Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fourteen dogs and 11 cats with various malignant tumors were treated daily with benzaldehyde at a dosage rate of 10 mg/kg of body weight, orally, divided into 4 doses. Clinical signs of toxicosis were not observed. A partial response (greater than 50% regression) was observed in animals with an oral squamous cell carcinoma and an oral melanoma. A minimal response (less than 50% regression) was observed in animals with a sweat gland adenocarcinoma and a mast cell sarcoma. One dog with an oral melanoma had stabilization of tumor growth for 8 weeks. Seemingly, benzaldehyde has only minimal anti-tumor activity at the dose studied.
 ...
PMID:Anti-tumor evaluation of benzaldehyde in the dog and cat. 395 33

Gastrointestinal neoplasms other than lymphosarcomas and mast cell tumors were diagnosed in 44 cats during a 14-year period at the Washington Animal Disease Diagnostic Laboratory. All the tumors were malignant; 31 metastasized or recurred. One cat had fibrosarcoma; another, leiomyosarcoma. The other 42 cats had adenocarcinomas, which were subclassified into three histologic patterns: tubular adenocarcinoma; undifferentiated carcinoma; and mucinous adenocarcinoma. The cats averaged 10.6 years of age. There was no sex predisposition. Siamese cats had a higher frequency of adenocarcinomas than other breeds. Osseous and chondroid metaplasia occurred in nine adenocarcinomas.
 ...
PMID:Nonhematopoietic gastrointestinal neoplasia in cats: a retrospective study of 44 cases. 728 60

Histological examination of the metastatic rat mammary adenocarcinoma line MTLn3 showed that macrophages and mast cells were frequently localized at the tumor periphery in the stromal tissues adjacent to the zones of tumor invasion. The interactions of these host cells with tumor cells and tumor-associated fibroblasts could be important in stimulating the production of extracellular matrix-degrading enzymes that facilitate tumor invasion and metastatic spread. Therefore, we examined the effects of isolated, activated macrophages and mast cells on the secretion of collagenolytic activities by normal fibroblasts, metastatic mammary adenocarcinoma cells and tumor-associated fibroblasts. Medium from activated macrophages or degranulated mast cells stimulated significant increases in production of collagenolytic activities by normal and tumor-associated fibroblasts and MTLn3 tumor cells. Medium from activated macrophages that had been pretreated with medium from degranulated mast cells, however, were less stimulatory to fibroblasts and tumor cell production of collagenolytic activities than medium from degranulated mast cells alone. We also examined the effects of two cytokines, interleukin-1 alpha and tumor necrosis factor-alpha on activated macrophage- and degranulated mast cell-stimulation of fibroblast and tumor cell collagenolytic activities. The two cytokines alone or in combination stimulated increased production of collagenolytic activities by fibroblasts and tumor cells. Addition of the cytokines to degranulated mast cell products resulted in secretion of higher collagenolytic enzyme activities by normal fibroblasts (but not by tumor-derived fibroblasts or tumor cells) than with degranulated mast cell product-treatment of either target cell alone. Cytokines used in combination with macrophage-conditioned medium were less effective in stimulating fibroblast and tumor cell collagenase activities than cytokines alone. Thus normal infiltrating host cells such as macrophages and mast cells can have profound effects on the production of degradative enzymes by tumor cells and tumor-associated stromal fibroblasts.
 ...
PMID:Effects of mast cell-macrophage interactions on the production of collagenolytic enzymes by metastatic tumor cells and tumor-derived and stromal fibroblasts. 782 Sep 54

