In recent years, the number of advanced non-small cell lung cancer (NSCLC) patients has gradually increased, and the treatment methods have also been significantly increased. However, there are no standard treatment plans at home and abroad for third-line and above patients who are refractory to targeted therapy epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) or chemotherapy. The clinical treatment effect is also not satisfactory. Anlotinib is a novel TKI targeting the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-Kit. ALTER0303 trail, phase III study has demonstrated that Anlotinib significantly prolonged overall survival (OS) and progression-free survival (PFS) in advanced NSCLC patients as 3rd line treatment.Here we report a case of advanced lung adenocarcinoma harboring KRAS mutation treated with Anlotinib.
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Adenocarcinoma ; drug therapy ; enzymology ; genetics ; pathology ; Adenocarcinoma of Lung ; Aged ; Antineoplastic Agents ; therapeutic use ; Humans ; Indoles ; therapeutic use ; Lung Neoplasms ; drug therapy ; enzymology ; genetics ; pathology ; Male ; Mutation ; Proto-Oncogene Proteins p21(ras) ; genetics ; metabolism ; Quinolines ; therapeutic use

Adenocarcinoma ; drug therapy ; genetics ; metabolism ; pathology ; surgery ; Adenocarcinoma, Bronchiolo-Alveolar ; drug therapy ; genetics ; metabolism ; pathology ; surgery ; Adenocarcinoma, Papillary ; metabolism ; pathology ; Cadherins ; metabolism ; Diagnosis, Differential ; Genes, erbB-1 ; genetics ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; surgery ; Lymphatic Metastasis ; Mucin-1 ; metabolism ; Mutation ; Neoplasm Invasiveness ; beta Catenin ; metabolism

AIMTo explore whether the anti-tumor action of 17beta-estradiol is enhanced by re-expression of the homeodomain transcription factor Nkx3.1 in PC3 human prostate cancer cells.

METHODSPC3 cells were stably transfected with pcDNA3.1-Nkx3.1-His vector, which carries a full-length cDNA of human Nkx3.1. The PC3 cells stably transfected with vector pcDNA3.1 were set as a control. The expression of Nkx3.1 protein in the cells was confirmed by Western blot analysis. The effect of Nkx3.1 on cell proliferation of PC3 cells was examined with MTT assay. The antiproliferative and apoptotic effects of 17beta-estradiol alone or in combination with Nkx3.1 were estimated on PC3 cells by using MTT growth tests and flow cytometric analyses. The expression of apoptosis-related proteins was analyzed using Western blotting.

RESULTSThe plasmid carrying Nkx3.1 gene induced high expression of Nkx3.1 protein in PC3 cells. The re-expression of exogenous Nkx3.1 did not cause a significant reduction in cellular proliferation, whereas the expression of Nkx3.1 enhanced the 17beta-estradiol anti-proliferative effect in PC3 cells. Nkx3.1 expression promoted 17beta-estradiol-induced apoptosis of PC3 cells, as shown by analysis of Bcl-2, Bax, Caspase-3 and poly (ADP-ribose) polymerase expression.

CONCLUSIONThe present study demonstrates that re-expression of Nkx3.1 enhances 17beta-estradiol anti-tumor action in PC3 human prostate cancer cells. The in vitro study suggests that re-expression of Nkx3.1 is worthy of further consideration as an adjuvant treatment of androgen independent prostate cancer with estrogen anti-tumor therapies.

Adenocarcinoma ; drug therapy ; genetics ; pathology ; Androgen-Insensitivity Syndrome ; drug therapy ; genetics ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Estradiol ; pharmacology ; Flow Cytometry ; Gene Expression Regulation, Neoplastic ; drug effects ; genetics ; Homeodomain Proteins ; genetics ; metabolism ; Humans ; Male ; Prostatic Neoplasms ; drug therapy ; genetics ; pathology ; Transcription Factors ; genetics ; metabolism ; Transfection

OBJECTIVETo investigate the correlation between mutation in EGFR tyrosine kinase domain and tumor response as well as prognosis in advanced stage non-small cell lung cancer (NSCLC) treated with iressa.

METHODSFrom May 2002 to Feb. 2005, iressa was orally administered at a dose of 250 mg once daily for 106 advanced stage NSCLC patients until occurrence of disease progression or intolerable toxicity. Cancer tissue was obtained from these patients, and DNA was extracted for analysis of mutation in exon 18 to 24 of EGFR. Exon 18 to 24 of EGFR were amplified by nest PCR, sequenced and analyzed from both sense and antisence directions.

