Biomedical subjects

Pan-Chyr Yang

Publications and source records attributed to Pan-Chyr Yang.

At least 19 recordsLinked to original sources

PubMed2026

Plasma signals of lung tumor promotion for molecular cancer prevention.

Predicting lung cancer risk would enhance prevention trials. Although the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial demonstrated reduced lung cancer incidence with interleukin (IL)-1β inhibition, the high number needed to treat (NNT) to prevent lung cancer limits its use in unselected populations. Using machine learning, we identified a 14-protein plasma signature predicting lung cancer more than 5 years before diagnosis. The signature, validated across eight cohorts, was elevated in current smokers and individuals exposed to particulate matter (PM) and linked to lung myeloid and alveolar cells. In epidermal growth factor receptor (EGFR)-driven lung adenocarcinoma, diverse epithelial lineages converged on a keratin8+/claudin4+ alveolar transitional state (KAC), whose transcriptional programs correlated with signature emergence. Components of the signature were induced by PM, oncogenic EGFR, or IL-1β, whereas IL-1β inhibition restrained PM-driven KAC expansion and early tumorigenesis. In CANTOS, the signature identified individuals who seemed to benefit more from anti-IL-1β therapy, lowering the NNT threshold and nominating circulating signals of tumor promotion for prevention.

Humans↗

PubMed2006

Design of microarray probes for virus identification and detection of emerging viruses at the genus level.

BACKGROUND: Most virus detection methods are geared towards the detection of specific single viruses or just a few known targets, and lack the capability to uncover the novel viruses that cause emerging viral infections. To address this issue, we developed a computational method that identifies the conserved viral sequences at the genus level for all viral genomes available in GenBank, and established a virus probe library. The virus probes are used not only to identify known viruses but also for discerning the genera of emerging or uncharacterized ones. RESULTS: Using the microarray approach, the identity of the virus in a test sample is determined by the signals of both genus and species-specific probes. The genera of emerging and uncharacterized viruses are determined based on hybridization of the viral sequences to the conserved probes for the existing viral genera. A detection and classification procedure to determine the identity of a virus directly from detection signals results in the rapid identification of the virus. CONCLUSION: We have demonstrated the validity and feasibility of the above strategy with a small number of viral samples. The probe design algorithm can be applied to any publicly available viral sequence database. The strategy of using separate genus and species probe sets enables the use of a straightforward virus identity calculation directly based on the hybridization signals. Our virus identification strategy has great potential in the diagnosis of viral infections. The virus genus and specific probe database and the associated summary tables are available at http://genestamp.sinica.edu.tw/virus/index.htm.

Animals↗

PubMed2006

Knockdown of contactin-1 expression suppresses invasion and metastasis of lung adenocarcinoma.

Numerous genetic changes are associated with cancer cell metastasis and invasion. In search for key regulators of invasion and metastasis, a panel of lung cancer cell lines with different invasive ability was screened. The gene for contactin-1 was found to play an essential role in tumor invasion and metastasis. Suppression of contactin-1 expression abolished the ability of lung adenocarcinoma cells to invade Matrigel in vitro as well as the polymerization of filamentous-actin and the formation of focal adhesion structures. Furthermore, knockdown of contactin-1 resulted in extensive inhibition of tumor metastasis and in increased survival in an animal model. RhoA but not Cdc42 or Rac1 was found to serve a critical role in contactin-1-mediated invasion and metastasis. Contactin-1-specific RNA interference resulted in loss of metastatic and invasive capacity in both in vitro and in vivo models. This loss was overturned by constitutive expression of the active form of RhoA. Contactin-1 was differentially expressed in tumor tissues, and its expression correlated with tumor stage, lymph node metastasis, and patient survival. Contactin-1 is proposed to function importantly in the invasion and metastasis of lung adenocarcinoma cells via RhoA-mediated mechanisms.

Actins↗

PubMed2006

Epidermal growth factor receptor mutations in needle biopsy/aspiration samples predict response to gefitinib therapy and survival of patients with advanced nonsmall cell lung cancer.

