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PubMed2002

Novel use of similarity factors f2 and Sd for the development of diltiazem HCl modified-release tablets using a 3(2) factorial design.

The objective of this study was to develop modified-release tablets of diltiazem HCl using a direct compression technique. A 3(2) factorial design was employed using the amount of alkali-treated guar gum and cetyl alcohol as independent variables. This article proposes the use of a novel approach-f2 and Sd values as dependent variables-to evaluate the effect of selected independent variables along with other dependent variables (i.e., percentage drug released in x min, Yx; time required for z% drug release, tz; and mean dissolution time (MDT)). It is concluded that when a decision is to be made for the selection of a best batch, it is perhaps more realistic to use the f2 or Sd value which takes into account the dissolution profile as a whole, as opposed to Yx and tz values which use just one point from the dissolution plot. The batch showing the f2 value nearest to 100 or the Sd value nearest to zero is ranked as the best batch (diltiazem HCl 90 mg, alkali-treated guar gum 80 mg and cetyl alcohol 15 mg). The gel strength and matrix erosion of the formulated tablets were dependent on the type and amount of the adjuvants. The drug release rate is well correlated with matrix erosion. The kinetics of drug release fitted best to the Korsmeyer and Peppas model. It is concluded that by using a proper combination of the hydrophilic polymer and cetyl alcohol one can achieve a desirable drug release pattern.

Delayed-Action Preparations↗

PubMed1986

Selection of effective maximal expiratory parameters to differentiate asthmatic patients from healthy adults by discriminant analysis using all possible selection procedure.

Maximal expiratory volume-time and flow-volume (MEVT and MEFV) curves were drawn for young male nonsmoking healthy adults and for young male nonsmoking asthmatic patients. Eleven parameters, two MEVT (%FVC and FEV1.0%), six MEFV (PFR, V75, V50, V25, V10 and V50/V25), and three MTC parameters (MTC75-50, MTC50-25 and MTC25-RV) were used for the multivariate analysis. The multivariate analysis in this study consisted of correlation coefficient matrix computation, the test for mean values in the multivariates, and the linear discriminant analysis using the all possible selection procedure (APSP). Correlation coefficients among flow rate parameters and flow rate related parameters in high lung volumes were different between the two groups. In the eleven-parameter discriminant analysis by APSP using single parameters, PFR, V75 (flow rate at 75% of forced vital capacity), and FEV1.0% were considered to be the effective parameters. In the seven-parameter discriminant analysis using the parameter groups, the group of all parameters and the %FVC and flow rate-related parameter group were considered to be the effective numerical alternatives to MEFV curves discriminating between healthy adults and asthmatic patients.

Adult↗

PubMed1998

Applications of random field theory to functional connectivity.

Functional connectivity between two voxels or regions of voxels can be measured by the correlation between voxel measurements from either PET CBF or BOLD fMRI images in 3D. We propose to look at the entire 6D matrix of correlations between all voxels and search for 6D local maxima. The main result is a new theoretical formula based on random field theory for the p-value of these local maxima, which distinguishes true correlations from background noise. This can be applied to crosscorrelations between two different sets of images--such as activations under two different tasks, as well as autocorrelations within the same set of images.

Brain Mapping↗

PubMed2003

Phosphine in various matrixes.

Matrix-bound phosphine was determined in the Jiaozhou Bay coastal sediment, in prawn-pond bottom soil, in the eutrophic lake Wulongtan, in the sewage sludge and in paddy soil as well. Results showed that matrix-bound phosphine levels in freshwater and coastal sediment, as well as in sewage sludge, are significantly higher than that in paddy soil. The correlation between matrix bound phosphine concentrations and organic phosphorus contents in sediment samples is discussed.

Aquaculture↗

PubMed1999

Matrix metalloproteinase-9 is increased and correlates with severity in Guillain-Barré syndrome.

