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

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.
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PMID:Mast cell interaction with tumor cells in small early gastric cancer: ultrastructural observations. 909 28

We present the case of a 44-year-old white male who developed multiple myeloma complicated by acute renal failure 8 years after the onset of urticaria pigmentosa. Mast cell disease has been associated with a number of haematological malignancies, particularly those from the myeloid lineage. Lymphoproliferative disorders have also been linked with mast cell disease but an association with multiple myeloma has not previously been described. Patients with urticaria pigmentosa should undergo simple screening blood tests to exclude an underlying haematological malignancy.
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PMID:Urticaria pigmentosa coexisting with multiple myeloma. 913 58

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.
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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

YU-311 is a monoclonal antibody that reacts with a human leukemia cell line resistant for cytosine arabinoside and that identifies a 92 kDa membrane protein. The reactivity of YU-311 in normal organs, various non-hematopoietic tumors and in mast cell tumors in formalin-fixed, paraffin-embedded specimens was examined using immunohistochemical methods. In normal organs, YU-311 reacted with fundic glands of the stomach, the intercalated duct of the pancreas, the distal portion and the loop of Henle of renal tubules and tissue mast cells. Benign neoplasms of various organs showed no immunoreaction with YU-311, except for mast cell tumors. Some types of malignant neoplasms were occasionally positive against YU-311, suggesting neoplasms arising from or differentiating along normal YU-311-positive counterparts. Some other types of malignancies were rarely positive for YU-311, although their normal counterparts showed no immunoreactivity with YU-311. None of the non-epithelial tumors reacted with YU-311, except for one case of malignant melanoma. In contrast, normal tissue mast cells and their related tumors, such as urticaria pigmentosa or solitary mastocytoma, were constantly positive for YU-311. None of the non-hematopoietic human tumor cell lines examined in the present study was reactive with YU-311. These findings indicate that YU-311 is a good marker of some types of tumors and mast cell tumors and that an aberrant expression of YU-311 rarely occurs.
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PMID:Reactivity of antibody YU-311 in formalin-fixed, paraffin-embedded specimens of normal organs, non-hematopoietic tumors, and mast cell tumors. 929 30

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).
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PMID:Development of methotrexate alpha-peptides as prodrugs for activation by enzyme-monoclonal antibody conjugates. 938 87

Seventeen dogs with mast cell tumours received chemotherapy. Fifteen dogs were treated with a vincristine, cyclophosphamide, hydroxyurea, and prednisolone (VCHP) regimen. Seven of these were later switched to doxyrubicin and prednisolone either because they stopped responding or because they did not respond from the start of the treatment. Two dogs received the latter regimen as the primary therapy. All dogs were treated with cimitidine and metoclopramide to minimize the effect of paraneoplastic syndrome associated with histamine release. Ten of the 17 dogs were found to respond (4/17 complete response (CR), 6/17 partial response (PR)). Response duration varied from 39 to 910 days (median 53 days), including 3 dogs with a CR that lasted more than 2 years. Survival time in responders varied from 41 to 910 days (median 97 days) and from 30 to 126 (median 39) in the other 7 dogs. Dogs that became refractory to VCHP did not respond to doxyrubicin and prednisolone. It is concluded that multi-agent chemotherapy has anti-tumour activity in a considerable proportion of dogs with mast cell tumours, but its efficacy is variable. The multivariate analyses showed that significant factors predicting survival in dogs with mast cell tumours were sex (P = 0.009), absence or presence of non-abdominal distant metastases, or abdominal metastases, respectively (P = 0.023), and malignancy grade of the tumours (P = 0.053).
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PMID:Multi-agent chemotherapy for mast cell tumours in the dog. 947 33

We present the case of a 40-year-old man with aggressive systemic mast cell disease. The patient had a predominant near-haploid clone in his bone marrow cells, detected by cytogenetic analysis performed at the time of diagnosis. The similarities between this case and a previously published case of near-haploidy in a patient with malignant mastocytosis suggest that near-haploidy may be a characteristic of aggressive systemic mast cell disease rather than an incidental finding.
Cancer Genet Cytogenet 1998 Jun
PMID:A near-haploid bone marrow karyotype in systemic mast cell disease: is it characteristic of the disease or an incidental finding? 961 10