Recently, mutations in the epidermal growth factor receptor (EGFR) gene in nonsmall cell lung cancer (NSCLC) patients were reported to correlate with gefitinib response. Less than 30% of NSCLC patients are surgically resectable; however, molecular analysis has to rely on nonsurgical diagnostic tissue samples. The objective of this study is to investigate EGFR mutation analysis on needle biopsy/aspiration samples and its correlations with gefitinib response and patients' survival. EGFR mutation was assessed from DNA of 63 paraffin-embedded small needle biopsy/aspiration specimens from 62 patients with NSCLC treated with gefitinib. The peripheral blood lymphocyte DNA of the patients was sequenced to verify the EGFR mutation. EGFR mutations were found in 47% of 62 patients (60% of 20 CT-guided biopsies, 44% of 18 ultrasound-guided biopsies, 31% of 16 endoscopic biopsies and 44% of 9 effusion cell blocks). EGFR mutations were frequently present in females (p = 0.006) and never smokers (p = 0.04). Patients with EGFR mutations had a significantly better response rate compared to that of the nonmutation group (p < 0.001). Multivariate analysis showed that EGFR mutation (p < 0.001) and PS 0-1 (p = 0.02) were independently associated with a better response rate. Cox regression analysis showed that EGFR mutation was the independent prognostic factor for progression-free survival (p = 0.008) and overall survival (p = 0.03). In conclusion, EGFR mutation analysis is feasible in needle biopsy/aspiration paraffin-fixed specimens. EGFR mutation is an independent predictor of gefitinib response and survival in patients of advanced NSCLC treated by gefitinib.

Aged↗

PubMed2006

Spontaneous bilateral bacterial empyema in a patient with nephrotic syndrome.

Spontaneous bacterial empyema (SBEM), a rare infectious complication among liver cirrhosis patients, is characterized by infection in the presence of pleural effusion without evidence of pre-existing pneumonia. The prevalence of SBEM in cirrhotic patients with hydrothorax is about 13%. However, it has previously not been reported in medical literature in patients with nephrotic syndrome. The most common microorganism identified is Escherichia coli, followed by Streptococcus species, Enterococcus species, Klebsiella pneumoniae, and Pseudomonas stutzeri. We present a patient with a history of nephrotic syndrome caused by membranous nephropathy, who received steroids and cyclophosphamide. He developed bilateral SBEM due to Aeromonas hydrophila and E. coli, which were isolated from the left- and right-side pleural fluid, respectively. The detailed clinical course, treatment, and outcome are described.

Adult↗

PubMed2006

The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells.

Flt-4, a VEGF receptor, is activated by its specific ligand, VEGF-C. The resultant signaling pathway promotes angiogenesis and/or lymphangiogenesis. This report provides evidence that the VEGF-C/Flt-4 axis enhances cancer cell mobility and invasiveness and contributes to the promotion of cancer cell metastasis. VEGF-C/Flt-4-mediated invasion and metastasis of cancer cells were found to require upregulation of the neural cell adhesion molecule contactin-1 through activation of the Src-p38 MAPK-C/EBP-dependent pathway. Examination of tumor tissues from various types of cancers revealed high levels of Flt-4 and VEGF-C expression that correlated closely with clinical metastasis and patient survival. The VEGF-C/Flt-4 axis, through upregulation of contactin-1, may regulate the invasive capacity in different types of cancer cells.

Adenocarcinoma↗

PubMed2006

Predictive value of rapid shallow breathing index measured at initiation and termination of a 2-hour spontaneous breathing trial for weaning outcome in ICU patients.

BACKGROUND/PURPOSE: The rapid shallow breathing index (RSBI) is a weaning parameter usually measured at the start of a spontaneous breathing trial (SBT). This study investigated the value of RSBI measured at the beginning and termination of SBT as a predictor of weaning outcome. METHODS: RSBI was measured during the initial 1 minute (RSBI1) and at termination (RSBI2) of an SBT in 172 patients recovering from acute respiratory failure. RESULTS: Weaning was successful in 106 patients and failed in 66 patients. Among the 66 patients with weaning failure, 12 required reintubation within 48 hours (extubation failure), and the remaining 54 patients could not be extubated after SBT (trial failure). There were no differences between RSBI1 in the three groups (69.4 +/- 27.5, 81.7 +/- 24.4 and 75.5 +/- 26.5, respectively), but RSBI2 was significantly higher in patients with extubation failure (95.9 +/- 20.6) and trial failure (98.0 +/- 50.0) than in patients with weaning success (64.6 +/- 26.3) (both p < 0.001). Logistic regression revealed that RSBI2 was superior to RSBI1 and various physiologic indices in predicting weaning outcome. For the 118 extubated patients, the mean area under the receiver operating characteristic curve for RSBI2 and RSBI1 was 0.83 and 0.63, respectively. Using a threshold value of 105, the sensitivity, specificity, accuracy and likelihood ratio for weaning outcome were 0.91, 0.25, 0.85 and 1.38 for RSBI2 and 0.89, 0.16, 0.60 and 1.06 for RSBI1, respectively. CONCLUSION: This study found that RSBI measured at the completion of SBT was superior to that measured at the start in predicting weaning outcome in critically ill patients.

