Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033774 (pruritus)
 14,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cbl proteins have RING finger-dependent ubiquitin ligase (E3) activity that is essential for down-regulation of tyrosine kinases. Here we establish that two WW domain HECT E3s, Nedd4 and Itch, bind Cbl proteins and target them for proteasomal degradation. This is dependent on the E3 activity of the HECT E3s but not on that of Cbl. Consistent with these observations, in cells expressing the epidermal growth factor receptor, Nedd4 reverses Cbl-b effects on receptor down-regulation, ubiquitylation, and proximal events in signaling. Cbl-b also targets active Src for degradation in cells, and Nedd4 similarly reverses Cbl-mediated Src degradation. These findings establish that RING finger E3s can be substrates, not only for autoubiquitylation but also for ubiquitylation by HECT E3s and suggest an additional level of regulation for Cbl substrates including protein-tyrosine kinases.
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PMID:WW domain HECT E3s target Cbl RING finger E3s for proteasomal degradation. 1290 74

Cytotoxic chemotherapy treatment options for patients with non-small-cell lung cancer (NSCLC) have limited efficacy and are often associated with significant toxicity. Therefore, there is an unmet need for novel drugs that are not only effective in treating this disease but are also well tolerated. Gefitinib is an orally active epidermal growth factor receptor tyrosine kinase inhibitor that blocks the signal transduction pathways implicated in cancer cell growth and survival. It has recently been approved for the treatment of advanced/refractory NSCLC. This review presents the tolerability data from phase I and II gefitinib monotherapy trials, along with data from the worldwide 'Expanded Access Programme' and post-marketing use of gefitinib. Gefitinib was found to be generally well tolerated at the approved dosage of 250 mg/day; the most commonly reported adverse drug reactions (ADRs) were mild to moderate skin rash and diarrhoea, which were manageable and non-cumulative. Other ADRs observed with the use of gefitinib included: dry skin, pruritus, acne, nausea, vomiting, anorexia, asthenia and asymptomatic elevations in liver transaminase levels. Well recognised adverse effects seen with cytotoxic chemotherapy (such as bone marrow depression, neurotoxicity and nephrotoxicity) were not observed. Although the frequency and severity of ADRs increased with the dosage across the range studied (50-1000 mg/day), few patients required dosage reductions or the withdrawal of treatment, and those who did usually received gefitinib >or=600 mg/day.Thus, the available data indicate that gefitinib is well tolerated in patients with a range of solid tumours, including locally advanced or metastatic NSCLC.
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PMID:Overview of the tolerability of gefitinib (IRESSA) monotherapy : clinical experience in non-small-cell lung cancer. 1555 44

Erlotinib (Tarceva) is an epidermal growth factor receptor (EGFR) inhibitor, a member of a new group of molecular targeted drugs that combine high efficacy against tumours with less, often self-limiting, toxicity, compared with traditional chemotherapeutics. It is used for treatment of solid-organ tumours, especially as second- or third-line therapy for non-small-cell lung cancer. Dose-related cutaneous side-effects and diarrhoea may be a significant obstacle to treatment compliance. We present two cases with long-lasting acneiform eruptions, complicated by significant impetiginization, resulting in hospitalization in one case. The other patient suffered from sleep-disturbing, itching crusts on the scalp. As the use of EGFR inhibitors is increasing, clinicians should be aware of their side-effects. Early and timely dermatological intervention may diminish adverse events for patients treated with these agents and improve quality of life.
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PMID:Erlotinib-induced florid acneiform rash complicated by extensive impetiginization. 1798 55