Mastocytosis is a term used for a spectrum of disorders characterized by abnormal growth and accumulation of mast cells. The cutaneous variants of the disease have to be distinguished from systemic mastocytosis (SM), in which at least one extracutaneous organ is involved. In contrast to cutaneous mastocytosis, SM is often associated with another hematologic neoplasm. In most cases clonal myeloid malignancies such as a myeloproliferative or myelodysplastic syndrome occur. In a few cases of SM, however, clonal lymphoid disorders have been described. We here report on a case of SM associated with multiple myeloma. At first presentation, the 48-year old female patient showed monoclonal IgGlambda gammopathy and bone marrow (BM) mastocytosis, but no BM plasma cell infiltrates. Eight years later, the patient presented with BM mastocytosis and overt multiple myeloma. The co-existence of myeloma and mastocytosis was demonstrable by staining serial BM sections with antibodies against mast cell tryptase, CD68R, and the plasma cell marker VS38c. Interphase FISH analysis of BM sections revealed a numeric gain of chromosome 5 and chromosome 7 in the plasma cells but not in the mast cell infiltrates, thereby confirming the presence of two different neoplastic cell populations. To our knowledge, this is the first report describing the co-existence of multiple myeloma and mastocytosis.
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PMID:A case of bone marrow mastocytosis associated with multiple myeloma. 961 35

Inflammation with infiltrations of eosinophils and mast cells into the walls of airways is considered to increase airway hyperresponsiveness (AHR), which in turn characterizes asthma. We present a child with AHR in whom the clinical course of asthma was related to eosinophilic bronchitis. Our patient was admitted at age 6 months with bronchiolitis and at age 4 years with asthma. Inhaled corticosteroids were begun at age 7 years. At age 8 he developed a meningeal sarcoma. While on chemotherapy, his asthma symptoms resolved and he no longer required prophylactic asthma treatment. After 14 months off all chemotherapy, he again had mild episodic asthma. While receiving chemotherapy for malignancy, he had an admission with a coagulase negative staphylococcal bacteremia. During sputum induction with 4.5% saline, he developed cough, wheeze, and a 20% reduction in peak expiratory flow (220 to 180 L/min) that reversed after treatment with salbutamol. The sputum cell count was 1.7 x 10(6)/ml with 1.1 x 10(6) being neutrophils. Two weeks later and prior to the induction of the second sputum, a 21% increase in FEV1 was recorded after bronchodilator inhalation (82% to 99% of predicted). The second sputum contained 2.7 x 10(6)/ml cells with 1.6 x 10(6)/ml neutrophils. Neither eosinophils nor mast cells were identified in the sputum. A third sputum obtained 14 months after the cessation of chemotherapy showed a sputum cell count of 16 x 10(6)/ml, with 11.6 x 10(6) neutrophils and 0.4 x 10(6) eosinophils; no mast cells were detected. A reversible 15% reduction in FEV1 was detected on hypertonic saline challenge testing. This boy had persistent airway hyperreactivity and reversible airways obstruction on three occasions during and following chemotherapy. When he developed asthma symptoms, his sputum contained neutrophils and eosinophils; while on chemotherapy his sputum did not contain eosinophils and he was symptom-free and off all asthma therapy. One can speculate that chemotherapy for malignancy can induce a remission in asthma symptoms but not AHR, and remission in symptoms is associated with a lack of eosinophilic or mast cell infiltrates in the sputum.
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PMID:Chemotherapy for malignancy induces a remission in asthma symptoms and airway inflammation but not airway hyperresponsiveness. 971 Feb 82

5-Ethylamino-9-diethylaminobenzo[a]phenothiazinium chloride (EtNBS) is a novel photodynamic therapy (PDT) photosensitizer with efficacy against experimental murine tumors. In this preliminary study, dogs and cats with naturally occurring tumors were treated with EtNBS-PDT to determine safety and efficacy. Fifteen treatments were performed on 13 animals (9 treatments in 8 cats and 6 treatments in 5 dogs), generally using 400 J of 652 nm light. Two feline sublingual squamous cell carcinomas (SCCs) responded briefly (minor response). Six feline facial SCCs were treated, resulting in two partial responses and four long-term complete responses (CR). Two canine intraoral SCCs were treated; one responded minimally for 2 weeks (minor response), and one achieved long-term CR. One canine cutaneous mast cell tumor achieved CR, and one canine ocular mast cell tumor responded briefly. One canine ocular melanoma did not respond to treatment. Systemic reactions included nausea associated with photosensitizer injection in two cats and two dogs, elevated body temperatures during treatment in two dogs, elevated body temperature 2 days after PDT in one cat, and inappetance for 2 weeks in one cat. A peripheral neuropathy of undetermined cause occurred in one cat 2 weeks after PDT and resolved without treatment. Local reaction was well tolerated in 13 of 15 treatments. All animals were exposed to normal daylight after less than 5 days (mean, 3.5 days) without residual photosensitization. EtNBS-PDT is safe for dogs and cats and has activity against selected naturally occurring tumors, with an overall objective response rate (partial response + CR) of 61.5%.
Clin Cancer Res 1998 Sep
PMID:Photodynamic therapy of naturally occurring tumors in animals using a novel benzophenothiazine photosensitizer. 974 41


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