Aged↗

PubMed2006

Severe community-acquired pneumonia due to Legionella pneumophila Serogroup 6.

Legionella pneumophila is a common cause of sporadic community-acquired pneumonia, but culture-proven legionellosis is rarely diagnosed. There is no laboratory test for Legionnaires' disease that can detect all patients with the disease. Culture is the standard diagnostic method and should be initiated as soon as possible in suspected cases. We describe a rare case of community-acquired pneumonia caused by L. pneumophila serogroup 6. A 77-year-old man was admitted to a tertiary care hospital because of high fever, productive cough, and progressive dyspnea. Chest radiography showed bilateral pneumonia, which led to respiratory failure necessitating mechanical ventilatory support. Despite antibiotic therapy, his condition continued to deteriorate and acute renal failure also developed. Urine was negative for L. pneumophila. Culture of the sputum yielded L. pneumophila serogroup 6, although there was no elevation of the serum antibody titer. Pneumonia resolved gradually and he was extubated after treatment with levofloxacin followed by erythromycin. L. pneumophila other than serogroup 1 should be included in the differential diagnosis of patients with suspected atypical community-acquired pneumonia.

Aged↗

PubMed2006

Polymorphism of the angiotensin-converting enzyme gene affects the outcome of acute respiratory distress syndrome.

OBJECTIVE: There has been increasing evidence that angiotensin II may play an important role in the pathogenesis and in the evolution of acute lung injury. It was therefore hypothesized that polymorphisms of the angiotensin-converting enzyme gene affects the risk and outcome of acute respiratory distress syndrome (ARDS). DESIGN: Prospective, observational study. PATIENTS AND SETTINGS: The ARDS group consisted of 101 patients treated at the medical intensive care unit; the control groups consisted of 138 "at-risk" patients treated at the medical intensive care unit due to acute respiratory failure but did not meet the ARDS criteria throughout the hospital course, and 210 non-at-risk subjects. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The ARDS patients and control subjects were genotyped for the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme gene. Association of the polymorphism and the risk and the outcome of ARDS was analyzed. There was no significant difference in the frequencies of the genotypes between the ARDS, at-risk, and non-at-risk groups. The 28-day mortality rates were significantly different between the three angiotensin-converting enzyme genotypes (42%, 65%, and 75% for II, ID, and DD, respectively; p = .036). Survival analysis showed that the II genotype favorably affected 28-day survival (hazard ratio, 0.46; 95% confidence interval, 0.26-0.81; p = .007), whereas ARDS caused by hospital-acquired pneumonia had a negative effect (hazard ratio, 2.34; 95% confidence interval, 1.25-4.40; p = .008). The II genotype (hazard ratio, 0.53; 95% confidence interval, 0.32-0.87; p = .012) and ARDS caused by hospital-acquired pneumonia (hazard ratio, 2.13; 95% confidence interval, 1.24-3.68; p = .006) were also significant prognostic factors for the in-hospital mortality. CONCLUSIONS: The angiotensin-converting enzyme I/D polymorphism is a significant prognostic factor for the outcome of ARDS. Patients with the II genotype have a significantly better chance of survival. This study did not show an increased risk for ARDS in Chinese patients with the D allele.

China↗

PubMed2006

Multifunctional transcription factor YY1: a therapeutic target in human cancer?

The multifunctional transcription factor Yin Yang 1 (YY1) is a complex protein that has been shown to play pivotal roles in development, differentiation, cellular proliferation and apoptosis. It can act as a transcriptional repressor, an activator, or an initiator element binding protein that directs and initiates transcription of numerous cellular and viral genes. Because the expression and function of YY1 are known to be intimately associated with cell-cycle progression, the physiological significance of YY1 activity has recently been applied to models of cancer biology. Several lines of evidence imply that YY1 expression and/or activation is associated with tumourigenesis, in addition to its regulatory roles in normal biological processes. However, controversial results also raised and indicated that further studies are still needed to piece all of the seemingly contradictory data into a complete picture. On the basis of YY1 regulations and functions, novel drugs and specific treatment strategies may be developed with new therapeutic applications for tumour patients in the future.