Methotrexate-alpha-phenylalanine (MTX-Phe), a second-generation prodrug in the MTX alpha-peptide series designed for activation to MTX by carboxypeptidase-mAb conjugates, was synthesized by reaction of the p-nitrophenyl ester of 4-amino-4-deoxy-10-methylpteroic acid with L-glutamyl-alpha-L-phenylalanine. Production of MTX from MTX-Phe, catalyzed by bovine pancreas carboxypeptidase A (CPA), was 250-fold faster than the corresponding reaction involving methotrexate-alpha-alanine, previously the best MTX peptide substrate for the enzyme. The amount of CPA required to make MTX-Phe equitoxic with MTX, when tested against UCLA-P3 human lung adenocarcinoma cells in vitro, was more than 10-fold lower than that required to achieve the same result with MTX-alpha-alanine. When the lung tumor cells were treated with CPA conjugated to KS1/4 (a mAb targeted to these cells) and excess conjugate removed by extensive washing, the ID50 for MTX-Phe improved from 2.2 x 10(-6) M (no enzyme present) to 6.3 x 10(-8) M; the latter value was comparable to that of the parent drug MTX (4.5 x 10(-8) M). [3H]MTX-Phe was synthesized and used to investigate the mechanism by which the prodrug exerts its cytotoxic effect in the presence and absence of CPA. The present results demonstrate that, for use in conjunction with CPA-mAb conjugates, the alpha-phenylalanine derivative is the optimal prodrug form of MTX (and probably other antifols that contain the glutamate moiety).
 ...
PMID:Methotrexate-alpha-phenylalanine: optimization of methotrexate prodrug for activation by carboxypeptidase A-monoclonal antibody conjugate. 783 11

Twenty-eight epithelial and 22 nonepithelial feline tumors were studied immunohistochemically. Epithelial tumors were 10 squamous cell carcinomas, two basal cell tumors, two sebaceous gland carcinomas, three apocrine gland carcinomas, three thyroid papillary carcinomas, one thyroid solid carcinoma, one renal clear cell carcinoma, one renal papillary carcinoma, one endometrial carcinoma, and four lung bronchioloalveolar carcinomas. Nonepithelial tumors were 10 fibrosarcomas, one liposarcoma, one leiomyosarcoma, one rhabdomyosarcoma, one hemangiosarcoma, two mast cell tumors, one osteosarcoma, three melanomas, and two lymphomas. Commercially available antibodies directed against high- and low-molecular-weight keratins (keratin, RCK-102, NCL-5D3), vimentin, desmin, glial fibrillary acidic protein (GFAP), and neurofilament intermediate filament (IF) proteins were used in the avidin-biotin-peroxidase complex technique on formalin-fixed, paraffin-embedded tumor tissue samples. All epithelial tumors except the endometrial carcinoma expressed some type of keratin protein. Squamous cell carcinomas expressed high-molecular-weight keratins exclusively. Coexpression of high- and low-molecular-weight keratins was observed in one basal cell tumor, sebaceous and apocrine adenocarcinomas, and thyroid, renal, and lung carcinomas. In addition to keratins, vimentin immunoreactivity was found in all basal cell tumors, all sebaceous gland, thyroid papillary, renal, and lung adenocarcinomas, and one of the apocrine gland adenocarcinomas. Immunoreactivity with GFAP antibody was found in one basal cell tumor and one sebaceous gland adenocarcinoma. The endometrial carcinoma did not react with any of the antibodies applied. Nonepithelial tumors analyzed expressed either vimentin (fibrosarcomas, liposarcoma, haemangiosarcoma, mast cell tumors, osteosarcomas, melanomas) or vimentin and desmin (leiomyosarcoma, rhabdomyosarcoma, one fibrosarcoma) IF proteins exclusively. Lymphomas did not react with any of the antibodies employed. These findings indicate that IF proteins antibodies can be included in diagnostic panels of antibodies for immunocharacterization of feline tumors. In addition, they can be used as a basis for the diagnoses of poorly differentiated or undifferentiated feline neoplasms.
 ...
PMID:Immunohistochemical distribution pattern of intermediate filament proteins in 50 feline neoplasms. 859 5

