Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new immunohistochemical assay was developed for the detection of human monoclonal antibody (HuMAb) bound to human biopsied tumor tissues. A murine anti-idiotype monoclonal antibody, alpha type, 18C6 (IgGl), was raised against an IgM HuMAb, L612, defining a tumor-associated ganglioside antigen (GM3) and used as a probe in a three step cell-binding assay (HuMAb + anti-id + biotinylated anti-mouse Ig). Anti-id 18C6 has an exclusive binding specificity for HuMAb L612, but does not interfere with the binding of L612 to antigen positive melanoma cell lines or to a purified antigen, GM3. The applicability of 18C6 in the three step cell-binding assay was tested first using a melanoma cell line, UCLASO-M12. L612 bound to M12 cells was specifically detected by 18C6 without any background reactivity in ELISA. When this assay was compared with the standard two-step cell-binding assay (HuMAb + peroxidase-conjugated anti-human IgM) using various cultured tumor cell lines, parallel reactivity was observed. The three-step cell-binding assay was then applied to various fresh-frozen human tumor sections. Positive reactivity was demonstrated on various histologic types of human tumor tissues: primary melanoma (10/10), metastatic melanoma (4/4), nevus (10/10), lung cancer (3/6), breast cancer (2/6), and colon cancer (1/1). Adjacent normal tissues were unstained. Control experiments included the cell-binding assay with L612 alone, 18C6 alone. L612 + unrelated mouse IgG, and unrelated IgM HuMAb (L72) + 18C6; but biotinylated anti-mouse IgG did not react with these control preparations. The results indicate that anti-id 18C6 is a highly specific probe to assess the expression of the ganglioside antigenic epitope recognized by the L612 HuMAb on biopsied human tumor tissues.
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PMID:Murine monoclonal anti-idiotype antibody (alpha) as a probe to detect human monoclonal antibody bound to human tumor tissues. 223 Jan 46

Multidrug resistance (MDR) phenotype in mammalian cells is often correlated with overexpression of P-glycoprotein or multidrug resistance-associated protein (MRP1). Both proteins are energy-dependent drug efflux pumps that efficiently reduce the intracellular accumulation and hence the cytotoxicity of many natural cytotoxins. The influx and efflux of drugs across the cell membrane are in large part responsible for their intracellular concentrations, and in the search for new compounds able to overcome MDR, it is of prime importance to determine the molecular parameters whose modification would lead to an increase in the kinetics of uptake and/or to a decrease in the pump-mediated efflux. Here, we studied three members of a new family of benzoperimidine antitumor compounds which exhibit comparable cytotoxicity towards resistant cells expressing P-glycoprotein, or MRP1, and sensitive cells. We used spectrofluorometric methods to determine the kinetics of the uptake and release of these three drugs in different cell lines: the erythroleukemia cell line K562 and the resistant K562/Adr expressing P-glycoprotein, the small-cell lung cancer cell line GLC4 and resistant GLC4/Adr expressing MRP1. We also studied, using confocal microscopy, the intracellular distribution of these drugs in NIH/3T3 cells. Our data show that (i) the kinetics for the uptake of these drugs is very rapid, higher than 2 x 10(-17) mole cell(-1) s(-1), (ii) the drugs are strongly accumulated in the nucleus and lysosomes, (iii) the three drugs are recognized and pumped out by both transporters, as shown by the inhibition of P-glycoprotein- and MRP1-mediated efflux of pirarubicin by benzoperimidine, with inhibitory constants of 1.5 and 2.1 microM for P-glycoprotein and MRP1, respectively, suggesting that benzoperimidine is transported by the two transporters with K(m) approximately 2 microM. In conclusion, the fast uptake kinetics of the benzoperimidines counterbalance their efflux by P-glycoprotein and MRP1.
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PMID:Transport of new non-cross-resistant antitumor compounds of the benzoperimidine family in multidrug resistant cells. 1122 86

