Identification of Tumor Suppressor Loci on the Long Arm of Chromosome 4 in Primary Small Cell Lung Cancers

Recent cytogenetic studies have indicated that loss of the long arm of chromosome 4 is a frequent event in small cell lung cancer (SCLC), which suggests the presence of tumor suppressor genes there. To precisely map tumor-suppressor loci on chromosome 4q for further positional cloning efforts, we tested 15 primary SCLCs. Forty two polymorphic microsatellite markers located on chromosome 4q were used in the microsatellite analysis. We found that 12 (80%) of the 15 tumors exhibited loss of heterozygosity (LOH) in at least one of the tested microsatellite markers, and that 3 (25%) of these 12 tumors exhibited a larger area of deletion on chromosome 4q. Frequent LOH, defined as occurring in more than 50% of the tumors, was observed in five commonly deleted regions on 4q, namely 4q24, 4q27-28.3, 4q33, 4q34.1, and 4q34.3-35.2. Of these 5, LOH at 4q33 was the most frequent (61.5%). Six (40%) of the 15 tumors exhibited shifted bands in at least one of the tested microsatellite markers. Shifted bands occurred in 3.7% (23 of 630) of the loci tested. Our data demonstrated that at least five tumor-suppressor loci exist on the long arm of chromosome 4 and that they may play an important role in the development and progression of primary small cell lung cancer tumorigenesis.

A Study of Microsatellite Instability in Primary Small Cell Lung Cancers by Microsatellite Analysis / 결핵

BACKGROUND: Genomic instability, which is manifested by the replication error (RER) phenotype, has been proposed for the promotion of genetic alterations necessary for carcinogenesis. Merlo et al. reported frequent microsatellite instability in primary small cell lung cancers. However, Kim et al. found that instability occurred in only 1% of the loci tested and did not resemble the replication error-positive phenotype. The significance of microsatellite instability in the tumorigenesis of small cell lung cancer ( as well as the relationship between microsatellite instability and its clinical prognosis was investigated in our study. METHODS: Fifteen primary small cell lung cancers were chosen for this study. The DNAs extracted from paraffin-embedded tissue blocks with both primary tumor and corresponding control tissue were investigated. This phrase is unclear. Does this mean the blocks contained both primary tumor and control tissue samples? Forty microsatellite markers on chromosome 1p, 2p, 3p, 5q, 6p, 6q, 9p, 9q, 13q, and 17p were used in the microsatellite analysis. RESULTS: 1) Thirteen (86.7%) of 15 tumors exhibited LOH in at least one of the tested microsatellite markers. 2) Three of 13 tumors exhibiting LOH lost a larger area in chromosome 9p. 3) LOH was shown in 72.7% on chromosome 2p, 40% on 3p, 50% on 5q, 46.7% on 9p, 69.2% on 13q, and 66.7% on 17p(Table 1). 4) Nine (60%) of 15 tumors exhibited shifted bands in at least one of the tested microsatellite markers. 5) Nine cases exhibiting shifted bands showed altered loci ranging 2.5~52.5% (mean 9.4% +/-16.19)(Table 2). 6) Shifted bands occurred in 5.7% (34 of 600) of the loci tested Table 2. 7) Nine cases with shifted bands exhibited LOH ranging between 0~83.3%(,) and the median survival duration of those cases was 35 weeks. Six cases without shifted bands exhibited LOH ranging between 0~83.3%(,) and the median survival duration of those cases was 73 weeks. There was no significant difference between median survival durations of the two groups(p=0.4712). CONCLUSION: Microsatellite instability as well as the inactivation of several tumor suppressor genes may play important roles in the development and progression process of tumors. However, the relationship between microsatellite instability and its clinical prognosis in primary small cell lung cancer could not be established.

Identification of tumor suppressor loci on the long arm of chromosome 5 in primary small cell lung cancers / 결핵

BACKGROUND: Recent cytogenetic studies indicated that loss of the long arm of chromosome 5 is a frequent event in small cell lung cancer (SCLC), suggesting the presence of a tumor suppressor gene is its place. To map the precise tumor-suppressor loci on the chromosome arm for further positional cloning efforts, we tested 15 primary SCLCs. METHODS: The DNAs extracted from paraffin-embedded tissue blocks with primary tumor and corresponding control tissue were investigated. Nineteen polymorphic microsatellite markers located in the long arm of chromosome 5 were used in the microsatellite analysis. RESULTS: We found that ten (66.7%) of 15 tumors exhibited LOH in at least one of tested microsatellite markers. Two (13%) of 10 tumors exhibiting LOH lost a larger area in chromosome 5q. LOH was observed in five common deleted regions at 5q. Among those areas, LOH between 5q34-qter and 5q35.2-35.3 was most frequent (75%). LOH was also observed in more than 50% of the tumors at four at other regions, between 5q14-15 and 5q23-31, 5q31.1, 5q31.3-33.3, and 5q34-35. Three of 15 tumors exhibited shifted bands in at least one of the tested microsatellite markers. Shifted bands occurred in 2.5% (7 of 285) of the loci tested. CONCLUSION: Our data demonstrated that at least five tumor-suppressor loci exist in the long arm of chromosome 5 and that they may play an important role in small cell lung cancer tumorigenesis.

Effect of Synthetic Tyrosine Kinase Inhibitor(ZM260603) on the Growth of Prostate Cancer Cell Lines: Differences According to Androgen Dependency and Bcl-2 Expression / 대한비뇨기과학회지

PURPOSE: We determined the effect of tyrosine kinase inhibitor(TKI), ZM260603 on the growth of prostate cancer cell lines. MATERIALS AND METHODS: Using the synthetic TKI, ZM260603, cytotoxicity test and cell cycle analysis were performed on LNCaP, DU-145 and PC3 prostate cancer cell lines. The bcl-2 and bax protein expressions were observed in PC3 prostate cancer cell line by western blotting. The inhibitory effect of TKI was determined under the presence or absence of dehydrotestosterone, in androgen-dependent LNCaP prostate cancer cell line. RESULTS: The synthetic TKI, ZM260603 showed definite cytotoxicity on all prostate cancer cell lines studied regardless of androgen-dependency. The IC50 were 0.35+/-0.08microM, 0.12+/-0.06microM and 0.21+/-0.09microM for LnCaP, DU-145 and PC-3 cell lines, respectively. The G0/G1 phase arrests were observed commonly in all of these cell lines by flowcytometric analysis. Decrement in bcl-2 expression and increment of bax protein expression in the PC-3 cell line was observed by western blotting. The IC50 of hormone-dependent LNCaP prostate cancer cell line on TKI was increased about four folds by the addition of dihydrotestosterone. CONCLUSIONS: Our results suggest that the changes in the expression of bcl-2 and bax proteins are related with inhibitory process of the synthetic TKI, ZM260,603 on the growth of prostate cancer cell lines. Androgen seems to act as compromising or weakening the effects of TKI in androgen-dependent prostate cancer cell line, although the exact relationships between androgen-dependency and bcl-2 expression are unclear.