bay-12-9566 and Neoplasms

The cancer cells secrete proteolytic enzymes, which are important in the tumor spreading. The cells must cross basement membrane and extracellular matrix barriers in order to spread. The matrix metalloproteinases are a family of endopeptidases, which enzymatic activity depends on the presence of zinc ion in the catalytic domain. Matrix metalloproteinases hydrolyze extracellular matrix components such as collagen, laminin, fibronectin, proteoglycans and contribute to the spreading of tumor cells by eliminating the surrounding extracellular matrix and basement membrane barriers. This review describes matrix metalloproteinases family classification and structure, their role under physiological conditions and induced proteolysis during pathological processes. There is a balance between proteolytic extracellular matrix degradation and proteolysis inhibition, but under pathological state (e. g. tumor development) the proteolysis becomes uncontrolled. We review tissue inhibitors of matrix metalloproteinases and synthetic matrix metalloproteinase inhibitors, their perspective in cancer treatment; as well as different matrix metalloproteinases expression in patients with tumors and its prognostic significance during cancer progression.

Topics: Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Clinical Trials as Topic; Diphosphonates; Disease Progression; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Humans; Hydroxamic Acids; Imidazoles; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Organic Chemicals; Phenylalanine; Phenylbutyrates; Prognosis; Protease Inhibitors; Thiophenes; Time Factors; Tissue Inhibitor of Metalloproteinases

With an increasing number of targeted agents available for testing, clinical trials must be rationally designed based on sound knowledge of the molecular mechanisms linking target and disease, fortified by strong preclinical data demonstrating how this relationship is modified by the targeted agent. Patients and resources are precious and should be expended judiciously on clinical trials that are well planned. Although traditional trial designs and endpoints may not be adequate for developing contemporary targeted drugs, transiting directly from phase I to phase III testing should be avoided except in distinct circumstances. Increased research efforts should be spent on the prospective evaluation and validation of novel biologic endpoints and innovative clinical designs, such that promising targeted agents can be effectively developed to benefit the care of cancer patients.

Topics: Animals; Antineoplastic Agents; Benzamides; Biomarkers; Biphenyl Compounds; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Controlled Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Imatinib Mesylate; Matrix Metalloproteinase Inhibitors; Mice; Neoplasm Proteins; Neoplasms; Organic Chemicals; Outcome Assessment, Health Care; Patient Selection; Phenylbutyrates; Piperazines; Protein-Tyrosine Kinases; Pyrimidines; Randomized Controlled Trials as Topic; Rats

The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Biphenyl Compounds; Clinical Trials as Topic; Drugs, Investigational; Enzyme Inhibitors; Humans; Hydroxamic Acids; Imidazoles; Matrix Metalloproteinase Inhibitors; Neoplasms; Organic Chemicals; Phenylalanine; Phenylbutyrates; Protease Inhibitors; Pyrazines; Sulfonamides; Tetracycline; Tetracyclines; Thiophenes

Matrix metalloproteinases (MMPs) have been implicated in the invasive growth and spread of tumours. Potent and selective inhibitors of MMPs have been synthesized. These inhibitors can prevent tumour invasion in vitro and have suppressed tumour growth and metastasis in animal cancer models. Several MMP inhibitors have now reached clinical trials. Phase I studies indicate that the inhibitors can be given by mouth and that over the short term they are well tolerated. Longer, randomised studies in cancer patients are now underway.

Topics: Antineoplastic Agents; Biphenyl Compounds; Clinical Trials as Topic; Humans; Metalloendopeptidases; Neoplasms; Organic Chemicals; Phenylbutyrates; Protease Inhibitors