Cetuximab is a recombinant human/mouse chimeric monoclonal antibody that targets the extracellular domain of the epidermal growth factor receptor (EGFR). Cetuximab is approved by the US Food and Drug Administration for the treatment of EGFR-expressing metastatic colorectal cancer as monotherapy in patients who are intolerant to irinotecan-based chemotherapy, or in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy. Due to the important role of the EGFR in skin homeostasis, cutaneous reactions are a common adverse effect of cetuximab, mainly as acneiform follicular eruption seen in almost 85% of patients. We report on a 46-year-old female Caucasian patient with metastatic colorectal cancer, referred to our department for acneiform eruption induced by cetuximab in combination with irinotecan. Four days after the first infusion the patient developed intense acneiform eruption consisting of erythematous follicular papules and pustules spread to the face, neck and upper part of the trunk, accompanied by intense pruritus and fever (38.0 degrees C). There were no comedones. Biopsy specimen revealed superficial and florid neutrophilic suppurative folliculitis. She was treated with erythromycin tablet 600 mg, three times a day for 1 month, and topical clindamycin solution 3%. After 1 month of treatment, the lesions consistently faded, and the patient continued receiving immunochemotherapy.
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PMID:Acneiform eruption induced by cetuximab. 1809 54

Biologic agents targeting the epidermal growth factor receptor (EGFR) have emerged as a robust treatment option for various solid tumors. Despite lower systemic side effects than conventional chemotherapy, the majority of patients treated with these agents experience cutaneous toxicities, including papulopustular rashes, hair and nail changes, xerosis and pruritus, which have a significant impact on health and quality of life. Currently no consensus or management guidelines exist for these untoward events. Therefore, a retrospective survey was carried out across 110 oncology practioners in the US that were administering EGFR inhibitors. Providers were queried on the impact and management of these untoward events in their practices. Responses suggest that combination therapies (topical and oral) were more effective than either therapy alone, and also lead to a more rapid resolution of the papulopustular rash. Providers also reported that patients frequently complained of physical symptoms associated with the rash (itching and pain), and that they had a positive perception when being treated for their cutaneous side effects. The survey results support that attentive cutaneous care is important in patients treated with EGFR inhibitors, and that proactive/combined interventions may enhance quality of life and optimize consistent drug administration.
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PMID:Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. 1816 Aug 5

Extramammary Paget's disease (EMPD) is considered to be an intraepithelial adenocarcinoma. Typically involved anatomical sites are the vulvar, perianal, perineal, scrotal and penile regions. Clinically, the lesions present as well-defined, moist, erythematous plaques usually accompanied by pruritus. An unusual feature of EMPD is its association with cutaneous, adnexal-structure adenocarcinomas and its association with internal malignancies. Histopathological examination shows epidermal acanthosis and elongated rete ridges. Paget's cells are large intraepidermal cells with a large nucleous and abundant pale cytoplasm. Recent studies of perianal and vulvar EMPD have described distinct immunohistochemical subtypes termed cutaneous and endodermal. Cutaneous EMPD is characteristically positive for cytokeratin (CK)7, negative for CK20, and positive for gross cystic disease fluid protein (GCDFP)15+, whereas endodermal EMPD shows a CK7+ CK20+ GCDFP15- phenotype. Surgery remains the treatment of choice, with either wide surgical excision or Mohs' micrographic surgery. We present a case of EMPD with an underlying carcinoma, which combined immunohistochemical findings suggestive of the cutaneous subtype (positive for CK7, GCDFP15, mucin (MUC)1, human epidermal growth factor receptor (HER)2/neu positive) and the endodermal subtype, frequently associated with internal malignancy (CK20, MUC2, CDX-2 positve); however, our patient had no associated internal malignancy.
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PMID:Extramammary Paget's disease of the groin with underlying carcinoma and fatal outcome. 1848 20