Angiogenesis is critical in melanoma progression and metastasis and relies on the synthesis and release of proangiogenic molecules such as vascular endothelial growth factor (VEGF)-A and fibroblast growth factors (FGFs). S100A13 is a small calcium-binding protein that facilitates the release of FGF-1, the prototype of the FGF family. S100A13 is upregulated in astrocytic gliomas, in which it correlates with VEGF-A expression, microvessel density and tumor grading, and promotes a more aggressive, invasive phenotype in lung cancer-derived cell lines. To investigate the involvement of S100A13 in human cutaneous melanoma, we analyzed a series of 87 cutaneous melanocytic lesions: 14 common acquired melanocytic nevi, 14 atypical, so-called 'dysplastic' nevi, 45 melanomas (17 radial growth phase and 28 vertical growth phase) and 14 melanoma metastases. Main clinical and pathological features, including histotype, Breslow thickness, Clark's level and outcome were recorded. Microvessel density was determined with CD105/endoglin staining. Semiquantitative determination of S100A13, FGF-1 and VEGF-A protein expression was obtained by immunostaining. Quantification of S100A13 mRNA was achieved by real-time PCR. We found that S100A13 was expressed in melanocytic lesions; compared with benign nevi, S100A13 protein expression was significantly upregulated in melanomas (P=0.024), in which it correlated positively with the intensity of VEGF-A staining (P=0.041) and microvessel density (P=0.007). The level of expression of S100A13 mRNA also significantly increased with progression of disease, from radial growth phase (0.7+/-0.7) to vertical growth phase (3.6+/-3.1) to metastases (7.0+/-7.0) (P<0.001). Furthermore, S100A13 mRNA correlated positively with VEGF-A (P=0.023), TNM stage (P=0.05), risk of relapse (P=0.014) and status at follow-up (P=0.024). In conclusion, S100A13 is expressed in melanocytic lesions when the angiogenic switch occurs and it may cooperate with VEGF-A in supporting the formation of new blood vessels, favoring the shift from radial to vertical tumor growth. Therefore, S100A13 may represent a new angiogenic and prognostic marker in melanoma.
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PMID:S100A13 is a new angiogenic marker in human melanoma. 2020 80

Cutaneous melanoma is the most rapidly increasing malignancy in the white European population; its clinical significance is enhanced because it can affect younger individuals (1-3). The high mortality rate among melanoma patients, second to lung cancer, is related to melanoma's resistance to therapy once the metastastic process has started (4-6). The tumor derives from epidermal melanocytes, either activated or genetically altered; thus, important precursors include activated melanocytes present within solar lentigo or forming prema- lignant lesions such as lentigo maligna (7-10). Melanoma can also arise from relatively benign or atypical nevomelanocyte lesions (7-10). Benign lesions that can nevertheless result in melanoma include congenital melanocytic nevus, nevus of Ota, nevus of Ito, and cellular blue nevus. The atypical lesions with the same possible outcome are represented by acquired dysplastic melanocytic nevus, melanocytic dysplasia on the acral or mucosal surface, spindle cell and/or atypical epithelioid melanocytic nevus (Spitz nevus), and dysplastic and/or congenital nevus spilus (7-10).
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PMID:Role of molecular biology in diagnostic pathology of melanoma. 2232 56

Epidermal growth factor receptor (EGFR) mutations, especially EGFR-exon 19 deletions and EGFR-L858R, are the most frequent actionable genomic events in lung adenocarcinomas. Tumors arise due to constitutively activated EGFR signaling and are susceptible to EGFR tyrosine kinase inhibitors (TKIs). First generation EGFR TKIs (gefitinib and erlotinib) and the second generation EGFR TKI afatinib are approved worldwide. Although targeted therapies against EGFR mutants induce dramatic initial responses, acquired resistance (through multiple biological mechanisms) to erlotinib, gefitinib and afatinib emerges within the first 1-2 years of continued monotherapy. EGFR-T790M accounts for more than half of acquired resistance to first or second generation EGFR TKIs by modifying ATP affinity and drug binding kinetics. Two new studies have shown that two covalent pyrimidine inhibitors-AZD9291 and rociletinib of EGFR-T790M (i.e., third generation EGFR TKIs) shown remarkable clinical activity in patients with acquired resistance to erlotinib, gefitinib and afatinib when the tumor carries EGFR-T790M in conjunction with an activating mutation. However, and regrettably, acquired resistance to these third generation EGFR TKIs has already been reported in preclinical models and clinical specimens; such as a tertiary mutation at EGFR-C797S that prevents covalent binding of EGFR TKIs. The experience with sequential EGFR TKI monotherapy highlights tumor heterogeneity and adaptability (i.e., relentless game of whack-a-mole played between TKIs and cancer), and will help shape future clinical development of novel combinatory approaches to manage EGFR mutated lung adenocarcinomas.
Transl Lung Cancer Res 2015 Dec
PMID:Whacking a mole-cule: clinical activity and mechanisms of resistance to third generation EGFR inhibitors in EGFR mutated lung cancers with EGFR-T790M. 2679 93

