batimastat and Lung-Neoplasms

In this study, we investigated the effect of the matrix metalloproteinase inhibitor batimastat on the lung colonisation of orthotopically implanted malignant pancreatic tumor cells in SCID mice.. Following intraperitoneal anaesthesia, 10(6) Panc-TU-1 cells were orthotopically implanted in the head of the pancreas in 20 SCID mice. Seven days later, treatment of 10 of these mice with an intraperitoneal injection of batimastat (30 mg/kg body weight) was begun and continued for 14 days. Of the mice in the untreated control group, 3 were sacrificed and examined after 7 days, a further 3 after 14 days and the remainder together with the group that had been treated after 21 days.. Tumor growth was clearly visible between the 14th. and the 21st. postoperative day. The orthotopically implanted tumor cells metastasized between the 2nd. and 3rd. postoperative week in the lung. In the control group, a diffuse metastasis of the lung was observed, but in the group of treated mice no lung metastases were found.. In this mouse model, a clear reduction and inhibition of lung metastases from orthotopically implanted pancreatic tumor cells was achieved by treatment with the matrix metalloproteinase inhibitor batimastat.

Topics: Animals; Antineoplastic Agents; Drug Evaluation; Injections, Intraperitoneal; Lung; Lung Neoplasms; Matrix Metalloproteinase Inhibitors; Mice; Mice, SCID; Neoplasm Transplantation; Pancreas; Pancreatic Neoplasms; Phenylalanine; Protease Inhibitors; Thiophenes; Tumor Cells, Cultured

Overexpression of matrix metalloproteinases (MMPs) facilitates tumor cell invasion. Synthetic MMP inhibitors such as batimastat have been designed to treat cancer. We report that because of batimastat treatment, human breast carcinoma cells metastasized to the liver in nude mice and that an increase of liver metastases of murine T-cell lymphoma cells was observed in syngeneic mice. Batimastat treatment also caused liver-specific overexpression of MMPs-2, -9, and mRNA up-regulation of angiogenesis factors and caspase-1, even in tumor-free animals. Induction of organ-specific side effects need to be taken into account regarding further development and clinical use of synthetic MMP inhibitors.

Topics: Angiogenesis Inducing Agents; Animals; Antineoplastic Agents; Caspase 1; Female; Humans; Liver; Liver Neoplasms, Experimental; Lung Neoplasms; Lymphoma, T-Cell; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred DBA; Mice, Nude; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; Phenylalanine; Protease Inhibitors; RNA, Messenger; Thiophenes; Up-Regulation

We developed an orthotopic model of human lung cancer that exhibits highly predictable regional and systemic metastases. This study examines the response of the model when treated with conventional and experimental chemotherapy.. NCI-H460 tumor fragments were implanted into the right caudal lung lobe of a nude rat. Treatment commenced 2 weeks later. We assessed response by comparing primary tumor and mediastinal lymph node weights, total body weight, and length of survival with untreated, tumor-bearing control animals. We also calculated the incidence of metastasis to kidney, bone, brain, and contralateral lung in treated versus untreated animals.. Mitomycin and cisplatin showed broad activity against primary and metastatic disease. The matrix metalloproteinase inhibitor batimastat, low-dose cisplatin, and mitomycin significantly prolonged survival. High-dose cisplatin caused renal toxicity that shortened survival. Brain metastases did not respond to mitomycin, consistent with its poor blood-brain barrier penetration.. Responses were similar to NCI-H460 in vitro data and consistent with clinical experience for these drugs. Drug-related toxicities similar to those seen in clinical practice were detected.

Topics: Analysis of Variance; Animals; Antineoplastic Agents; Carcinoma, Large Cell; Cisplatin; Disease Models, Animal; Doxorubicin; Humans; Lung Neoplasms; Male; Mitomycin; Neoplasm Invasiveness; Neoplasm Transplantation; Phenylalanine; Rats; Rats, Nude; Survival Rate; Thiophenes; Treatment Outcome; Xenograft Model Antitumor Assays

