Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lack of tumor models that can reliably predict for response to anticancer agents remains a major deficiency in the field of experimental cancer therapy. Although heterotransplants of certain human solid tumors can be successfully grown in nude mice, they have never been appropriately explored for prediction of in vivo chemosensitivity to anticancer agents. We determined the tumor response rate and studied the influence of several biological and molecular tumor parameters on the in vivo sensitivity to paclitaxel in a series of heterotransplanted human non-small cell lung cancer (NSCLC) tumors. One hundred consecutive resected NSCLC tumors were heterotransplanted s.c. in nude mice. The in vivo sensitivity to i.v. paclitaxel (60 mg/kg every 3 weeks) was studied in 34 successfully grown heterotransplants. Treatment started when the tumors reached a size of 5 mm in diameter, and strict standard clinical criteria (>50% shrinkage in tumor weight or cross-sectional surface) were used to define tumor response. Baseline multidrug resistance protein (MRP), Her-2/neu, and epidermal growth factor receptor (EGFR) expression, and pre- and posttherapy bax and bcl-2 expression were determined by Western blot analysis. p53 status was determined by sequencing. The overall take rate was 46% (95% confidence interval, 36-56%) and was significantly higher (P < 0.05) for squamous carcinoma tumors (75%) than for adenocarcinoma tumors (30%) and bronchoalveolar tumors (23%). The heterotransplants were morphologically very similar to the original tumors. The response rate to paclitaxel was 21% (95% confidence interval, 9-38%). Baseline tumor parameters associated with response were no Her-2/neu expression (none of the responding tumors expressed Her-2/neu versus 48% of the nonresponding tumors, P = 0.05) and baseline bcl-2 expression (all responding tumors expressed bcl-2 versus only 43% of the nonresponding tumors, P = 0.02). There was a trend toward a higher response rate in bax-positive tumors, and MRP- and EGFR-negative tumors, but it was not statistically significant. The response was independent of baseline p53 status and baseline mitotic index. Responding tumors had a higher bax/bcl-2 ratio 24 h after therapy, but the difference was only marginally significant (2.8 for responding tumors versus 1.1 for nonresponding tumors, P = 0.07). The extent of mitotic arrest at 24 h after therapy was not associated with response. Human NSCLC heterotransplants are morphologically identical to the original tumors and have a response rate to paclitaxel that is equivalent to that reported in Phase II studies in patients with advanced NSCLC treated with single-agent paclitaxel. NSCLC heterotransplants deserve to be explored to evaluate new agents for lung cancer and to predict clinical response on an individual basis in selected groups of patients.
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PMID:Response and determinants of sensitivity to paclitaxel in human non-small cell lung cancer tumors heterotransplanted in nude mice. 1115 54

Chemotherapy plays a vital role in the treatment and management of breast cancer and is associated with significant improvements in survival. Regimens such as CMF (cyclophosphamide/methotrexate/5-fluorouracil) and, more recently, TAC (docetaxel/doxorubicin/cyclophosphamide) have been used with good response rates and complete remissions achieved in approximately 15% of cases. However, a significant proportion of women experience a recurrence of metastatic disease, with an average survival between 1-2 years. The monoclonal antibody trastuzumab is used in the treatment of HER2/neu-positive breast cancer. Although such targeted agents have heralded an exciting new era in cancer therapy, they are limited by the fact that only a subset of patients can benefit from treatment and by the emergence of resistance. Thus, the pursuit of a strategy that modulates resistance to standard chemotherapeutics remains valid. Accumulating evidence indicates that a number of mechanisms known to contribute to clinical drug resistance might be relevant to breast cancer. Tumor cell drug resistance might arise as a result of systemic pharmacologic factors, changes in the tumor microenvironment (eg, pH), cellular pharmacokinetics, drug metabolism and detoxification, drug target modifications, DNA repair, and apoptotic mechanisms. The adenotriphosphate-binding cassette membrane transporter family contributes to clinical drug resistance, especially in breast cancer. The most frequently described of this family is P-glycoprotein, followed by multidrug resistance protein-1. This review describes the factors thought to play a role in clinical breast cancer drug resistance and describes potential methods by which it might be circumvented.
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PMID:The role of efflux pumps in drug-resistant metastatic breast cancer: new insights and treatment strategies. 1802 75