OBJECTIVE: To study the expression and activity of matrix metalloproteinases (MMPs) MMP-2 (72-kd type IV collagenase, gelatinase A), MMP-3 (58-kd stromelysin-1), and MMP-9 (92-kd type IV collagenase, gelatinase B) and tissue inhibitors of MPs (TIMP) in patients with Guillain-Barre syndrome (GBS). BACKGROUND: MMPs are able to proteolysis of basement membranes and other matrix components, promoting transmigration of inflammatory cells from circulation to nerve tissue. METHODS: Twenty-five patients with GBS were analyzed according to the phase of the disease, i.e., progression, plateau, early recovery, and late recovery. Determinations of MMP-2, MMP-3, MMP-9, and TIMP-1 were performed using ELISA, zymography, and immunocytochemistry in circulation or peripheral nerve. RESULTS: MMP-9 plasma levels were increased in 67% of patients on admission and decreased from progression to late recovery (p < 0.002). During the course of GBS, MMP-9 was progressively balanced by its inhibitor TIMP-1, as assessed by the MMP-9/TIMP-1 ratio. MMP-9 and TIMP-1 plasma levels and the MMP-9/TIMP-1 ratio correlated positively with disability. MMP-2 expression was similar to controls. MMP-3 activity was not detected, and plasma levels were not different from those in controls. Positive MMP-9 immunolabeling was 51 +/- 11% of circulating lymphocytes. It was observed in some endothelial cells and mononuclear cells adherent to the endothelium and close to myelinated fibers. CONCLUSIONS: Circulating matrix metalloproteinases (MMP-9) correlates with disease severity in Guillain-Barré syndrome (GBS). MMP-9 likely represents an important molecule in the pathogenesis of GBS and therefore could represent an interesting therapeutic target.

Biopsy↗

PubMed2001

Expression of MMP-2 is associated with progression and lymph node metastasis of gastric carcinoma.

AIMS: One important step in tumour invasion is the penetration of the basement membrane. Matrix metalloproteinases (MMPs) play a key role in the migration of normal and malignant cells through the basement membrane. The aim of this study was to investigate correlations between matrix metalloproteinase 2 (MMP-2) immunoreactivity and currently used classification systems and possible relationships between lymph node metastasis and MMP-2 expression. METHODS AND RESULTS: This prospective study analysed specimens obtained from 114 gastric cancer patients (mean age 64 years; range 33-86 years) who underwent gastrectomy with extended lymphadenectomy. All specimens were categorized according to UICC classification, WHO classification, tumour differentiation, Laurén classification, Ming classification and Goseki classification. Formalin-fixed paraffin-embedded tumour specimens were stained using an avidin-biotin complex peroxidase assay. MMP-2 expression in the tumour epithelium was studied by immunohistochemistry with semiquantitative (score 0-3) evaluation. The MMP-2 staining pattern was positive (score 1-3) in 93 (81.6%) specimens and negative (score 0) in 21 (18.4%) samples. No significant correlations were found between MMP-2 expression and other variables such as age, tumour differentiation, WHO, Lauren, Goseki, and Ming classifications. In contrast, the intensity of MMP-2 staining in tumour cells correlated significantly with depth of tumour infiltration (T-stage), lymph node metastasis (N-stage), distant metastasis (M-stage), and UICC stage. CONCLUSIONS: Expression of MMP-2 is strongly associated with tumour progression and lymph node metastasis in gastric cancer. Therefore MMP-2 staining may be clinically useful as predictor of tumour progression, especially for lymph node metastasis.

Adult↗

PubMed2004

Correlation between plasma levels of matrix metalloproteinase (MMP)-9 /MMP-2 ratio and alpha-fetoproteins in chronic hepatitis carrying hepatitis B virus.

BACKGROUND: Matrix metalloproteases (MMP) and alpha-fetoproteins (AFP) are involved in hepatitis B virus (HBV)-induced chronic hepatitis. In the present study, we have determined the correlation between the MMP-9/MMP-9 ratio and AFP levels in the serum of patients during chronic viral B hepatitis. METHODS: Twenty-eight healthy individuals (18 men and 10 women) with a mean age of 36.3 years (range 23-58 years) and 50 patients (42 men, 8 women) with a mean age of 39.7 years (range 22-61 years) participated in the study. Forty-eight participants had HBV and the remaining two were either hepatitis G virus (HGV) or hepatitis C virus (HCV) carriers. Values of patients were compared with those obtained from 12 blood donor controls (5 men, 7 women), mean age 36 years (range 21-46 years). Patients' sera were subjected to examination of hepatitis B surface (HBs) and hepatitis B early (Hbe) antigen, SGOT, SGPT, AFP, MMP-2 and MMP-9. Serum levels of MMP-2 and MMP-9 activities were measured by a zymogram protease assay and densitometric measurement. The ratios of MMP-9 to MMP-2 were calculated by dividing the densitometric results. RESULTS: Compared with the healthy controls, the mean serum concentrations of MMP-2 were slightly increased in the chronic HBV patients. In contrast, compared with the healthy controls, the mean serum concentrations of MMP-9 were significantly increased in the chronic HBV patients. When the ratios of the MMP-9/MMP-2 and amounts of the serum AFP were compared, a specific correlation between these two parameters was observed. Higher amounts of AFP were detected in the patients with a low ratio of MMP-9/MMP-2. Patients with hepatocellular carcinoma (HCC) and cirrhosis showed relatively low MMP-9/MMP-2 ratios in chronic hepatitis B. In addition, AFP levels of HCC and cirrhosis were higher than in chronic HBV patients. CONCLUSIONS: These results indicate that the AFP level and ratio of MMP-9 and MMP-2 is highly correlated in chronic HBV-induced hepatitis. Because the serum MMP activities were significantly varied between each stage of AFP production in liver disease, an individual profile of these parameters might serve as an easy accessing serum marker to monitor the progression of liver disease.

