Expression and Function of ABC Transporters as Multidrug Resistance Mechansims in Gastric Cancer Cells

PURPOSE: Multidrug resistance (MDR) is a phenomenon whereby tumor cell acquire resistance to a broad range of structurally and functionally diverse chemotherapeutic drugs. The most widely implicated mechanism of MDR is that of altered membrane transporter in tumor cells. P-glycoprotein (Pgp), multidrug resistance protein (MRP), and breast cancer-resistance protein (BCRP) are well known membrane transporters, which pump out antitumor agents via an ATP-dependent process, the so called ATP-binding cassette (ABC) superfamily or transporter. This study was undertaken to test the prevalence of each ABC transporter, and which of then exhibit functional activity in various gastric cancer cells. METHODS: The expressions of Pgp, MRP, and BCRP mRNA were determined by RT-PCR assay on 10 gastric cancer cells. The sensitivity to anticancer agents, substrates for each ABC transporter in the gastric cancer cells was determined using the MTT assay. The intracellular accumulation of fluorescent compounds for the functional detection of each ABC transporter was determined using flow cytometry. RESULTS: The Pgp mRNA was expressed at various levels in 9 out of the 10 gastric cancer cells tested, but significantly low. MRP mRNA was constitutively expressed in all the cells. BCRP mRNA was differentially expressed in 5 of the gastric cancer cells. There was no relation between the expressions of Pgp and MRP and the cytotoxicity to each substrate. It was observed that the accumulations of paclitaxel and VP-16 were significantly increased on the additions of PSC833 and probenecid, respectively, in all tested cells. The reversal effect of drug accumulation by each inhibitor was much higher in the MRP than Pgp. With BCRP, the observed cytotoxic effect and amount of mitoxanthrone accumulation were less than in the cells expressing the highest levels of BCRP compared to those that did not. However the mitoxanthrone accumulation was not increased on the addition of FTC in the either cell type. CONCLUSION: This study suggests that of the ABC transporters, MRP has primarily functional activity, whereas that of Pgp is only slight, in the gastric cancer cells. Other possible MDR mechanisms involved will have to be explored in further studies.

Intractable Chyloperitoneum after Curative Surgery for Gastrointestinal Malignancy

Chyloperitoneum, also called chylous ascites, is a rarely reported complication of abdominal surgery. In most cases, the diagnosis and treatment is not difficult. The characteristic milky colored odorless fluid is easily detected by drainage or aspiration. With the help of diagnostic radiology and laboratory tests, it has become easier to detect the chyloperitoneum. Chyloperitoneum subsides spontaneously or responds well to medical treatment. Death from chyloperitoneum is extremely rare. However, 3 cases of medically intractable chyloperitoneum were encountered at our hospital after curative surgery for gastrointestinal malignancies (two colorectal cancers and one gastric cancer). Herein, the authors report these case and discuss their treatments.

The Comparison between Transanal and Transvaginal Ultrasonography of Anal Sphincter in Normal Women

PURPOSE: The purpose of this study was to evaluate the normal value of the anal canal structures by transvaginal sonography in normal woman and compare this technique with the more commonly used transanal technique. METHODS: Transvaginal ultrasonography was performed in 25 parous patients between 4th and 8th decade of age, using a Bruel and Kajer type-1890. This procedure was followed by transanal sonography using the same system. The thickness of mucosa and submucosa, internal and external anal sphincter and puborectalis muscle were measured by both methods. RESULTS: The thickness of mucosa- submucosa, internal anal sphincter, external anal sphincter and puborectalis muscle by transvaginal sonography were 2.84 0.2 (2.6~3.0) mm, 2.98 0.4 (2.6~3.3) mm, 7.4 0.3 (7.1~7.7) mm, 7.5 0.5 (7.4~7.6) mm respectively(mean value standard deviation and range). The detection rate of external anal sphincter and puborectalis muscle by transvaginal sonography were between 55.5% (5/9) and 71.4% (5/7). CONCLUSIONS: The thickness of internal anal sphincter was increased with age(p<0.05). The thickness of mucosa-submucosa, internal anal sphincter measured.