To study the inhibitory effect of matrix metalloproteinase inhibitor BB-94 on the invasion and metastasis of salivary adenoid cystic carcinoma in vitro and in vivo.. Reconstituted basement membrane invasion assay was used to evaluate invasive ability of cancer cells. Type IV collagenase was assessed by PAGE substrate zymography. In addition, the antimetastasis effect of the compound was studied in in vivo experiments using nude mice model of pulmonary metastasis with ACC-M line of human salivary adenoid cystic carcinoma.. BB-94, at the concentrations of 10 mumol/L and 100 mumol/L, suppressed the reconstituted basement invasion of ACC-M human salivary adenoid cystic carcinoma by 32.9%, 53.2% and reduced Type IV collagenase activities in the serum-free supernatant of the same cells. The pulmonary metastasis rate of the control and treated groups was 90.0% and 20.0%, respectively (P < 0.01). The lung weight of the control and treated groups was (0.2090 +/- 0.0667) g and (0.1532 +/- 0.0378) g, respectively (P < 0.05).. These results suggest that the matrix metalloproteinase inhibitor BB-94 has a strong inhibitory effect on invasion and metastasis of salivary adenoid cystic carcinoma.

Topics: Animals; Carcinoma, Adenoid Cystic; Disease Models, Animal; Female; Lung Neoplasms; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Phenylalanine; Protease Inhibitors; Salivary Gland Diseases; Thiophenes

We have examined the effects of the synthetic matrix metalloproteinase inhibitor, batimastat (BB-94) and the angiotensin-converting enzyme inhibitor, captopril, on metalloproteinase activity of murine Lewis-lung-carcinoma cells (3LL) in vitro, and on local growth and lung metastasis of the same tumor implanted intramuscularly in syngeneic C57BL/6 mice. The effect of BB-94 and captopril on the survival of the 3LL-tumor-bearing mice was also examined. Here we report that captopril treatment resulted in decreased transcription and protein levels of gelatinase A by 3LL cells. Both BB-94 and captopril also prevented substrate degradation by gelatinase A and B released in conditioned medium by cultured cells. Treatment of tumor-bearing animals with BB-94 (i.p.) or captopril (in drinking water) resulted in significant inhibition of the mean tumor volume (25 and 33% respectively) and of the mean lung metastasis number (26 and 29% respectively). When both agents were given, they acted in synergy, resulting in 51 and 80% inhibition of tumor growth and metastasis. The survival time of the mice treated with both BB-94 and captopril was also significantly longer compared with the groups treated with each agent alone or with the vehicle. Our data support the hypothesis of an essential role of metalloproteinase(s) in the metastatic process. Moreover, blockade of invasion, angiogenesis and other processes mediated by metalloproteinases may underlie the anti-tumor and anti-metastatic effect of BB-94 and captopril and their combination. It is conceivable that this combination could be tested in selected clinical conditions as an adjuvant modality to cytotoxic therapy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antineoplastic Agents; Blotting, Northern; Blotting, Western; Captopril; Carcinoma, Lewis Lung; Cell Division; Collagenases; Culture Media, Conditioned; Female; Gelatin; Gelatinases; Lung Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Phenylalanine; Protease Inhibitors; Survival Rate; Thiophenes

We examined the effects of the synthetic matrix metalloproteinase inhibitor batimastat (BB-94) on lung colonization and spontaneous metastasis of a rat mammary carcinoma, HOSP.1P. This tumor expresses both latent and active forms of the matrix metalloproteinases MMP-2 and MMP-9, although the former, as in human breast cancer, is the most prominent. Administration of batimastat (6 x 30 mg/kg i.p.) inhibited by up to 80% both the number and median weights of HOSP.1P lung colonies following i.v. inoculation of cells. This implies an effect both on seeding efficiency and subsequent tumor development. In spontaneous metastasis assays, limited treatment with batimastat (commencing when s.c. tumors were established and continuing until 5 or 14 days after their surgical removal) significantly inhibited lung metastasis but had little effect on lymphatic metastasis. However, when treatment was initiated 2 days prior to surgery and continued until day 70, 100% of animals survived to day 120 when there was no evidence of metastatic disease. All control animals (n = 25) in two separate experiments died before day 100 with lymphatic, lung, and extrapulmonary metastases. Taken together, these data suggest that lymphatic dissemination by HOSP.1P tumor cells is less susceptible to inhibition by batimastat than vascular invasion, but that long-term treatment can effectively prevent the outgrowth of putative micrometastases in both lymph nodes and lungs, allowing sustained tumor-free survival.