RESULTSPrimary NSCLC tissue specimens consisted of 25 frozen tissue blocks and 81 paraffin-embedded tumor tissue blocks from 106 consecutive NSCLC patients. Mutation was found to be more frequent in the adenocarcinoma than in the squamous cell carcinoma (35.9% vs 14.3%, P =0.033). Mutation was identified in 32 patients (30.2%). Response rate to iressa was 71.9% in the patients with EGFR mutation versus 13.5% in those without mutation (P <0.01). Compared with the patients without EGFR mutation, those with mutation had longer overall survival (median, 13.45 vs. 5.25 months; P<0.01) and median time to progression (median, 8.35 vs. 3.0 months; P <0.01).

CONCLUSIONEGFR mutation may be positively correlated with the response and survival in advanced stage Chinese NSCLC patient treated with iressa.

Adenocarcinoma ; drug therapy ; genetics ; pathology ; Adolescent ; Adult ; Aged ; Antineoplastic Agents ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; pathology ; Carcinoma, Squamous Cell ; drug therapy ; genetics ; pathology ; Exons ; Female ; Follow-Up Studies ; Humans ; Kaplan-Meier Estimate ; Lung Neoplasms ; drug therapy ; genetics ; pathology ; Male ; Middle Aged ; Neoplasm Staging ; Point Mutation ; Prognosis ; Quinazolines ; therapeutic use ; Receptor, Epidermal Growth Factor ; genetics ; Sequence Deletion

OBJECTIVETo establish a 5-fluorouracil (5-FU)-resistant pancreatic adenocarcinoma (PAC) cell strain, and to investigate its biological characteristics.

METHODSThe PAC cell strain SW1990 was selected into a multidrug-resistant cell strain stepwise with 5-FU, one of the most common drugs used in PAC chemotherapy, for 12 months and subsequently named SW1990/FU. The cell strain was characterized in terms of morphology, biology, and cross-resistance to adriamycin(ADM), mitomycin-C (MMC), and gemcitabine. BHLB/c-m nude mice tumor growth and CEA and CA19-9 levels were analyzed. In addition, karyotyping and FACS analysis were performed in SW1990/FU and SW1990.

RESULTSThe SW1990/FU cell strain was 132.7 times more resistant to 5-FU than the parental SW1990 cells, and exhibited cross-resistance to other agents. Compared to the parental cells, SW1990/FU cells exhibited a smaller growth rate, delayed cell-doubling time, and specific changes in chromosomes 18. Tumor diameters in multidrug resistance and parental cells inoculated in in vivo experiments were (1.5 +/- 0.30) cm and (0.8 +/- 0.15) cm, respectively.

CONCLUSIONSMorphological adaptation and intracellular changes can be induced by drug challenge in PAC cells. SW1990/FU may be used as an experimental system for the search to overcome drug resistance and to elucidate possible mechanisms of acquired drug resistance in human pancreatic cancer.

Adenocarcinoma ; drug therapy ; pathology ; Animals ; Antimetabolites, Antineoplastic ; pharmacology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; genetics ; Fluorouracil ; pharmacology ; Humans ; Mice ; Mice, Nude ; Pancreatic Neoplasms ; drug therapy ; pathology

BACKGROUND: There are significantly interindividual variations of the expression level of nuclear factor erythroid-2-related factor 2 (Nrf2) and/or Kelch-like ECH-associated protein 1 (Keap1) in our previous studies. It has been proven that Nrf2 or Keap1 is related to resistance of chemotherapeutic drugs and/or epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, the expression of Nrf2 and Keap1 in lung adenocarcinoma patients with different "driver gene" is not clear. The aim of this study is to investigate the protein expression level of Nrf2 and Keap1 in lung adenocarcinoma and to elucidate the correlation between Nrf2 or Keap1 expression and the status of EGFR gene mutation and to determine the effects of Nrf2 and Keap1 on the patients. METHODS: Immunohistochemical analysis of Nrf2 and Keap1 in tumor specimens was performed in a total of 104 lung adenocarcinoma patients with the status of EGFR gene mutations or EGFR wide-type. RESULTS: The Nrf2 positive rate was 71.2% and Keap1 high expression rate was 34.6% in 104 patients. The Nrf2 positive rate significantly correlated with gender, stage and status of EGFR gene mutation (P<0.05), but not with age, smoking, differentiation and subtype of lung adenocarcinoma (P>0.05). The high expression of Keap1 was not significantly correlated with gender, age, smoking, differentiation, subtype of lung adenocarcinoma and status of EGFR gene mutation (P>0.05). The progression -free survival (PFS) and overall survival (OS) of the patients treated by EGFR-TKIs were significantly correlated with the expression level of Nrf2, but not with Keap1. The PFS and OS of the patients with Nrf2 high expression were significantly shorter than the patients with low/negative expression (P<0.05). Furthermore, Nrf2 high expression was the independent predictive factor for EGFR-TKIs induced PFS and OS (P<0.05). CONCLUSIONS The Nrf2 positive rate significantly correlated with the status of EGFR gene mutation in lung adenocarcinoma. The Nrf2 high expression significantly correlated with PFS and OS of EGFR-TKIs. Therefore, Nrf2 may be a biomarker for predicting response of EGFR-TKIs and a potential target for overcoming resistance of EGFR-TKIs.
Adenocarcinoma ; drug therapy ; genetics ; metabolism ; pathology ; Adenocarcinoma of Lung ; Adult ; Aged ; Aged, 80 and over ; ErbB Receptors ; genetics ; metabolism ; Female ; Humans ; Kelch-Like ECH-Associated Protein 1 ; genetics ; metabolism ; Lung Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; Male ; Middle Aged ; Mutation ; NF-E2-Related Factor 2 ; genetics ; metabolism ; Neoplasm Staging ; Protein Kinase Inhibitors ; therapeutic use ; Young Adult