Clinical Significance of Loss of Heterozygosity on Chromosome 14q in Sporadic Colorectal Carcinomas

PURPOSE AND METHODS: Colorectal carcinogenesis is a process with multiple steps involving proto- oncogenes, tumor suppressive genes, and mutator genes. Losses of heterozygosity (LOH) on APC, DCC, and TP53 loci are well known chromosomal changes for the inactivation of tumor suppressive genes. Additionally, LOH in colorectal carcinomas (CRC) are frequently found at other loci, including 1p, 8p, 11q, 14q, and 22q. LOH on 14q are quite frequent in bladder, ovarian, renal-cell carcinomas, as well as other types of carcinomas. Previous studies on CRC showed overall rate of LOH on chromosome 14q to be high, the smallest region of overlap of deletion was located at the distal portion of 14q, and a higher rate of LOH was found in more advanced tumors. To investigate whether LOH on chromosome 14q is confined to the distal part or whether it is related with prognosis, we performed an LOH study with 6 microsatellite markers covering the entire arm of 14q in 77 sporadic colorectal cancers and compared it with clinical parameters. RESULTS: Thirty-six (36) tumors (46.7%) showed LOH at one or more markers, and the highest rate was observed in D14S48 (43.5%) and the lowest in D14S297 (30.6%). No statistical differences were seen at different loci of 14q. We observed LOH in 17 less- advanced tumors (Dukes' A & B) and in 19 advanced tumors (Dukes' C & D). There is little evidence that LOH of 14q is related to tumor recurrence, the disease-free survival rate, or the overall survival. CONCLUSION: These results indicate that the entire long arm of chromosome 14 may delete in sporadic colorectal cancers but this loss may not be related to tumor stage and prognosis. We provide evidence that one or more tumor suppressive loci on chromosome 14q may contribute to colorectal carcinogenesis.

Clinical Significance of Loss of Heterozygosity on Chromosome 14q in Sporadic Colorectal Carcinomas

PURPOSE AND METHODS: Colorectal carcinogenesis is a process with multiple steps involving proto- oncogenes, tumor suppressive genes, and mutator genes. Losses of heterozygosity (LOH) on APC, DCC, and TP53 loci are well known chromosomal changes for the inactivation of tumor suppressive genes. Additionally, LOH in colorectal carcinomas (CRC) are frequently found at other loci, including 1p, 8p, 11q, 14q, and 22q. LOH on 14q are quite frequent in bladder, ovarian, renal-cell carcinomas, as well as other types of carcinomas. Previous studies on CRC showed overall rate of LOH on chromosome 14q to be high, the smallest region of overlap of deletion was located at the distal portion of 14q, and a higher rate of LOH was found in more advanced tumors. To investigate whether LOH on chromosome 14q is confined to the distal part or whether it is related with prognosis, we performed an LOH study with 6 microsatellite markers covering the entire arm of 14q in 77 sporadic colorectal cancers and compared it with clinical parameters. RESULTS: Thirty-six (36) tumors (46.7%) showed LOH at one or more markers, and the highest rate was observed in D14S48 (43.5%) and the lowest in D14S297 (30.6%). No statistical differences were seen at different loci of 14q. We observed LOH in 17 less- advanced tumors (Dukes' A & B) and in 19 advanced tumors (Dukes' C & D). There is little evidence that LOH of 14q is related to tumor recurrence, the disease-free survival rate, or the overall survival. CONCLUSION: These results indicate that the entire long arm of chromosome 14 may delete in sporadic colorectal cancers but this loss may not be related to tumor stage and prognosis. We provide evidence that one or more tumor suppressive loci on chromosome 14q may contribute to colorectal carcinogenesis.