Adult↗

PubMed1993

[Urothelial tumors and the extracellular matrix].

The network of both intra- and intercellular, either physical (bioconductive connectional system) and/or chemical signals, plays a significant role in the maintenance of tissue architecture and integrity of epithelial cell layers. The basement membrane is not only a static barrier but a dynamic regulator of the urothelium. Any change in the basement membrane can lead, by the extracellular matrix-cytoskeleton-nuclear matrix interaction, to altered gene regulation of the urothelial cells. Abnormal production and deposition or proteolytic degradation of the extracellular matrix components correlate with tumour stage and progression. In some experimental models, tissue inhibitors of metalloproteinases or anti-proteinase antibodies can abrogate the proteolytic activity of those matrix metalloproteinase enzymes (collagenase IV, cathepsin, stromelysin, etc.) which promote tumour invasion. Finally, the current researches investigating the use of biologic protein (e.g., TIMP-1 e-2; agents that affect angiogenesis and spread of neoplasias) are aimed at offer new therapeutic opportunities in oncology.

Basement Membrane↗

PubMed2002

Enhanced production of matrix metalloproteinase-2 in human head and neck carcinomas is correlated with lymph node metastasis.

Matrix metalloproteinase (MMP)-2 and -9 degrade type IV collagen, which is one of the major components of the basement membrane in normal tissue and expressed in the surroundings of the cancer nest in squamous cell carcinoma. The degeneration of type IV collagen is an essential step in the metastasis to lymph nodes and distant organs. In this study, we examined MMP-2 and -9 levels of cancer tissue and serum obtained from patients with head and neck squamous cell carcinoma (HNSCC) in order to evaluate the relationship between the clinicopathologic features and MMPs. We examined the production of MMP-2 and -9 in cancer tissue homogenates of 73 patients who had HNSCC and the serum MMP levels of 16 patients with HNSCC and 8 healthy volunteers. We also studied the localization of MMP-2 in the carcinoma using an immunohistochemical approach. The concentrations of MMP-2 and -9 in the tissue homogenates and serum were measured by means of a sandwich enzyme immunoassay using a monoclonal antibody. Immunohistochemical analyses were performed with monoclonal antibody to MMP-2. The concentration of MMP-2 in the tumor tissue homogenates was unrelated to tumor size, but that in patients with lymph node metastases was significantly higher than in those without lymph node metastases. The concentration of MMP-9 was unrelated to lymph node metastasis and tumor size. The levels of both MMP-2 and -9 in serum were unrelated to lymph node metastasis. Immunohistochemistry indicated that MMP-2 was mainly expressed in cancer cells. Because MMP-2 degrades type IV collagen, the level of MMP-2 in carcinomas may be a useful indicator of the degree of invasion and metastasis.

Biomarkers, Tumor↗

PubMed2006

[Matrix metalloproteinase-2 expression and its correlation with mesorectal metastasis in middle and lower rectal cancer].

OBJECTIVE: To examine the expression of matrix metalloproteinase-2 (MMP-2) and to evaluate its correlation with mesorectal metastasis in middle and lower rectal cancer. METHODS: The resected primary tumors from 56 patients with middle and lower rectal cancer who received total mesorectal excision were studied from Dec. 2001 to Jul. 2003. RESULTS: The MMP-2 expression was positive in 42 (75%) cases. The positive rate of MMP-2 expression was 88.9% in T3 tumors and 69.6 % in T2 tumors respectively, while only 33.3% in T1 tumors (P=0.013). MMP-2 was positive in 91.2% (31/34) infiltrative rectal carcinomas while 40.0% (6/15) expansive rectal carcinomas (P=0.001). Mesorectal metastasis was detected in 36 (64.3%) of 56 cases. The expression of MMP-2 was positive in 31 (86.1%) of the 36 patients with mesorectal metastasis, while in 11(55%) of the 20 patients without mesorectal metastasis (P=0.01). CONCLUSIONS: The expression of MMP-2 in middle and lower rectal cancer is significantly associated with depth of tumor invasion and Ming classifications. The high expression of MMP-2 may play an important role in the development of mesorectal metastasis in middle and lower rectal cancer.