OBJECTIVETo investigate gene mutations of epidermal growth factor receptor (EGFR) and K-ras in Chinese patients with non-small cell lung cancer (NSCLC) and its clinicopathological significance, and to analyze the correlation between these mutations and tumor response to erlotinib treatment.

METHODSMutations of exons 18, 19, 20 and 21 of the EGFR and codons 12, 13 of the K-ras in 301 cases of NSCLC were detected by PCR-amplification and gene sequencing. The relationship between the mutations and clinicopathological characteristics of the 301 patients was analyzed.

RESULTSEGFR mutations were present in 32.9% (99/301) of the samples: 3 mutation in exon 18, 59 in exon 19, 2 in exon 20, and 35 in exon 21. Mutations of K-ras were present in 4.7% (14/301) of the samples: 13 in codon 12 and 1 in codon 13. EGFR mutations were never found in tumors with K-ras mutations, suggesting a mutually exclusive relationship. EGFR mutations were more common in adenocarcinomas, non-smokers and females. Seven out of 10 erlotinib-treated patients with disease control carried EGFR mutation.

CONCLUSIONThe frequency of EGFR mutation in Chinese NSCLC patients is higher than that in Westerners, but the frequency of K-ras mutation is quite opposite. Combined detection of EGFR gene and K-ras gene mutation may help clinicians to choose patients who may gain benefit from EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment, and to predict their response to erlotinib treatment and prognosis.

Adenocarcinoma ; drug therapy ; genetics ; pathology ; Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; pathology ; Carcinoma, Squamous Cell ; drug therapy ; genetics ; pathology ; Codon ; Erlotinib Hydrochloride ; Exons ; Female ; Genes, erbB-1 ; Genes, ras ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; pathology ; Male ; Middle Aged ; Mutation ; Protein Kinase Inhibitors ; therapeutic use ; Proto-Oncogene Proteins ; genetics ; Proto-Oncogene Proteins p21(ras) ; Quinazolines ; therapeutic use ; Receptor, Epidermal Growth Factor ; genetics ; Sex Factors ; Smoking ; Young Adult ; ras Proteins ; genetics

OBJECTIVETo evaluate the association between the polymorphisms of excision repair cross complementation group 1 (ERCC1), X-ray repair cross complementing 1 (XRCC1), glutathione S-transferase Pi 1 (GSTP1) and the survival of advanced gastric cancer patients treated with oxaliplatin-based combination chemotherapy.

METHODSEighty five patients with advanced gastric cancer accepted oxaliplatin/5-FU-based chemotherapy as first-line chemotherapy were investigated. Peripheral venous blood was taken before chemotherapy. DNA was extracted from peripheral venous blood. The genetic polymorphisms were detected by real-time PCR assay. The association between time to progression, overall survival and the polymorphisms was analyzed.

RESULTSThe median time to progression of the 85 cases was 5.3 months, and the median overall survival was 8.0 months. ERCC1-118 C/C, XRCC1-399 G/G and GSTP1-105 A/G + G/G were favorable genotypes and the number of the favorable genotypes was associated with survival of the patients. The median overall survival was 12.5 months, 10.0 months, 6.5 months and 4.5 months for patients with 3 favorable genotypes, 2 favorable genotypes, 1 favorable genotype and none favorable genotype, respectively, with a significant difference (χ(2) = 35.54, P < 0.01).

CONCLUSIONGenetic polymorphisms of ERCC1-118, XRCC1-399 and GSTP1-105 are associated with TTP and OS of advanced gastric cancer patients treated with oxaliplatin/5-Fu-based combination chemotherapy as the first-line chemotherapy.