The blind subterranean mole rat, Spalax ehrenbergi, is a model organism for hypoxia tolerance. This superspecies have adapted to severe environment by altering an array of hypoxia-mediated genes, among which an alteration in the p53 DNA binding domain (corresponding to R174K in humans) that hinders its transcriptional activity towards apoptotic genes. It is well accepted that apoptosis is not the only form of programmed cell death and that mechanisms that depend on autophagy are also involved. In the current work we have extended our research and investigated the possibility that Spalax p53 can activate autophagy. Using two complementary assays, we have established that over-expression of the Spalax p53 in p53-null cells (human lung cancer cells, H1299), potently induces autophagy. As Spalax is considered highly resistant to cancer, we further studied the relative contribution of autophagy on the outcome of H1299 cells, following transfection with Spalax p53. Results indicate that Spalax p53 acts as a tumor suppressor in lung cancer cells, inducing cell death that involves autophagy and caspases and inhibiting cell number, which is exclusively caspase-dependent. To conclude, the Spalax p53 protein was evolutionary adapted to survive severe underground hypoxia while retaining the ability to defy lung cancer.
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PMID:The double benefit of Spalax p53: surviving underground hypoxia while defying lung cancer cells in vitro via autophagy and caspase-dependent cell death. 2755 17

Ground glass opacity (GGO) is a good prognostic indicator for lung cancer and is useful for physicians to predict prognosis. Due to recent advances in computed tomography (CT), the chance to encounter GGO is rapidly increasing in clinical practice. Based on the studies on radiological pathological correlation, GGO represents pathological lepidic growth and consolidation on CT represents pathologically invasive components. Thus, consolidation tumor ratio 0.5 or less means pathological less invasiveness for lung cancer. Not a few studies have shown that sublobar resection is equivalent to lobectomy for radiological early lung cancers. Additionally, observation of GGO is one of the options for physicians. Indication of surgical intervention remains unclear. Physician observing GGO in practice should know the natural history of GGO to reach an optimal treatment decision. For multifocal GGO lesions clinical management is surely challenging. Whack-a-mole strategy, which means sublobar resection for radiological invasive cancer is one of the most promising strategies for such lesions.
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PMID:Whack-a-mole strategy for multifocal ground glass opacities of the lung. 2844 85

Cutaneous side effects such as acneiform eruption, xerosis, and paronychia are frequently observed in patients undergoing treatment with epidermal growth factor receptor (EGFR) inhibitors for non-small cell lung cancer and other solid tumors. Interestingly, these side effects appear to positively correlate with length of remission, indicating that disruption of homeostatic EGFR signaling in the skin may serve as a marker of therapeutic EGFR inhibition in tumors. We report the case of a woman with metastatic lung cancer in remission being treated with the EGFR inhibitor, erlotinib, who experienced numerous commonly occurring adverse cutaneous reactions early in her treatment, and after two years of treatment developed eruptive nevi as well as a nevoid melanoma. Changes in pigmented lesions and the development of melanoma have been described during treatment with the BRAF inhibitor, vemurafenib, and are believed to relate to paradoxical activation of BRAF and the MAPK pathway. We speculate that a similar mechanism may occur during treatment with EGFR inhibitors. Therefore, thorough skin examinations are essential for patients undergoing long term treatment with erlotinib.
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PMID:Nevoid melanoma and eruptive nevi from erlotinib. 3281 91