ErbB4, a member of the epidermal growth factor receptor family, plays a role in normal breast and breast cancer development by regulating mammary epithelial cell proliferation, survival and differentiation. In this study, we show that WWP1, a C2-WW-HECT type E3 ubiquitin ligase, binds, ubiquitinates and destructs ErbB4-CYT1, but much less efficiently for CYT2, isoforms (both JMa and JMb). The protein-protein interaction occurs primarily between the first and third WW domains of WWP1 and the second PY motif of ErbB4. Knockdown of WWP1 by two different small interfering RNAs increases the endogenous ErbB4 protein levels in both MCF7 and T47D breast cancer cell lines. In addition, overexpression of the wild type, but not the catalytic inactive WWP1, dramatically decreases the endogenous ErbB4 protein levels in MCF7. Importantly, we found that WWP1 negatively regulates the heregulin-beta1-stimulated ErbB4 activity as measured by the serum response element report assay and the BRCA1 mRNA expression. After a systematic screening of all WWP1 family members by small interfering RNA, we found that AIP4/Itch and HECW1/NEDL1 also negatively regulate the ErbB4 protein expression in T47D. Interestingly, the protein expression levels of both WWP1 and ErbB4 are higher in estrogen receptor-alpha-positive than in estrogen receptor-alpha-negative breast cancer cell lines. These data suggest that WWP1 and its family members suppress the ErbB4 expression and function in breast cancer.
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PMID:WW domain containing E3 ubiquitin protein ligase 1 targets the full-length ErbB4 for ubiquitin-mediated degradation in breast cancer. 1956 40

Recently, inhibitors of the epidermal growth factor receptor (EGFR), such as erlotinib, gefitinib, cetuximab or panitumumab, have been successfully established in the therapy of a variety of solid tumors. Cutaneous adverse effects are the most frequent side-effects of these so-called targeted cancer drugs and occur in 45-100% of patients. In addition to a characteristic papulo-pustular rash, adverse effects include painful paronychia, xerosis cutis, pruritus, alopecia or alterations of the hair structure. These often stigmatizing side-effects represent a serious threat to the patients' quality of life and compliance and may lead to dose-reduction or even cessation of the antineoplastic therapy. Considering the steadily growing numbers of patients who receive EGFR-targeting therapy, these medicament-associated cutaneous adverse effects are becoming increasingly more important in the routine clinical practice of dermatologists and oncologists.
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PMID:[Therapy with epidermal growth factor receptor inhibitors. Clinical spectrum of cutaneous adverse effects]. 2062 13

Cutaneous toxicities are the most common adverse effects of antineoplastic therapy with epidermal growth factor receptor (EGFR) inhibitors. Skin reactions to this class of agents usually present as papular and/or pustular follicular eruptions developing within two weeks of treatment onset. Other manifestations include generalized xerosis and pruritus, as well as abnormalities of the hair and nails. For most EGFR inhibitors, the incidence and severity of cutaneous toxicity are associated with clinical benefit. At the same time, cutaneous toxic effects may detract substantially from health-related quality of life, leading to interruption, discontinuation or dose reduction of EGFR inhibitor therapy in significantly affected patients. Current recommendations for treatment of EGFR inhibitor-induced eruptions are based primarily on anecdotal evidence from published case series and physicians' own experiences, and include antibiotics, corticosteroids and retinoids. Randomized controlled trials are needed to enable the development of evidence-based paradigms for the treatment of EGFR inhibitor-induced skin eruptions.
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PMID:Cutaneous reactions to epidermal growth factor receptor inhibitors. 2094 47

Chemotherapeutic agents targeting the human epidermal receptor (HER) family are being used with increasing frequency for a variety of solid tumors. Cutaneous side effects are commonly reported with HER inhibitors, especially those agents that inhibit epidermal growth factor receptor (EGFR) or HER1. However, inhibitors of HER2 are not associated with specific skin toxicity. We present a case of tufted hair folliculitis, an inflammatory scalp condition causing scaling and pruritus, in a woman being treated with trastuzumab, a selective HER2 inhibitor. This finding has not previously been reported as a side effect of trastuzumab therapy.
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PMID:Tufted hair folliculitis in a woman treated with trastuzumab. 2094 75


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