Adult↗

PubMed1987

Dissolution of cholesterol gallstones in vitro. Gallstone matrix content and diameter, not cholesterol content, predict gallstone dissolution in monooctanoin.

The goal of this study was to identify the structural and compositional features of human gallstones that influence in vitro gallstone dissolution in the cholesterol solvent monooctanoin. Gallstones were obtained from 86 consecutive patients who had at least three morphologically similar stones. One stone from each patient was dissolved in ethanol/ether to determine cholesterol and matrix composition. The remaining two matched stones were dissolved in either monooctanoin plus ethanol (n = 86) or monooctanoin plus 2-mercaptoethanol (n = 86). The thiol reducing agent 2-mercaptoethanol has been previously shown to solubilize the isolated gallstone matrix and to accelerate the dissolution of intact, small cholesterol stones. Stone matrix content and initial diameter had the most significant predictive value for stone dissolution (p less than 0.0001 for each), whereas cholesterol content had no predictive value (p = 0.558). Stones incubated in monooctanoin containing 2-mercaptoethanol dissolved more rapidly than those incubated in monooctanoin plus ethanol (16.7% of initial weight per day vs. 13.8% of initial weight per day, p less than 0.0001). Matrix content correlated significantly with the difference in dissolution rate between stones dissolved in monooctanoin plus ethanol or monooctanoin plus 2-mercaptoethanol (p less than 0.0001). These data indicate that the matrix content of human cholesterol gallstones significantly inhibits in vitro stone dissolution in the cholesterol solvent monooctanoin. This finding may be relevant to the clinical dissolution of gallstones.

Caprylates↗

PubMed2004

Metalloproteinase-2 expression correlates with aggressiveness of cutaneous squamous cell carcinomas.

Matrix metalloproteinases compose a family of enzymes involved in degradation of the extracellular matrix. Tumor cells must penetrate the basement membrane and traverse the extracellular matrix in order to invade surrounding structures and metastasize to distant sites. Gelatinases, particularly gelatinase A (matrix metalloproteinase-2), demonstrate degradative activity against components of the basement membrane and may be involved in the progression of in situ squamous cell carcinoma lesions. Matrix metalloproteinase-2 overexpression has been correlated with tumor invasiveness and metastasis in a wide variety of cancer types, including squamous cell carcinoma arising on mucous membranes. However, correlation between matrix metalloproteinase-2 overexpression and the spread and prognosis of cutaneous squamous cell carcinoma has not been characterized in the literature at present. In this study, we used immunohistochemical techniques to examine the expression of matrix metalloproteinase-2 in 10 actinic keratosis, 15 in situ, 13 invasive, 13 primary (with documented metastatic disease), 11 metastatic, and 8 recurrent squamous cell carcinoma cases. We found that while the average staining intensity (scale 0-3+, 3+ being strongest) of actinic keratosis and in situ lesions was not statistically significant (0.87-1.3 and 0.75-1.4, respectively), the average staining intensity of invasive squamous cell carcinomas (1.6-2.5) was significantly greater than that of actinic keratosis and in situ lesions. Likewise, while the average staining intensity of primary squamous cell carcinomas and metastatic squamous cell carcinomas was not found to be statistically significant (3.1-3.5 and 3.1-3.8, respectively), the average staining intensity of these lesions was significantly higher than that of invasive lesions. We also found that the intensity of matrix metalloproteinase-2 staining correlates with cellular atypia, inflammation, neovascularization, and the invasive tumor front, as well as tumor aggressiveness, and may play a role in the pathogenesis, invasion, and metastasis of cutaneous squamous cell carcinoma.

Carcinoma, Squamous Cell↗

PubMed1995

Partial circumvention of multi-drug resistance by annamycin is associated with comparable inhibition of DNA synthesis in the nuclear matrix of sensitive and resistant cells.

