmed by cytological analysis of ascites and histological examination of the organs in the peritoneal cavity. Treatment of nude mice bearing early-stage (3 days after tumor implantation) HOC22 or HOC8 with cisplatin or batimastat alone delayed tumor growth and increased the survival time of the mice, although all animals eventually died. In contrast, treatment with batimastat (60 mg/kg i.p. every other day, for a total of eight injections) concomitantly with cisplatin (4 mg/kg i.v., every 7 days for a total of three injections) completely prevented growth and spread of both xenografts, and all animals were alive and healthy on day 200. The potentiation of cisplatin's activity by batimastat was dose dependent and was observed in the treatment of both advanced (7 days after tumor inoculation) and late-stage (20 days after inoculation) tumor. The administration of batimastat following cisplatin therapy also led to significant improvement in the survival of mice compared to treatment with cisplatin alone. These results suggest a potentiation of the antineoplastic activity of cisplatin by batimastat and support the use of the two agents in combination in the treatment of ovarian cancer patients.

Topics: Animals; Antineoplastic Agents; Carcinoma; Cisplatin; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Female; Humans; Metalloendopeptidases; Mice; Mice, Nude; Ovarian Neoplasms; Phenylalanine; Protease Inhibitors; Survival Analysis; Thiophenes; Transplantation, Heterologous

Locoregional human IFN-gamma may have activity against refractory ovarian cancer. We investigated this further in an ovarian cancer xenograft model. Administered at clinically relevant doses, intraperitoneal IFN-gamma prolonged the survival of mice bearing multiple established peritoneal tumours, with optimal treatment giving a 3-6-fold increase in median survival time. Daily dosing, which was superior to intermittent treatment, decreased DNA synthesis and induced apoptosis in tumour cells with maximal effects after 7-21 days treatment. This was preceded by an increase in p53 protein at 48 h. The effect of IFN-gamma was not enhanced by sequential treatment with carboplatin. However, the matrix metalloprotease inhibitor, batimastat, further increased mouse survival when given after IFN-gamma. Thus IFN-gamma is cytotoxic to ovarian epithelial cells in vivo and intensive locoregional dosing over short periods is effective. Sequential administration of novel agents that perturb the host/tumour relationship may be of benefit.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carboplatin; Cell Division; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Cystadenocarcinoma, Serous; Drug Screening Assays, Antitumor; Drug Synergism; Female; Humans; Interferon-gamma; Metalloendopeptidases; Mice; Mice, Nude; Ovarian Neoplasms; Phenylalanine; Survival Rate; Thiophenes; Transplantation, Heterologous; Tumor Suppressor Protein p53

Matrix metalloproteinase inhibitors represent a new therapeutic approach to the treatment of advanced cancer. These inhibitors block the activity of proteolytic enzymes, matrix metalloproteinases, used by tumor cells to break down and remodel tissue matrices during the process of metastatic spread. As such they were regarded initially as inhibitors of metastasis. However, recent studies have shown that these inhibitors can also act to inhibit tumor growth by (i) preventing local invasion and promoting stromal encapsulation and (ii) by inhibiting tumor neovascularization. Matrix metalloproteinase inhibitors therefore have the potential to halt tumor progression and it is possible to envision their use as a low toxicity complement to cytotoxic therapies. Batimastat (BB-94) is the first inhibitor of this class to enter clinical trial in cancer patients. In a phase I/II trial in patients with malignant ascites batimastat was well tolerated and there were preliminary signs of efficacy.

Topics: Animals; Antineoplastic Agents; Colonic Neoplasms; Female; Humans; Melanoma, Experimental; Metalloendopeptidases; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasms; Ovarian Neoplasms; Phenylalanine; Protease Inhibitors; Thiophenes

We have examined the effect of a synthetic low-molecular-weight matrix metalloproteinase inhibitor, [4-(N-hydroxyamino)-2R-isobutyl-3S- (thiopen-2-ylthiomethyl)-succinyl]-L-phenylalanine-N-meth yla mide (BB-94), on human ovarian carcinoma xenografts growing in nude mice. The xenografts grew as thick intraperitoneal mucinous ascites containing free-floating tumor cell clumps. The ascites increased in volume, causing death approximately 3 weeks after introduction. Treatment with BB-94 caused resolution of ascitic disease. Tumor burden was dramatically reduced, and survival increased 5-6-fold. The increase in survival was dose dependent. The effects observed with BB-94 appeared to be due to its matrix metalloproteinase inhibiting effects, inasmuch as its inactive diastereoisomer had no effect on tumor biology. Following treatment with BB-94, free-floating clumps of tumor cells became surrounded by a capsule of host cells. These clumps of tumor cells typically formed one small (approximately 8 mm) avascular tumor of bright white appearance loosely attached to fat in the peritoneum. Tumor cells within these capsules often appeared to be necrotic. Gel substrate analysis demonstrated that activated Mr 92,000 type IV collagenase was present in the xenografts. We propose that inhibition of this enzyme causes the transition of ascites to solid tumors, concomitantly slowing tumor cell growth and allowing the development of tumor stroma.

Topics: Aged; Animals; Carcinoma; Cell Division; Extracellular Matrix; Female; Humans; In Vitro Techniques; Metalloendopeptidases; Mice; Molecular Structure; Neoplasm Transplantation; Ovarian Neoplasms; Phenylalanine; Survival Analysis; Thiophenes; Transplantation, Heterologous; Tumor Cells, Cultured