The authors studied the mast cells by light and electron microscopy in four small intramucosal early gastric cancers (EGC). Mast cells were found in the tumor stroma and among neoplastic cells of adenocarcinoma glands. Stromal and adenocarcinoma-infiltrating mast cells were ultrastructurally identified as T mast cells, and exhibited anaphylactic or piecemeal degranulation. Tumor cells in intimate contact with mast cells showed no cytopathic changes. These data do not support a mast cell-mediated cancer lysis, such as that reported in some systems in vitro. The interepithelial localization of T mast cell in adenocarcinoma glands is similar to that observed in some disease states, including interstitial cystitis, fibrotic lung disorders, and mucosal allergic reaction. The findings suggest that T mast cells may be involved in the pathophysiology of the host reaction to small intramucosal EGC.
 ...
PMID:Mast cell interaction with tumor cells in small early gastric cancer: ultrastructural observations. 909 28

Antibody-directed enzyme prodrug therapy (ADEPT) has the potential of greatly enhancing antitumor selectivity of cancer therapy by synthesizing chemotherapeutic agents selectively at tumor sites. This therapy is based upon targeting a prodrug-activating enzyme to a tumor by attaching the enzyme to a tumor-selective antibody and dosing the enzyme-antibody conjugate systemically. After the enzyme-antibody conjugate is localized to the tumor, the prodrug is then also dosed systemically, and the previously targeted enzyme converts it to the active drug selectively at the tumor. Unfortunately, most enzymes capable of this specific, tumor site generation of drugs are foreign to the human body and as such are expected to raise an immune response when injected, which will limit their repeated administration. We reasoned that with the power of crystallography, molecular modeling and site-directed mutagenesis, this problem could be addressed through the development of a human enzyme that is capable of catalyzing a reaction that is otherwise not carried out in the human body. This would then allow use of prodrugs that are otherwise stable in vivo but that are substrates for a tumor-targeted mutant human enzyme. We report here the first test of this concept using the human enzyme carboxypeptidase A1 (hCPA1) and prodrugs of methotrexate (MTX). Based upon a computer model of the human enzyme built from the well known crystal structure of bovine carboxypeptidase A, we have designed and synthesized novel bulky phenylalanine- and tyrosine-based prodrugs of MTX that are metabolically stable in vivo and are not substrates for wild type human carboxypeptidases A. Two of these analogs are MTX-alpha-3-cyclobutylphenylalanine and MTX-alpha-3-cyclopentyltyrosine. Also based upon the computer model, we have designed and produced a mutant of human carboxypeptidase A1, changed at position 268 from the wild type threonine to a glycine (hCPA1-T268G). This novel enzyme is capable of using the in vivo stable prodrugs, which are not substrates for the wild type hCPA1, as efficiently as the wild type hCPA1 uses its best substrates (i.e. MTX-alpha-phenylalanine). Thus, the kcat/Km value for the wild type hCPA1 with MTX-alpha-phenylalanine is 0.44 microM-1 s-1, and kcat/Km values for hCPA1-T268G with MTX-alpha-3-cyclobutylphenylalanine and MTX-alpha-3-cyclopentyltyrosine are 1.8 and 0.16 microM-1 s-1, respectively. The cytotoxic efficiency of hCPA1-268G was tested in an in vitro ADEPT model. For this experiment, hCPA1-T268G was chemically conjugated to ING-1, an antibody that binds to the tumor antigen Ep-Cam, or to Campath-1H, an antibody that binds to the T and B cell antigen CDw52. These conjugates were then incubated with HT-29 human colon adenocarcinoma cells (which express Ep-Cam but not the Campath 1H antigen) followed by incubation of the cells with the in vivo stable prodrugs. The results showed that the targeted ING-1:hCPA1-T268G conjugate produced excellent activation of the MTX prodrugs to kill HT-29 cells as efficiently as MTX itself. By contrast, the enzyme-Campath 1H conjugate was without effect. These data strongly support the feasibility of ADEPT using a mutated human enzyme with a single amino acid change.
 ...
PMID:Toward antibody-directed enzyme prodrug therapy with the T268G mutant of human carboxypeptidase A1 and novel in vivo stable prodrugs of methotrexate. 918 78