Adenocarcinoma ; drug therapy ; genetics ; pathology ; Adenocarcinoma, Mucinous ; drug therapy ; genetics ; pathology ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; DNA-Binding Proteins ; genetics ; Disease Progression ; Endonucleases ; genetics ; Female ; Fluorouracil ; administration & dosage ; Follow-Up Studies ; Glutathione S-Transferase pi ; genetics ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Organoplatinum Compounds ; administration & dosage ; Polymorphism, Genetic ; Stomach Neoplasms ; drug therapy ; genetics ; pathology ; Survival Rate ; X-ray Repair Cross Complementing Protein 1

This study was designed to investigate the different involvements of prostatic stromal cells from the normal transitional zone (TZ) or peripheral zone (PZ) in the carcinogenesis of prostate cancer (PCa) epithelial cells (PC-3) in vitro and in vivo co-culture models. Ultra-structures and gene expression profiles of primary cultures of human prostatic stromal cells from the normal TZ or PZ were analyzed by electron microscopy and microarray analysis. In vitro and in vivo co-culture models composed of normal TZ or PZ stromal cells and human PCa PC-3 cells were established. We assessed tumor growth and weight in the in vivo nude mice model. There are morphological and ultra-structural differences in stromal cells from TZ and PZ of the normal prostate. In all, 514 differentially expressed genes were selected by microarray analysis; 483 genes were more highly expressed in stromal cells from TZ and 31 were more highly expressed in those from PZ. Co-culture with PZ stromal cells and transforming growth factor-beta1 (TGF-beta1) increased the tumor growth of PC-3 cells in vitro and in vivo, as well as Bcl-2 expression. On the other hand, stromal cells of TZ suppressed PC-3 cell tumor growth in the mouse model. We conclude that ultra-structures and gene expression differ between the stromal cells from TZ or PZ of the normal prostate, and stroma-epithelium interactions from TZ or PZ might be responsible for the distinct zonal localization of prostate tumor formation.
Adenocarcinoma ; drug therapy ; genetics ; pathology ; Adult ; Animals ; Cell Line, Tumor ; Coculture Techniques ; Gene Expression ; drug effects ; Gene Expression Profiling ; Humans ; Male ; Mice ; Mice, Nude ; Oligonucleotide Array Sequence Analysis ; Prostate ; drug effects ; metabolism ; pathology ; Prostatic Neoplasms ; drug therapy ; genetics ; pathology ; Proto-Oncogene Proteins c-bcl-2 ; genetics ; metabolism ; RNA, Messenger ; metabolism ; Stromal Cells ; metabolism ; pathology ; Transforming Growth Factor beta ; pharmacology ; Young Adult

OBJECTIVETo investigate the role of mitogen activated protein kinase phosphatase-1 (MKP-1) in mediating acquired multidrug resistance in pancreatic adenocarcinoma cell line SW1990/Fu.

METHODSTo detect MKP-1 mRNA expression, Northern blot analysis was carried out in well established drug resistant pancreatic adenocarcinoma cell line SW1990/Fu, SW1990 and MiaPaCa-2 cell lines. To further elucidate the exact role of MKP-1, Western blot hybridization was performed in these three cell lines.

RESULTSNorthern blot analysis of total RNA isolated from SW1990/Fu, SW1990 and MiaPaCa-2 cell lines revealed the presence of the 2400 bp MKP-1 transcript 7 at relatively high levels in pancreatic cancer cell lines SW1990 and MiaPaCa-2. In the SW1990/Fu, the MKP-1 transcript was detectable at very low level. Densitometric analysis with normalization to 7S indicated that MKP-1 mRNA expression level was significantly decreased in SW1990/Fu in comparison with the parental and MiaPaCa-2 cell lines. MKP-1 protein expression level in SW1990/Fu detected by Western blot was coincident with mRNA level.

CONCLUSIONSMKP-1 may be involved in acquired multidrug resistance in pancreatic adenocarcinoma, and we could hypothesized that alterations of intra-cellular transduction signal system acts as an important role in multidrug resistance of tumor cells.

Adenocarcinoma ; drug therapy ; enzymology ; pathology ; Blotting, Northern ; Blotting, Western ; Cell Cycle Proteins ; biosynthesis ; genetics ; physiology ; Cell Line, Tumor ; Down-Regulation ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Dual Specificity Phosphatase 1 ; Humans ; Immediate-Early Proteins ; biosynthesis ; genetics ; physiology ; Pancreatic Neoplasms ; drug therapy ; enzymology ; pathology ; Phosphoprotein Phosphatases ; biosynthesis ; genetics ; physiology ; Protein Phosphatase 1 ; Protein Tyrosine Phosphatases ; biosynthesis ; genetics ; physiology ; RNA, Messenger ; genetics