Jhingook Kim

In vitro establishment of cis-diammine-dichloroplatinum(II) resistant lung cancer cell line and modulation of apoptotic gene expression as a mechanism of resistant phenotype

After exposure of H460 cells to an increasing concentrations of cis-diammine-dichloroplatinum(II) (cisplatin, CDDP) for 6 months, cisplatin resistant cells were isolated (H460/CIS). The biologic behaviors of H460 and H460/CIS cells were tested using animal experiments. Only the resistant cells developed lung metastases despite cisplatin treatment. The characteristics of H460/CIS cells are as follows, MTT analyses revealed that H460/CIS cells were markedly resistant to cisplatin compared with their parental cells. Also, H460/CIS cells exhibited cross-resistance to DNA damaging agents such as doxorubicin (DXR) and etoposide. Cisplatin treatment dramatically increased p53 expression in parental cells but not in H460/CIS cells which expressed basal levels of p53. Without cisplatin treatment, Bcl-2 and Bax were expressed in H460/CIS cells, but not in parental cell. Our data suggested that p53, Bax and Bcl-2 were up-regulated in H460/CIS cells. These changes could explain some of the mechanisms of cisplatin resistance. Thus, H460/CIS could be useful to investigate the mechanisms of drug resistance to cisplatin including apoptotic gene expressions conferring drug resistance, thereby making progress in the treatment of cisplatin-resistant tumor cells.

Fgfbp1 is essential for the cellular survival during zebrafish embryogenesis

Fibroblast growth factor binding protein 1 (FGFBP1) is expressed in various tumors and may serve as a diagnostic marker and/or a therapeutic target. Previous studies suggested FGFBP1 functions as an angiogenic switch molecule by regulating the activity of FGF2, and it was later found to associate with a broad spectrum of FGFs. To study FGFBP1, we used zebrafish, in which the function of extracellular matrix protein can be easily studied in intact tissues or organisms. When Fgfbp1 expression was knocked down, morphants manifested massive cell death and structural abnormalities. Cell death was most prominent in the brain and the neural tube, but not limited to those regions. These findings suggest that the primary function of Fgfbp1 may be to sustain cellular survival throughout embryogenesis. For comparison, the expression of fgf2 was limited to the early stage of embryogenesis and fgf2 morphants showed more severe phenotype, with high morbidity before reaching 14-somites. Taken together, our work reveals the physiologic function of Fgfbp1, and that its function could be exerted in a Fgf2-independent manner.

Differential gene expression during colon-to-lung metastasis.

Primary tumors in certain metastatic cases have potential dissemination mechanisms. However, they often lack the potential to colonize distant microenvironments, and consequently the disseminated cancer cells enter into a state of latency which can last for years. In order to investigate the metastatic colonization potential at the gene expression level, we compared such primary tumors with their matching, actively proliferating metastatic tumors. Six pairs of colon-to-lung metachronous tumor samples were examined for the expression levels of 84 well-known metastatic genes using the quantitative RT-PCR-based PCR Array technology. The unsupervised hierarchical clustering of all 12 samples together, resulted in the formation of one closely related cluster by the primary tumors, but highly diversified ones by the metastatic tumors. A pair-wise comparison of the matching primary-metastatic tumors showed that different groups of genes were activated in the lung metastases. Therefore we charted specific genes involved in the genetic diversification processes. A number of these genes showed similar differential expression (ΔCt) patterns in all the patients. These were the cancer cell-, the microenvironment- and the stem cell-specific gene groups. In conclusion, the results suggest that the primary colorectal cancer cells are diversified as regards colonization of the lung, which could explain why the effective therapies for primary colorectal cancers are often not appropriate for controling the growth of pulmonary metastases.

Predicting Recurrence Using the Clinical Factors of Patients with Non-small Cell Lung Cancer After Curative Resection

We present a recurrence prediction model using multiple clinical parameters in patients surgically treated for non-small cell lung cancer. Among 1,578 lung cancer patients who underwent complete resection, we compared the early-recurrence group with the 3-yr non-recurrence group for evaluating those factors that influence early recurrence within one year after surgery. Adenocarcinoma and squamous cell carcinoma were analyzed independently. We used multiple logistic regression analysis to identify the independent clinical predictors of recurrence and Coxs proportional hazard regression method to develop a clinical prediction model. We randomly divided our patients into the training and test subsets. The pathologic stages, tumor cell type, differentiation of tumor, neoadjuvant therapy and age were significant factors on the multivariable analysis. We constructed the model for the training set with adenocarcinoma (n=236) and squamous cell carcinoma (n=305), and we applied it to the test set with adenocarcinoma (n=110) and squamous cell carcinoma (n=154). It was predictive for the in adenocarcinoma (P<0.001) and the squamous cell carcinoma (P=0.037), respectively. Our results showed that our recurrence prediction model based on the clinical parameters could significantly predict the individual patients who were at high risk or low risk for recurrence.

A prospective randomized study on the mobilization of CD34 + cells comparing continuous intravenous vs subcutaneous administration of rhG-CSF in normal donors

Summary:The efficacy of mobilizing peripheral blood progenitor cells (PBPC) with continuous intravenous (c.i.v.) administration of rhG-CSF was randomly compared to subcutaneous (s.c.) administration, in 15 normal donors in each arm of the study for 6 days. The percentage and absolute numbers of CD34+ cells in the c.i.v. and s.c. groups increased maximally at day 3 and 5, respectively, when compared with the steady-state (day 0) level. Peak CD34+ cell levels were achieved on day 3 in the c.i.v. group, with more rapid results than in the s.c. group (49.3/μl vs 35.9/μl, P=0.043). Plasma rhG-CSF levels declined progressively during mobilization in each group as the WBC increased. The serum level of rhG-CSF did not correlate with CD34+ cell counts in the peripheral blood. Toxicity profiles in the c.i.v. and s.c. groups were similar. Each regimen was effective in successfully mobilizing the target CD34 cell number.

Genome-wide genotype-based risk model for survival in acute myeloid leukaemia patients with normal karyotype

Single nucleotide polymorphisms (SNP) are inter‐individual genetic variations that could explain inter‐individual differences of response/survival to chemotherapy. The present study was performed to build up a risk model for survival in 247 patients with acute myeloid leukaemia (AML) with normal karyotype (AML‐NK). Genome‐wide Affymetrix SNP array 6.0 was used for genotyping in discovery set (n = 118). After identifying significant SNPs for overall survival (OS) in single SNP analysis, a risk model was constructed. Out of 632 957 autosomal SNPs analysed, finally four SNPs (rs2826063, rs12791420, rs11623492 and rs2575369) were introduced into the risk model. The model could stratify the patients according to their OS in discovery set (P = 1·053656 × 10−4). Replication was performed using Sequenom platform for genotyping in the validation cohort (n = 129). The model incorporated with clinical and four SNP risk score was successfully replicated in a validation set (P = 5·38206 × 10−3). The integration of four SNPs and clinical factors into the risk model showed higher area under the curve (AUC) reults than in the model incorporating only clinical or only four SNPs, suggesting improved prognostic stratification power by combination of four SNPs and clinical factors. In conclusion, a genome‐wide SNP‐based risk model in 247 patients with AML‐NK can identify a group of high risk patients with poor survival.