This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in combination with doxorubicin in patients with advanced solid tumours, and to identify the maximum tolerated dose of these agents in combination and the dose for use in subsequent studies.. 14 patients were entered onto 3 dose levels consisting of escalating doses of doxorubicin (50 mg/m(2), 60 mg/m(2) and 70 mg/m(2)) with 800 mg po bid BAY 12-9566. At all three dose levels, patients received doxorubicin alone in cycle one on day 1. Daily oral dosing with BAY 12-9566 was started on day 8 of cycle 1, and thus doxorubicin was given concurrently with BAY 12-9566 in cycle 2. Patients were continued on treatment until a dose limiting toxicity or tumour progression occurred.. Pharmacokinetic studies from cycles 1 and 2 from the patients treated in the first three dose levels demonstrated that the addition of BAY 12-9566 increased the AUC(0-12h) levels of doxorubicin by a median of 48%. No effects were seen on the BAY 12-9566 pharmacokinetic values. Two dose limiting toxicities were seen at the third dose level. One patient experienced grade 3 stomatitis in cycle 2, and another patient experienced grade 4 granulocytopenia in cycle 1 and grade 4 thrombocytopenia in cycle 2. Thus the maximum tolerated dose of 60 mg/m(2) was declared. These toxicities were those that would have been expected from doxorubicin alone.. BAY 12-9566 can be safely administered with full doses of doxorubicin without evidence of clinical interaction. The recommended dose of doxorubicin to be combined with BAY 12-9566 800 mg po b.i.d is 60 mg/m(2), however, further development of BAY 12-9566 has been abandoned.

Topics: Adult; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Biphenyl Compounds; Carcinoma; Doxorubicin; Female; Humans; Male; Neoplasms; Organic Chemicals; Phenylbutyrates; Sarcoma; Tissue Inhibitor of Metalloproteinases

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade the extracellular matrix during the processes of invasion, metastasis and angiogenesis. BAY 12-9566 (BAY) is a selective, non-peptidic biphenyl inhibitor of MMPs, with nanomolar inhibitory activity against MMP-2, -3 and -9, and anti-invasive, anti-metastatic and anti-angiogenic activity in a variety of tumor models. This phase I study of oral BAY was conducted to evaluate the safety and pharmacokinetics of BAY when administered in combination with etoposide (VP-16) or in combination with VP-16 and carboplatin (CBDCA) in subjects with advanced cancer. The first cohort of patients (n=8) received a cycle of VP-16, 60 mg/m, followed 1 week later by a fixed daily oral dose of BAY, 800 mg b.i.d., to which three potential possible doses of VP-16 (low dose: 60 mg/m; mid dose: 90 mg/m; high dose: 120 mg/m) were added every 3 weeks as tolerated. The second cohort (n=5) received VP-16 (120 mg/m) and CBDCA (AUC=5) followed 1 week later by a fixed daily oral dose of BAY (800 mg) b.i.d., to which VP-16 (120 mg/m) and CBDCA (AUC=5) were added. Dose-limiting toxicity (DLT) was defined as toxicity grade 3 or above. Maximum tolerated dose was declared if two or more patients experienced DLT. A performance status of 0-2 and acceptable organ function were required for eligibility. Plasma concentrations of BAY and VP-16 were measured to investigate pharmacokinetic interactions. Eight eligible patients with a variety of tumor types (median age 64 years, range 44-76) were enrolled in the first cohort, six of who whom completed all three levels of VP-16. Progressive disease occurred in five of the eight patients; three patients continued on study with treatment. Drug level and pharmacokinetics analysis of BAY and VP-16 were also determined. The combination of BAY and VP-16 was tolerable in the first cohort, permitting enrollment of the second cohort. In the second cohort (n=5), the combination of BAY, VP-16 and CDBCA was intolerable at the doses used due to excessive hematologic toxicity in the first five patients enrolled. Pharmacokinetics and toxicity analysis was performed for this group of patients. Only Level 1 of treatment was completed for Cohort II. At this point the study was halted due to toxicity and the results of an interim analysis that failed to demonstrate sufficient clinical activity of this compound in other clinical trials. We conclude that the combination of BAY and VP-16 was well

Topics: Adult; Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Biphenyl Compounds; Carboplatin; Cohort Studies; Colonic Neoplasms; Enzyme Inhibitors; Etoposide; Female; Humans; Male; Matrix Metalloproteinase Inhibitors; Melanoma; Middle Aged; Neoplasms; Neoplasms, Unknown Primary; Neutropenia; Organic Chemicals; Phenylbutyrates; Thrombocytopenia; Thymoma; Treatment Outcome; Vomiting