We studied the subcellular and subnuclear distributions of the partially cross-resistant anthracycline Annamycin (Ann) in KB-3-1 and multi-drug resistant KB-VI cells. Subcellular drug localization was assessed qualitatively by fluorescence microscopy and quantitatively by cell fractionation and fluorescence measurements. Doxorubicin (Dox) localized predominantly in the nucleus in KB-3-1 cells and in the membranes in KB-VI cells. In contrast, the subcellular distribution of Ann was identical in both cell lines, with preferential drug localization in the perinuclear region, Golgi apparatus, endoplasmic reticulum and endosomes. Dox rate of efflux from the nucleus was negligible in KB-3-1 cells but markedly enhanced in KB-VI cells, whereas Ann was lost at a similar rate from the nucleus in both cell lines. In KB-3-1 cells Dox levels in the nuclear non-matrix were about 2-fold higher than those of Ann, while in the matrix the inverse relationship was observed. In spite of these differences, Dox and Ann had a similar inhibitory effect on new DNA synthesis in the nuclear matrix and non-matrix of KB-3-1 cells. Dox levels were reduced by 10-fold in the nuclear non-matrix and 2-fold in the matrix in KB-VI cells compared with KB-3-1 cells, whereas Ann levels were reduced by about 2- to 3-fold in the non-matrix and were unchanged in the matrix. In correlation with these findings, Dox did not cause inhibition of new DNA synthesis in either nuclear fraction in KB-VI cells, whereas inhibition of new DNA synthesis in the matrix by Ann was similar in both cell lines. Our results indicate that Ann's partial circumvention of multi-drug resistance is associated with its ability to cause comparable new DNA synthesis inhibition in the nuclear matrix of sensitive and resistant cells.

Antibiotics, Antineoplastic↗

PubMed1983

Status of the nuclear matrix in mature and embryonic chick erythrocyte nuclei.

The adult chicken erythrocyte nucleus was found to lack an internal nuclear matrix: even milder extraction procedures resulted in the production of empty shells of pore complex-lamina together with loose aggregates of core histone. In contrast, rat liver nuclei showed a typical intranuclear salt-resistant skeleton. These results show that an internal matrix is not an obligatory nuclear component, and is not required for the spatial organization of chromatin. 5-day-old embryonic erythrocytes did, however, contain an interchromatinic nuclear matrix, suggesting a correlation between the presence of matrix structures, and nuclear 'activity'.

Animals↗

PubMed1999

Gelatinolytic activity of matrix metalloproteinase in tumor tissues correlates with the invasiveness of oral cancer.

We examined whether or not the gelatinolytic activity in tumor tissue was associated with the invasion and metastasis of oral squamous cell carcinoma (OSCC). Tissue homogenates were prepared from 57 biopsy specimens of OSCC. The gelatinolytic activities in the homogenates were measured by gelatin zymography and its densitometric analysis. The Immnunoblot findings revealed the major gelatinolytic activities to be due to matrix metalloproteinase (MMP)-2 and -9. The zymography-detected gelatinolytic activities of MMP-2 and MMP-9 in the tissue specimens significantly correlated with the degree of immunohistochemical staining detected in frozen sections of the same biopsy specimens. According to a histopathological analysis of the mode of invasion, highly invasive cases showed the increased gelatinolytic activities of MMP-2 as well as MMP-9 in the tissue specimens. Although no significant differences were observed in the gelatinase activities between the metastatic cases and the non-metastatic cases, the levels of tissue inhibitor of MMP (TIMP)-1 in the tumor tissue specimens were higher in the non-metastatic cases than in the metastatic cases. The cases with the high levels of MMPs and low levels of TIMP-1 thus seemed to have a high potential to metastasize. As a result, the zymographic measurement of the gelatinolytic activity in biopsy tissue specimens may therefore be useful in predicting the behavior and prognosis of OSCC.

Carcinoma, Squamous Cell↗

PubMed2002

Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration.

Elevated hyaluronan biosynthesis and matrix deposition correlates with cell proliferation and migration. We ectopically expressed three isoforms of hyaluronan synthase (HAS1, HAS2, or HAS3) in nontransformed rat 3Y1 cells and observed a de novo, massive formation of a hyaluronan matrix that resulted in a partial loss of contact-mediated inhibition of cell growth and migration. All three HAS transfectants showed an enhanced motility in scratch wound assays, and a significant increase in their confluent cell densities. In high-density cultures, the HAS transfectants had a fibroblastic cell shape and markedly formed overlapping cell layers. This phenotype was more pronounced in the HAS2 transfectants than HAS1 or HAS3 transfectants, and occurred with significant alterations in the microfilament organization and N-cadherin distribution at the cell-cell border. Inhibition of a phosphatidylinositol 3-kinase (PI3-kinase) pathway resulted in reacquisition of the normal phenotype of HAS2 transfectants, suggesting that the intracellular PI3-kinase signaling regulates diminution of contact inhibition induced by formation of the massive hyaluronan matrix. Our observations suggest that hyaluronan and its matrix can modulate contact inhibition of cell growth and migration, and provide evidence for functional differences between hyaluronan synthesized by the different HAS proteins.