Selective delivery of lethal concentrations of drugs to tumors, allowing the latter to be eradicated without damage to other tissues, continues to be a major goal in cancer chemotherapy. Prodrugs (i.e. drugs that have been derivatized to prevent uptake into cells or interaction with targets), activated by enzyme-monoclonal antibody conjugates positioned at tumor sites, offer promise for achieving this objective. Methotrexate alpha-peptides (derivatives in which an amino acid is linked to the alpha-carboxyl group of the glutamate moiety) are ideal prodrugs, since they are not transported into cells and can be converted to the parent drug by carboxypeptidases. The L,L-diastereomer of MTX-alpha-Phe, synthesized in good yield by treatment of the p-nitrophenyl ester of 4-amino-4-deoxy-10-methylpteroic acid with Glu-alpha-Phe, was hydrolyzed readily by carboxypeptidase A (CP-A). Conjugate was prepared by derivatizing the enzyme and monoclonal antibody KS1/4 with linkers containing maleimide and sulfhydryl groups, respectively; interaction of these groups to form a stable thioether bond joined the proteins. When administered in vitro to UCLA-P3 human lung adenocarcinoma cells (ca. 5 x 10(4) antibody binding sites/cell) that had been pre-treated with the conjugate (whose antibody KS1/4 is targeted to these cells), and excess conjugate removed by extensive washing, MTX-Phe (ID50 = 6.3 x 10(-8) M) approached the toxicity of MTX (ID50 = 4.5 x 10(-8) M). In the absence of conjugate, MTX-Phe was much less toxic (ID50 = 2.2 x 10(-6) M).
 ...
PMID:Development of methotrexate alpha-peptides as prodrugs for activation by enzyme-monoclonal antibody conjugates. 938 87

Mast cell profile in common prostatic lesions was analysed in this study. 17B consecutive prostatic biopsy specimens specimens were categorised broadly into nodular hyperplasia without prostatitis (101), nodular heperplasia with prostatitis (50, prostatic intraepithelial neoplasia (2) and adenocarcinoma (25). Toluidine blue stain (0.1%) was used to demonstrate the mast cells and their count was expressed per square millimeter. Mast cell count was significantly higher in the fibromuscular stroma when compared to the glandular areas in nodular hyperplasia (p < .05). The mast cell counts were very significantly lower in inflammatory lesions (p < 0.0001) probably due to degranulation. Absence or a low count was the most significant finding in adenocarcinoma irrespective of the grade of the tumour with concentration of mast cells around the tumour. This study shows the variations in mast cell distribution in commonly encountered prostatic lesions. There is paucity of such studies in the literature and the possible utility of mast cell count to differentiate malignant from benign and atypical conditions needs further evaluation.
 ...
PMID:Mast cell profile in prostatic lesions. 1021 95

We have occasionally experienced eosinophilic abscess of the liver in patients with gastric carcinoma, suggesting that some eosinophil mobilizing (chemotactic and proliferative) factors might be produced by carcinoma cells. The aim of this study was to determine whether or not gastric carcinoma expresses the well-known eosinophil chemotactic factors (ECFs) and whether or not the expression is related to the histologic subtypes. Seventeen consecutive surgically removed tumor-bearing stomachs were collected: 7 signet ring cell type, 7 poorly differentiated tubular adenocarcinoma, and 3 moderately differentiated tubular adenocarcinoma. Hematoxylin-eosin stained sections were re-evaluated for eosinophil and mast cell infiltration. The expression of IL-2, IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) were examined by immunocytochemical stain. There was no available frozen tissue for IL-2 and IL-5 in one case. Gastric carcinoma expressed IL-2 in all 16 cases, IL-5 in 12 of 16 cases and GM-CSF in 10 of 17 cases. Of particular interest, 7 of 10 GM-CSF-expressing carcinomas were signet ring cell type. Even in the remaining 3 cases, most GM-CSF-positive cells were signet ring cells scattered within tubular adenocarcinoma. No correlation of ECF expression between either eosinophil/mast cell infiltration or peripheral blood eosinophilia was identified. In conclusion, most gastric carcinomas express the well-known ECFs and the expression of GM-CSF is specific for signet ring carcinoma cells.
 ...
PMID:Expression of eosinophil chemotactic factors in stomach cancer. 1033 16


<< Previous 1 2 3 4 5 6 Next >>