The expression of matrix metalloproteinases (MMPs) is often associated with invasiveness or grade of tumours. Increased blood levels of MMP proteins, including MMP-1, MMP-2, MMP-3 and MMP-9 have been detected in various types of cancers. With the exception of one study, MMPs in serum and plasma have been determined using ELISA. In the present study we measured the activity of the MMPs found in human plasma samples using gelatin enzymography and fluorimetric degradation assays. We used plasma samples from healthy control subjects and cancer patients enrolled in a dose-finding study for the MMP inhibitor, BAY 12-9566, to assess the activity of MMPs found in plasma and screen for efficacy of the MMP inhibitor. BAY 12-9566 has inhibitory activity toward MMP-2, MMP-3 and MMP-9. Patients with advanced solid tumours were enrolled in our study and plasma was collected on day 1 before dosing and at steady-state of the drug on day 15. Our results show that BAY 12-9566 was effective in lowering the plasma gelatinolytic activity in the group of 29 patients when considering the data obtained from a fluorimetric gelatinase assay. The data obtained from gelatin enzymography, however, did not reach significance. The fluorimetric degradation assay could be a useful tool to screen plasma from cancer patients in other clinical trials assessing MMP inhibitors.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biphenyl Compounds; Enzyme Inhibitors; Female; Humans; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Middle Aged; Neoplasms; Organic Chemicals; Phenylbutyrates

Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and have been implicated in breast, ovarian, colorectal, and lung cancer growth. We undertook a phase I study of BAY 12-9566, an inhibitor of MMP-2, MMP-9, and MMP-3, in patients with solid tumors to determine its safety, pharmacokinetics, and effects on potential surrogate markers of biologic activity.. BAY 12-9566 was orally administered daily at four dose levels; 400 mg daily, 400 mg b.i.d., 400 mg t.i.d., and 800 mg b.i.d. Drug disposition was determined on days 1 and 29 with weekly trough levels measured during the first four weeks. Plasma vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and urinary pyridinoline and deoxypyridinoline crosslinks were determined at baseline, once weekly for four weeks, and then every four weeks.. Thirteen patients were entered on trial. BAY 12-9566 was well tolerated, with only one grade 3 headache, one grade 3 anemia, one grade 3 thrombocytopenia, and no musculoskeletal effects. The median treatment duration was 57 days (range 7-560). Mean trough levels of BAY 12-9566 on day 28 ranged from 80.5 to 108.6 mg/l. Plasma trough levels were 1500-42,000-fold above the Ki's for MMP-2, MMP-3, and MMP-9 at the 800 mg p.o. b.i.d. dose level. There was no significant change in VEGF, bFGF, pyridinoline, and deoxypyridinoline crosslinks with BAY 12-9566 administration.. The recommended dose for further testing is 800 mg p.o. b.i.d.

Topics: Adult; Amino Acids; Antineoplastic Agents; Biphenyl Compounds; Dose-Response Relationship, Drug; Endothelial Growth Factors; Enzyme Inhibitors; Female; Fibroblast Growth Factor 2; Humans; Lymphokines; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organic Chemicals; Phenylbutyrates; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that are believed to be involved in primary and metastatic tumor growth by degrading the basement membrane and changing the extracellular matrix to facilitate invasion of malignant cells and angiogenesis. Overexpression of MMPs has been documented in various solid tumors. BAY12-9566 is a selective inhibitor of MMPs, in particular MMP-2, -3. and -9. The purpose of this trial was to define the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, pharmacokinetics and pharmacodynamics of orally administered BAY12-9566 in patients with incurable solid tumors.. The starting dose of BAY12-9566 for this single institution, outpatient phase I study was 100 mg/day orally. Patients were allowed to receive drug for up to 12 months. A total of 27 patients with various solid malignancies including colorectal, breast, lung, cervical and ovarian cancers were enrolled at doses from 100 to 1,600 mg/day. Patients were evaluated weekly while on treatment. Relevant radiologic examination was performed every 8 weeks to document and follow sites of measurable or evaluable disease.. Toxicities from BAY12-9566 included liver injury test abnormalities, anemia, shoulder and back pain. thrombocytopenia, mild nausea and fatigue, diarrhea, rash and deep vein thrombosis. No toxicity greater than grade III was observed. As doses were increased from 100 to 400 to 1,600 mg/day, even in divided doses, less than proportional increases in AUC were observed. At the highest dose level of 1600 mg/day, the day 29 AUC (3778.00 mg x h/l) remained similar to the day 29 AUC (3312.60 mg x h/l) at the dose level of 1200 mg/day. No responses were seen, but 14 patients remained on study with stable disease for 4 to 26 months.. BAY12-9566 was well tolerated at doses as high as 800 mg orally twice daily. Although mild alterations in liver injury tests, platelet count and hematocrit were noted, these were not dose-limiting. The drug was well absorbed. However, the absence of proportional increases in AUC with doses greater than 800 mg and the achievement of Css in the range associated with biologic activity in preclinical models led to the selection of 800 mg twice daily for further evaluation in phase III trials.