Agar↗

PubMed2006

Matrix factorization algorithms for the identification of muscle synergies: evaluation on simulated and experimental data sets.

Several recent studies have used matrix factorization algorithms to assess the hypothesis that behaviors might be produced through the combination of a small number of muscle synergies. Although generally agreeing in their basic conclusions, these studies have used a range of different algorithms, making their interpretation and integration difficult. We therefore compared the performance of these different algorithms on both simulated and experimental data sets. We focused on the ability of these algorithms to identify the set of synergies underlying a data set. All data sets consisted of nonnegative values, reflecting the nonnegative data of muscle activation patterns. We found that the performance of principal component analysis (PCA) was generally lower than that of the other algorithms in identifying muscle synergies. Factor analysis (FA) with varimax rotation was better than PCA, and was generally at the same levels as independent component analysis (ICA) and nonnegative matrix factorization (NMF). ICA performed very well on data sets corrupted by constant variance Gaussian noise, but was impaired on data sets with signal-dependent noise and when synergy activation coefficients were correlated. Nonnegative matrix factorization (NMF) performed similarly to ICA and FA on data sets with signal-dependent noise and was generally robust across data sets. The best algorithms were ICA applied to the subspace defined by PCA (ICAPCA) and a version of probabilistic ICA with nonnegativity constraints (pICA). We also evaluated some commonly used criteria to identify the number of synergies underlying a data set, finding that only likelihood ratios based on factor analysis identified the correct number of synergies for data sets with signal-dependent noise in some cases. We then proposed an ad hoc procedure, finding that it was able to identify the correct number in a larger number of cases. Finally, we applied these methods to an experimentally obtained data set. The best performing algorithms (FA, ICA, NMF, ICAPCA, pICA) identified synergies very similar to one another. Based on these results, we discuss guidelines for using factorization algorithms to analyze muscle activation patterns. More generally, the ability of several algorithms to identify the correct muscle synergies and activation coefficients in simulated data, combined with their consistency when applied to physiological data sets, suggests that the muscle synergies found by a particular algorithm are not an artifact of that algorithm, but reflect basic aspects of the organization of muscle activation patterns underlying behaviors.

Algorithms↗

PubMed1996

Effects of mebendazole on protein biosynthesis and secretion in human-derived fibroblast cultures.

Previous results of our group revealed that mebendazole, a broad spectrum anthelmintic drug with antimicrotubular properties, used for the treatment of liver cirrhosis, decreased total collagen content and biosynthesis in liver upon treatment. In the present study, we have evaluated the effects of mebendazole (5-50 micrograms/mL) on protein synthesis, secretion, and deposition in human-derived fibroblast cultures. The results showed a decrease in cell viability (18.5 +/- 0.9%) at 50 micrograms/mL. [3H]Thymidine incorporation diminished gradually with increasing mebendazole concentrations, reaching a plateau (53.67%) between 30 and 50 micrograms/mL. In late logarithmic phase cultures, the drug caused a decrease of [3H]proline incorporation (43.10%) and collagen biosynthesis (58.61%) in the extracellular matrix. This correlated with an increase in radioactivity in total proteins (51.28%) of the intracellular fraction. Similar results were obtained when mebendazole was assayed in post-confluent fibroblast cultures. The electrophoretic patterns of the extracellular matrix showed a decrease of radioactive collagenous components (alpha chains and beta dimers). By contrast, in the intracellular fraction an increase of radioactive collagen precursors (pro alpha chains) was observed. Immunofluorescence studies and immunotransfer analysis, using polyclonal anti-type I collagen antibodies, revealed an accumulation of intracellular collagen which included: collagen pro alpha chains, alpha chains, and low molecular weight peptides. The results obtained suggest that mebendazole interferes with the transcellular mobilization of proteins, resulting in a decrease of secretion and deposition of extracellular matrix proteins, and an accumulation of intracellular collagenous components. The intracellular accumulation of newly synthesized proteins could cause a feedback regulation in fibroblast cultures.

Antinematodal Agents↗