Animals↗

PubMed2005

Emergence of disseminated infections due to nontuberculous mycobacteria in non-HIV-infected patients, including immunocompetent and immunocompromised patients in a university hospital in Taiwan.

OBJECTIVES: Although disseminated nontuberculous mycobacteria (NTM) infection has been increasingly reported in patients with AIDS, this condition is still considered rare in non-HIV-infected patients. METHODS: We retrospectively reviewed the medical records of non-HIV-infected patients treated at National Taiwan University Hospital from January 1997 to December 2004 to search for epidemiological trends in disseminated NTM infection. Data analyzed included etiology, demographic characteristics, underlying disease, initial symptoms and signs, treatment, and outcomes. RESULTS: Disseminated NTM infections occurred in 15 non-HIV-infected patients during the study period. The mean age of these patients was 51 years (range 13-80). Among these patients, eight were males, and eight had various immunocompromised conditions. Fever was an initial presentation in 12 patients (80%). Diagnosis was made by positive blood (seven patients) or bone marrow culture (five patients) in the majority (73%) of patients. Infectious etiologies included Mycobacterium avium complex (MAC) in eight, rapidly growing mycobacteria (RGM) in four and Mycobacterium kansasii in three. The mean time from initial presentation to initiation of anti-NTM therapy was 130 days (ranged from 9 days to 17 months). Mortality was highest in patients with M. kansasii (100%), followed by RGM (25%) and MAC (12.5%). CONCLUSIONS: Although disseminated NTM infection is an emerging condition among patients without HIV infection, it is a condition which is associated with immune deficiency. A high level of clinical suspicion should be maintained for avoiding delayed diagnosis, especially in patients with underlying immunosuppression. Blood culture might play an important role in the early diagnosis of disseminated NTM disease. Early diagnosis can lead to appropriate diagnosis and reduce mortality.

Adolescent↗

PubMed2005

Transcription repressor slug promotes carcinoma invasion and predicts outcome of patients with lung adenocarcinoma.

PURPOSE: In a previous genome-wide gene expression profiling analysis using an invasion cancer cell lines model, we have identified Slug as selectively overexpressed in the highly invasive cancer cells. Here, we investigated the clinical significance of Slug in lung adenocarcinoma and the role of Slug in the process of cancer cell invasion and metastasis. EXPERIMENTAL DESIGN: Real-time quantitative reverse transcription-PCR was used to investigate Slug mRNA in surgically resected lung adenocarcinoma of 54 patients and its correlation with survival. We overexpressed Slug in a lung adenocarcinoma cell line with very low Slug levels and investigated the in vitro and in vivo effects of Slug expression. RESULTS: High expression of Slug mRNA in lung cancer tissue was significantly associated with postoperative relapse (P = 0.03) and shorter patient survival (P < 0.001). The overexpression of Slug enhanced xenograft tumor growth and increased microvessel counts in angiogenesis assay. Both inducible and constitutive overexpression of Slug suppressed the expression of E-cadherin and increased the in vitro invasive ability. Zymography revealed increased matrix metalloproteinase-2 activity in Slug overexpressed cells. ELISA, reverse transcription-PCR, and immunohistochemistry confirmed the increase of matrix metalloproteinase-2 proteins and mRNA in Slug overexpressed cells and xenograft tumors. CONCLUSIONS: Slug expression can predict the clinical outcome of lung adenocarcinoma patients. Slug is a novel invasion-promoting gene in lung adenocarcinoma.

Adenocarcinoma↗

PubMed2005

Elevation of telomerase activity positively correlates to poor prognosis of patients with non-small cell lung cancer.

Increased telomerase activity has been found in various types of human malignancies, including lung cancer. However, the correlation between the level of telomerase activity and the clinical characteristics of lung cancer patients remains unclear. The levels of telomerase activity in lung cancer specimens and adjacent non-neoplastic tissues obtained from 68 patients who underwent surgery were measured by using a non-radioactive quantitative method. Clinical and pathologic parameters were evaluated with respect to the level of telomerase activity. Prominent telomerase activity was detected in 58 (85.3%) lung cancer tissues and 21 (30.9%) adjacent non-neoplastic tissues. There was a trend of increase in relative telomerase activity in regard to the advanced pathological stage, and lymph node metastasis. Using Cox regression analysis, we found that every 100 unit of increase in relative telomerase activity was associated with an increase in the hazard ratio of death by 13% after controlling for other variables such as age, gender, and stage (Hazard ratio=1.13; 95% CI: 1.03-1.23, P=0.006). For patients with stage I disease, an increase of every 100unit of relative telomerase activity was associated with an even higher increase of 33% in the hazard ratio of death (Hazard ratio=1.33; 95% CI: 1.07-1.65, P=0.011) and a 16% increase in the hazard of disease recurrence (Hazard ratio=1.16, 95% CI: 1.01-1.33, P=0.032). The level of telomerase activity is positively correlated with the risk of recurrence and mortality of lung cancer. The level of telomerase activity would predict the prognosis of lung cancer patients.