Topics: Administration, Oral; Adult; Aged; Anemia; Antineoplastic Agents; Area Under Curve; Biphenyl Compounds; Dose-Response Relationship, Drug; Humans; Liver; Middle Aged; Neoplasms; Organic Chemicals; Phenylbutyrates; Thrombocytopenia

To evaluate the feasibility of administering BAY 12-9566, a matrix metalloproteinase (MMP) inhibitor with relative specificity against MMP-2, MMP-3, and MMP-9, on a protracted oral daily dosing schedule in patients with advanced solid malignancies. The study also sought to determine the principal toxicities of BAY 12-9566, whether plasma BAY 12-9566 steady state concentrations (C(ss)) of biologic relevance could be sustained for prolonged periods, and whether BAY 12-9566 affected plasma concentrations of MMP-2, MMP-9, and tissue inhibitor of MMP-2 (TIMP-2).. Patients with solid malignancies were treated with BAY 12-9566 at daily oral doses ranging from 100 to 1,600 mg. BAY 12-9566 dose schedules included 100 mg once daily, 400 mg once daily, 400 mg twice daily, 400 mg three times daily, 400 mg four times daily, and 800 mg twice daily. Plasma was collected to study the range of BAY 12-9566 C(ss) values achieved, and exploratory studies were performed to assess the effects of BAY 12-9566 on plasma concentrations of MMP-2, MMP-9, and TIMP-2.. Twenty-one patients were treated with 47 28-day courses of BAY 12-9566. The most common side effects were headache, nausea, vomiting, abnormalities in hepatic functions, and thrombocytopenia, which were rarely clinically significant. BAY 12-9566 was well tolerated on all dose schedules, and there was no consistent dose-limiting toxicity that precluded treatment in the range of dose schedules evaluated. Instead, dose escalation was terminated because BAY 12-9566 plasma C(ss) values increased less than proportionately and plateaued as the daily dose was increased within the dose range of 100 to 1,600 mg/d, suggesting saturable drug absorption. Mean plasma C(ss) values achieved with all dose schedules exceeded BAY 12-9566 concentrations required to inhibit MMPs in vitro and in vascular invasion and tumor proliferation in vivo models. There were no consistent effects of BAY 12-9566 on the plasma concentrations of MMP-2 and MMP-9 over the continuous dosing period at any dose schedule level. However, plasma levels of TIMP-2 seemed to increase in a dose-dependent manner (r(2) =.50, P =.046).. The recommended dose of BAY 12-9566 for subsequent disease directed studies is 800 mg twice daily, which resulted in biologically relevant plasma C(ss) values and an acceptable toxicity profile. Although exploratory studies of MMPs in plasma were not revealing, it is conceivable that some tumor types and disease settings are more likely to produce more readily quantifiable levels of activated MMPs than others. Therefore, attempts to identify and quantify surrogate markers of MMP inhibitory effects should continue to be performed in disease-directed studies in more homogenous patient populations.

