batimastat and Ascites

Topics: Adult; Aged; Animals; Antineoplastic Agents; Ascites; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Extracellular Matrix; Female; Humans; Male; Metalloendopeptidases; Mice; Middle Aged; Neoplasms; Phenylalanine; Pleural Effusion, Malignant; Protease Inhibitors; Rats; Thiophenes

This was an open Phase I study of i.p. matrix metalloproteinase inhibitor BB94 in patients with malignant ascites. The objective of the study was to determine the effect of increasing i.p. doses of BB94 with reference to the tolerance, safety, and pharmacokinetics of the compound. Twenty-three patients with malignant ascites had BB94 instilled into the peritoneal cavity after paracentesis. The compound was well tolerated; no serious adverse events were seen, and no specific toxicities were observed. High plasma concentrations were seen an hour after dosing, and BB94 was still present in the plasma at day 28 after treatment at levels in excess of the IC50 identified in preclinical studies. Five of the 23 patients neither reaccumulated ascites nor died up to 112 days after dosing. Seven patients died without reaccumulating ascites. Although the study was not designed to demonstrate clinical efficacy, the results were encouraging and support the further therapeutic evaluation of matrix metalloproteinase inhibitors in the management of malignant ascites.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Ascites; Dose-Response Relationship, Drug; Female; Humans; Male; Metalloendopeptidases; Middle Aged; Neoplasms; Phenylalanine; Protease Inhibitors; Thiophenes

Matrix metalloproteinases have been shown to be important in tumour invasion and metastasis, and the use of matrix metalloproteinase inhibitors in animal models has suggested that these agents may be useful in the control of malignant disease. This article reports the results of an early clinical trial of batimastat, one of the first generation of metalloproteinase inhibitors, in patients with malignant ascites. The drug was well absorbed via the intraperitoneal route and associated with few side-effects. Furthermore, a response to treatment was seen in about half the evaluable patients with advanced malignant disease. The results suggest that further research on the use of matrix metalloproteinase inhibitors in patients with malignant disease is worthwhile.

Topics: Aged; Antineoplastic Agents; Ascites; Gastrointestinal Neoplasms; Humans; Infusions, Parenteral; Metalloendopeptidases; Middle Aged; Phenylalanine; Protease Inhibitors; Thiophenes; Treatment Outcome

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: Animals; Antineoplastic Agents; Ascites; Drugs, Investigational; Humans; Matrix Metalloproteinase Inhibitors; Metalloendopeptidases; Mice; Neoplasms; Phenylalanine; Pleural Effusion, Malignant; Protease Inhibitors; Thiophenes

Matrix metalloproteinases (MMPs) are thought to play a significant role in tumor invasion and metastasis as well as angiogenesis. Batimastat, also known as BB-94, acts as an inhibitor of metalloproteinase activity by binding the zinc ion in the active site of MMPs. In our study, the hormone-independent MDA435/LCC6 human breast cancer cell line was used to seed solid tumors s.c. into the region of the mammary fat pad in athymic nude mice. Mice were treated with 50 mg/kg batimastat i.p. Tumor volume measurements showed a statistically significant decrease in tumor size between batimastat-treated and control animals. In contrast, we also used the same MDA435/LCC6 cell line to propagate a malignant ascites in nude mice, which yielded a very different response to batimastat. Batimastat, in previously published literature, had been shown to prolong the life of mice bearing ovarian ascites tumors. Treatment with batimastat in our ascites model produced no increase in survival or significant suppression of ascites formation. However, treated animals showed dramatic tumor cell consolidation and less dispersed ascites cells compared with control animals. Two potential targets of batimastat, gelatinase A and B (MMP-2 and -9, respectively), were examined in both tumor sites. These metalloproteinases were present in both solid tumor and ascites fluid and in both cases were host derived and not produced by the tumor. We conclude that batimastat may have different effects on tumor progression and growth depending on the site of tumor implantation.

Topics: Animals; Antineoplastic Agents; Ascites; Female; Gelatinases; Humans; Mammary Neoplasms, Experimental; Metalloendopeptidases; Mice; Mice, Nude; Neoplasm Transplantation; Phenylalanine; Protease Inhibitors; Thiophenes; Transplantation, Heterologous; Tumor Cells, Cultured