Adult↗

PubMed2005

Mycobacterium tuberculosis in Taiwan.

OBJECTIVE: The resurgence of tuberculosis (TB) and the emergence of drug resistance of Mycobacterium tuberculosis (MTB) isolates are of great impact on public health. METHODS: Taiwanese data on disease burden of TB and anti-microbial resistance of MTB identified from Annual Reports of Centre for Disease Control, Department of Health, Taiwan and from peer-reviewed publications from MEDLINE (1995-2004). RESULTS: In Taiwan in 2002, the incidence (per 100,000 population) of tuberculosis was 74.6 and it was higher in aborigines (289.8) and in people living in mountainous regions (256.0). The mortality rate of tuberculosis in Taiwan in 2002 was 5.68 per 100,000 population. Susceptibility data summarized from 1990 to 2002 reports showed primary resistance ranged from 4.7 to 12% for isoniazid, 0.7 to 5.9% for rifampin, 1 to 6% for ethambutol, and 4 to 11% for streptomycin. The overall rates of multidrug-resistant tuberculosis (MDRTB) among new cases and previously treated cases were 1 to 3% and 15 to 46%, respectively. The increasing burden of patients with MDRTB infection, the persistent high rate of mortality, the lack of nationwide surveillance system using the standard methodology to determine the trends and current status of resistance, and the inadequate current TB control infrastructure and training to accomplish the tasks required to implement the directly observed treatment short-course (DOTS) strategy are having a great impact on public health in Taiwan. CONCLUSIONS: High disease burden of TB and high resistance rates in MTB as well as inappropriateness of the current control infrastructure for TB services illustrate increasingly serious health problems from TB in Taiwan.

Adolescent↗

PubMed2005

EMP-1 is a junctional protein in a liver stem cell line and in the liver.

In an attempt to discover cell markers for liver stem cells, a cDNA microarray analysis was carried out to compare the gene expression profiles between an adult liver stem cell line, Lig-8, and mature hepatocytes. Several genes in the categories of extracellular matrix, cell membrane, cell adhesion, transcription factor, signal molecule, transporter, and metabolic enzyme were shown to be differentially expressed in Lig-8 cells. Among them, epithelial membrane protein (EMP)-1 has been previously implicated with stem cell phenotypes. Antiserum to EMP-1 was produced to localize its expression. On monolayers of Lig-8 cells, EMP-1 was expressed along the intercellular border. In the liver harboring proliferating oval cells, the liver progenitors, EMP-1 was localized as ribbon bands, a staining pattern for epithelial junctions, all the way through bile duct epithelia, oval cell ductules, and into peri-hepatocytic regions. These peri-hepatocytic regions were proved to be bile canaliculi by co-localization of EMP-1 and dipeptidyl peptidase IV, an enzyme located on bile canaliculi. This report is the first to indicate EMP-1 to be a junctional protein in the liver.

Animals↗

PubMed2005

CD13 (aminopeptidase N) can associate with tumor-associated antigen L6 and enhance the motility of human lung cancer cells.