Topics: Administration, Oral; Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Biphenyl Compounds; Dose-Response Relationship, Drug; Female; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Maximum Tolerated Dose; Metalloendopeptidases; Middle Aged; Neoplasms; Organic Chemicals; Phenylbutyrates; Tissue Inhibitor of Metalloproteinase-2

This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced solid tumours, and to identify the maximum tolerated dose and dose for use in subsequent studies.. BAY 12-9566 was administered to 29 patients at doses ranging from 100 mg o.d. to 1600 mg (given either 400 mg q.i.d. or 800 mg b.i.d.). Blood samples for pharmacokinetic analyses were drawn on days 1-5, day 15 and days 29 and 30. Patients were continued on daily oral treatment of BAY 12-9566 until a dose limiting toxicity or tumour progression occurred.. A maximum tolerated dose was not defined because plasma levels of BAY 12-9566 could not be sufficiently increased, even with escalating doses of drug. Pharmacokinetic analysis suggested that absorption was saturable at higher doses. The predominant toxicities related to drug were asymptomatic reversible effects on platelets and transaminases and mild anemia. There were no significant musculoskeletal toxicities. No objective responses were seen at the doses tested, but stable disease was observed in some patients based on tumour measurements.. The recommended dose of BAY 12-9566 for further studies is 800 mg b.i.d. as this dose provides maximal plasma levels that can be achieved with a convenient dosing schedule for a chronically administered oral agent.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Biphenyl Compounds; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Neoplasms; Organic Chemicals; Phenylbutyrates

BAY 12-9566N (BAY), which is a substituted 4-biarylbutyric acid and has the properties of a matrix metalloproteinase (MMP) inhibitor, was tested in the accelerated cancer bioassay (ACB). In the ACB, three different genotoxic carcinogens were administered individually to groups of male and female Wistar rats, in initiation (IN) segments lasting 10 weeks, followed by BAY in promotion segments lasting 42 weeks, for a total of 52 weeks of treatment, followed by 12 weeks of recovery. The IN target organs in males were the liver using diethylnitrosamine (DEN), and the lungs, using N-nitrosodimethylamine (NDA), and in females, the mammary gland using 7,12-dimethylbenz(a)anthracene (DMBA). The study consisted of eight groups of 24 rats each as follows: controls (male and female), DEN alone (male), DEN/BAY (male), NDA (male), NDA/BAY (male), DMBA (female), and DMBA/BAY (female). The daily dose of BAY was 240 mg/kg in the diet, yielding a cumulative dose of 70,560 mg/kg. The cumulative doses of carcinogens were 220 mg/kg DEN, 150 mg/kg NDA, or 15 mg/kg DMBA. No significant difference in body-weight gain pattern was evident between any of the groups at 52 or 64 weeks. Rather, in males, DEN-induced hepatocellular adenomas were reduced with BAY treatment from 29% to 21% (p < 0.05) and carcinomas from 42% to 29% (p < 0.01). Also, in males, NDA-induced pulmonary adenomas were reduced with BAY treatment from 38% to 21% (p < 0.01) and carcinomas from 21% to 4% (p < 0.01). In females, DMBA-induced mammary gland adenomas were reduced from 13% to 4% (p < 0.01) and carcinomas from 54% to 42% (p < 0.05). Thus, BAY produced a consistent and significant reduction of neoplasm development in both genders in three target tissues of carcinogenicity in which neoplasms were induced by three different DNA-reactive initiators. This inhibition may be due to inhibition of MMP, leading to reduced neoplastic growth and development.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenoma; Animals; Antineoplastic Agents; Biphenyl Compounds; Carcinogens; Diethylnitrosamine; Dimethylnitrosamine; Drug Screening Assays, Antitumor; Female; Liver Neoplasms; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Matrix Metalloproteinase Inhibitors; Neoplasms; Organic Chemicals; Phenylbutyrates; Rats; Rats, Wistar; Sex Factors

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Biphenyl Compounds; Cathepsins; Disease Models, Animal; Enzyme Inhibitors; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Neoplasms; Organic Chemicals; Phenylbutyrates; Plasminogen Activators; Plasminogen Inactivators; Predictive Value of Tests; Prognosis; Tissue Inhibitor of Metalloproteinases; Treatment Failure; Urokinase-Type Plasminogen Activator

Topics: Antineoplastic Agents; Biphenyl Compounds; Clinical Trials as Topic; Humans; Matrix Metalloproteinase Inhibitors; Neoplasms; Organic Chemicals; Phenylbutyrates

Topics: Antineoplastic Agents; Biphenyl Compounds; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Organic Chemicals; Phenylbutyrates

Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Chick Embryo; Drugs, Investigational; Humans; Metalloendopeptidases; Mice; Neoplasms; Organic Chemicals; Phenylbutyrates; Protease Inhibitors