Topics: Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Female; Gelatinases; Lung Neoplasms; Mammary Neoplasms, Animal; Matrix Metalloproteinase 2; Metalloendopeptidases; Neoplasm Metastasis; Phenylalanine; Rats; Specific Pathogen-Free Organisms; Survival Rate; Thiophenes

Matrix metalloproteinases (MMPs) are involved in the invasion and metastasis of human cancers by mediating the degradation of extracellular matrix components. Therefore, these enzymes constitute promising targets in the development of anticancer therapies. Batimastat ([(4-N-hydroxyamino)-2R-isobutyl-3S-(thienyl-thiomethyl)succinyl]-L- phenyl-alanine-N-methylamide) is one of a new class of agents designed to inhibit MMP activity.. We asked whether batimastat, given as adjuvant therapy after primary tumor resection, could inhibit local-regional tumor regrowth and the formation of lung metastases in a human breast cancer xenograft model. We also explored possible effects of batimastat on breast cancer cell viability and on the accumulation of specific messenger RNAs (mRNAs).. Human MDA-MB-435 breast cancer cells were treated in vitro for 6 days with batimastat at concentrations ranging from 0.1 to 10.0 microM, and then viable cell counts were performed. The activity of collagenases, directly associated with cultured MDA-MB-435 cells or released into their culture fluids, was assessed by gelatin zymography after 1 and 3 days of batimastat treatment (drug range, 0.2-2.0 microM). Athymic nude mice were given daily intraperitoneal injections of batimastat (30 mg/kg body weight) after resection of MDA-MB-435 primary tumors grown in their mammary fat pads; the volumes of tumor regrowths and the numbers and volumes of lung metastases were calculated; neovascularization in the regrowths was assessed by immunohistochemical analysis with an antibody directed against CD31, an endothelial cell antigen. The effect of batimastat treatment on the accumulation of mRNAs encoding specific MMPs and the tissue inhibitor of metalloproteinases-2 (TIMP-2) in cultured cells, primary tumors, and tumor regrowths was measured by RNA dot blotting and hybridization with complementary probes. Linear regression analysis, Student's t tests, and chi-squared analysis were used to evaluate the data.. The viability of cultured MDA-MB-435 cells was not affected by treatment with batimastat; however, measured activities for the 72-kd and 92-kd collagenases released by these cells were reduced after batimastat treatment. Intraperitoneal injection of batimastat significantly inhibited the local-regional regrowth of resected MDA-MB-435 tumors in athymic nude mice (in comparison with control mice, P = .035), and it reduced the incidence (P < .05), number (P = .0001), and total volume (P = .0001) of lung metastases. Batimastat treatment did not affect cellular levels of MMP or TIMP-2 mRNAs.. Batimastat inhibits human breast cancer regrowth and metastasis in a nude mouse xenograft model. Potential mechanisms for batimastat's inhibitory activity do not include direct cell toxicity or alteration of MMP or TIMP mRNA levels.

Topics: Animals; Breast Neoplasms; Chemotherapy, Adjuvant; Chi-Square Distribution; Collagenases; Female; Humans; Linear Models; Lung Neoplasms; Metalloendopeptidases; Mice; Mice, Nude; Neoplasm Recurrence, Local; Neoplasm Transplantation; Phenylalanine; RNA, Messenger; RNA, Neoplasm; Thiophenes; Tumor Cells, Cultured

The synthetic matrix metalloproteinase inhibitor batimastat was tested for its ability to inhibit growth and metastatic spread of the B16-BL6 murine melanoma in syngeneic C57BL/6N mice. Intraperitoneal administration of batimastat resulted in a significant inhibition in the number of lung colonies produced by B16-BL6 cells injected i.v. The effect of batimastat on spontaneous metastases was examined in mice inoculated in the hind footpad with B16-BL6 melanoma. The primary tumor was removed surgically after 26-28 days. Batimastat was administered twice a day from day 14 to day 28 (pre-surgery) or from day 26 to day 44 (post-surgery). With both protocols, the median number of lung metastases was not significantly affected, but there was a significant reduction in the weight of the metastases. Finally, the effect of batimastat was examined on s.c. growth of B16-BL6 melanoma. Batimastat administered daily, starting at day of tumor transplantation, resulted in a significant growth delay, whereas treatment starting at advanced stage tumor only reduced tumor growth marginally. Our results indicate that a matrix metalloproteinase inhibitor can not only prevent the colonization of secondary organs by B16-BL6 cells but also limit the growth of solid tumors.

Topics: Animals; Cell Division; Dose-Response Relationship, Drug; Female; Lung Neoplasms; Melanoma, Experimental; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Phenylalanine; Thiophenes; Tissue Distribution