Cancer metastasis is a multiple-step process that involves the regulated interaction of diverse cellular proteins. We recently reported that the expression of tumor-associated antigen L6 (TAL6) promoted the invasiveness of lung cancer cells and was inversely correlated with disease-free survival of squamous lung carcinoma patients. We now report that CD13 (aminopeptidase N) can associate with TAL6 and can enhance cancer cell migration. CD13 was shown by coimmunoprecipitation to associate in vitro with TAL6 on several cancer cell lines and to associate in vivo by antibody-mediated copatching immunofluorescence. CD13 was selectively expressed on highly invasive CL1-5 lung cancer cells as compared to poorly invasive CL1-0 lung cancer cells. The role of CD13 aminopeptidase activity in regulating cell motility was investigated with chemical inhibitors, specific antibodies and a catalytically inactive CD13 protein. Inhibition of CD13 aminopeptidase activity by nontoxic concentrations of leuhistin modestly decreased the migration of CL1-5 cells. In contrast, binding of CD13 by specific antibodies significantly reduced both the migration and the invasion of CL1-5 cells. Poorly invasive CL1-0 cells that stably expressed CD13 displayed significantly (p < or = 0.0005) enhanced cell migration (300% of control). Expression of an enzymatically inactive CD13 mutant on CL1-0 cells also significantly (p < or = 0.0005) enhanced cell migration (200% of control). Our results show that TAL6 and CD13 can form a complex on lung cancer cells, that these molecules can modulate cell migration and invasion and that the influence of CD13 on cell motility did not strictly depend on its aminopeptidase activity.

Adenocarcinoma↗

PubMed2005

Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation.

BACKGROUND: Theophylline has been used widely as a bronchodilator for the treatment of bronchial asthma and has been suggested to modulate immune response. While the importance of macrophages in asthma has been reappraised and emphasized, their significance has not been well investigated. We conducted a genome-wide profiling of the gene expressions of macrophages in response to theophylline. METHODS: Microarray technology was used to profile the gene expression patterns of macrophages modulated by theophylline. Northern blot and real-time quantitative RT-PCR were also used to validate the microarray data, while Western blot and ELISA were used to measure the levels of IL-13 and LTC4. RESULTS: We identified dozens of genes in macrophages that were dose-dependently down- or up-regulated by theophylline. These included genes related to inflammation, cytokines, signaling transduction, cell adhesion and motility, cell cycle regulators, and metabolism. We observed that IL-13, a central mediator of airway inflammation, was dramatically suppressed by theophylline. Real-time quantitative RT-PCR and ELISA analyses also confirmed these results, without respect to PMA-treated THP-1 cells or isolated human alveolar macrophages. Theophylline, rolipram, etazolate, db-cAMP and forskolin suppressed both IL-13 mRNA expression (~25%, 2.73%, 8.12%, 5.28%, and 18.41%, respectively) and protein secretion (<10% production) in macrophages. These agents also effectively suppressed LTC4 expression. CONCLUSION: Our results suggest that the suppression of IL-13 by theophylline may be through cAMP mediation and may decrease LTC4 production. This study supports the role of theophylline as a signal regulator of inflammation, and that down regulation of IL-13 by theophylline may have beneficial effects in inflammatory airway diseases.

Anti-Inflammatory Agents↗

PubMed2005

Gefitinib reverses chemotherapy resistance in gefitinib-insensitive multidrug resistant cancer cells expressing ATP-binding cassette family protein.

Gefitinib inhibits the ATP-binding site of the tyrosine kinase associated with the epidermal growth factor receptor. It is conceivable that gefitinib may inhibit functions of ATP-binding cassette (ABC) transporters by binding at their ATP-binding sites. The aim of this study is to systematically explore the combined effect of gefitinib and chemotherapeutic agents in gefitinib-insensitive multidrug resistant (MDR) cells that overexpress ABC transporters. MCF7 breast carcinoma cells and CL1 lung adenocarcinoma cells were both insensitive to gefitinib. MDR cancer cells were developed by stepwise escalating concentrations of each chemotherapeutic agent in culture media. Cells that overexpress P-glycoprotein (MCF7/Adr and CL1/Pac), breast cancer-resistant protein (MCF7/TPT and CL1/Tpt), and MDR-associated protein 1 (MCF7/Vp) were used in this study. All resistant mutants were insensitive to gefitinib. Gefitinib (0.3-3 micromol/L) added to culture media had no effect on IC50 values of paclitaxel, topotecan, doxorubicin, or etoposide in wild-type MCF7 or CL1 cells. In contrast, these concentrations of gefitinib caused a dose-dependent reversal of resistance to paclitaxel in CL1/Pac cells, to doxorubicin in MCF7/ADR cells, and to topotecan in CL1/Tpt and MCF7/TPT cells. Gefitinib had no influence on sensitivity to etoposide in MDR-associated protein1 overexpressing MCF7/VP cells. Topotecan efflux was inhibited and accumulation was partially restored in CL1/Tpt and MCF7/TPT cells when cells were incubated simultaneously with gefitinib. Our results suggest that the interaction of gefitinib and chemotherapeutic agents does occur in cells expressing one of these two proteins.

ATP-Binding Cassette Transporters↗