Predictive biomarkers in precision medicine and drug development against lung cancer / 癌症

The molecular characterization of various cancers has shown that cancers with the same origins, histopathologic diagnoses, and clinical stages can be highly heterogeneous in their genetic and epigenetic alterations that cause tumorigenesis. A number of cancer driver genes with functional abnormalities that trigger malignant transformation and that are required for the survival of cancer cells have been identified. Therapeutic agents targeting some of these cancer drivers have been successfully developed, resulting in substantial improvements in clinical symptom amelioration and outcomes in a subset of cancer patients. However, because such therapeutic drugs often benefit only a limited number of patients, the successes of clinical development and applications rely on the ability to identify those patients who are sensitive to the targeted therapies. Thus, biomarkers that can predict treatment responses are critical for the success of precision therapy for cancer patients and of anticancer drug development. This review discusses the molecular heterogeneity of lung cancer pathogenesis; predictive biomarkers for precision medicine in lung cancer therapy with drugs targeting epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 receptor tyrosine kinase (ROS1), and immune checkpoints; biomarkers associated with resistance to these therapeutics; and approaches to identify predictive biomarkers in anticancer drug development. The identification of predictive biomarkers during anticancer drug development is expected to greatly facilitate such development because it will increase the chance of success or reduce the attrition rate. Additionally, such identification will accelerate the drug approval process by providing effective patient stratification strategies in clinical trials to reduce the sample size required to demonstrate clinical benefits.

Action of apoptosis-induced ligand gene in relation to tumor necrosis factor on human colon cancer cell line HT29 / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To evaluate the gene therapeutic efficiency of apoptosis-inducing ligand (TRAIL) related to tumor necrosis factor on human colon cancer cell line HT29.</p><p><b>METHODS</b>Human colon cancer cell line HT29 was transfected with adenovirus-mediated TRAIL gene Ad/GT-TRAIL. The morphological changes, cell growth and apoptosis were measured by phase contrast microscope, MTT method and flow cytometry.</p><p><b>RESULTS</b>Obvious morphological changes in HT29 cells was induced by Ad/GT-TRAIL and Ad/PGK-GV16. The cell suppression percentage and the percentage of apoptotic cells were 54.3% and 11.1%, respectively. When used in combination with Ad/PGK-GV16, HT29 was suppressed to 82.7% and the percentage of apoptotic cells was 24.6%. This result showed significantly enhanced therapeutic efficiency on HT29 and thus inhibiting of its growth (P < 0.05).</p><p><b>CONCLUSION</b>Ad/GT-TRAIL is able to induce apoptosis of HT29 and inhibit its growth. Ad/GT-TRAIL shows significantly enhanced therapeutic efficiency for HT29 when used in combination with Ad/PGK-GV16.</p>

Studies of killing and bystander effect of tumor necrosis factor related apoptosis-inducing ligand gene on hepatic carcinoma cell / 中华消化杂志

Objective To study the bystander effect of tumor necrosis factor related apoptosis inducing ligand(TRAIL) gene and it's mechanism. Methods Full length cDNA of human TRAIL was transfected into SMMC7721 with binary adenoviral vectors system. RT PCR was used to determine the expression of TRAIL gene. By MTT assay the effects of the TRAIL gene on the proliferation of SMMC7721 was studied; The apoptosis inducing ability of TRAIL gene on SMMC7721 was tested by fluorescence activated cell sorting (FACS). Bystander effect by testing the proliferation of the mixed cells of SMMC7721/TRAIL and SMMC7721 with different ratios, and the mechanism of bystander effect by testing the proliferation of SMMC7721 cultured with media of SMMC7721/TRAIL without cell components were also studied. Results TRAIL gene expressed by binary adenoviral vector system was able to inhibit proliferation(91.2%) and induce apoptosis(29.07%) of SMMC7721, significant difference between TRAIL gene and the other three controls were observed(PBS, LacZ, Bax)( P

Effects of different chemotherapeutic agents on reversing the acquired resistance to TRAIL gene in DLD1 colon cancer cells / 中国病理生理杂志

AIM:To evaluate effects of different chemotherapeutic agents on reversing the acquired resistance to TRAIL gene and clarify the involved mechanisms in DLD1-TRAIL/R colon cancer cells.METHODS: Human colon cancer cell line DLD1-TRAIL/R cells that were resistant to TRAIL-expressing adenovector(Ad/gTRAIL) were treated with Ad/gTRAIL combined with different chemotherapeutic agents.Then,the cell viability was measured by MTT method,and apoptotic signaling conditions,including activation of caspase-3 and caspase-8,expression of Bax and Bcl-XL,were measured by Western blotting analysis.RESULTS: In vitro data showed that several chemotherapeutic agents,including 5-fluorouracil(5-FU) and mitomycin c(MMC),overcome the acquired resistance to TRAIL gene in DLD1-TRAIL/R colon cancer cells.The combination of Ad/gTRAIL and 5-FU effectively suppressed tumor growth in vivo in subcutaneous tumors established from DLD1-TRAIL/R cells.Further data showed that treatment with the combination of Ad/gTRAIL and 5-FU or MMC led to enhance the activation of caspase-3.Moreover,MMC but not 5-FU induced overexpression of Bax gene that was sufficient to overcome the resistance to TRAIL gene in DLD1-TRAIL/R cells.CONCLUSION: Chemotherapeutic agents,such as 5-FU and MMC,overcome the acquired resistance to TRAIL gene in DLD1-TRAIL/R cells.The candidate mechanisms for MMC but not 5-FU to overcome this resistance might involve the induction of over-expressed Bax protein in DLD1-TRAIL/R cells.

Chrysanthemum morifolium Ramat sensitizes TNF-related apoptosis inducing ligand-induced apoptosis in human colon cancer cell line DLD-1 / 中国病理生理杂志

AIM: To explore the influence of Chrysanthemum morifolium Ramat on TNF-related apoptosis inducing ligand (TRAIL)-mediated apoptosis in human colon cancer cell line DLD-1 and its possible mechanism. METHODS: Adenovirus-mediated TRAIL gene AD/hTERT-gTRAIL was applied either alone or by combination with Chrysanthemum morifolium Ramat in human colon DLD-1 cell line. Cell growth and apoptosis were measured by inverted microscope, MTT method and flow cytometry. The expression of TRAIL mRNA, TRAIL-Rs mRNA and TRAIL protein expression after exposure to Chrysanthemum morifolium Ramat were measured by semi-quantitive RT-PCR and FACS, respectively. RESULTS: The suppression percentages and apoptotic rate of DLD-1 by Ad/hTERT-gTRAIL alone were 31.4% and 13.5%, respectively. Combination of TRAIL gene transfection with Chrysanthemum morifolium Ramat, the suppression and the apoptosis rate raised to 93.1% and 45.4%, respectively (P