Biomedical subjects

Kun-Huei Yeh

Publications and source records attributed to Kun-Huei Yeh.

At least 19 recordsLinked to original sources

PubMed2026

Diversified cell origin of Helicobacter pylori eradication-responsive gastric diffuse large B-cell lymphomas.

A significant proportion of gastric diffuse large B-cell lymphoma with mucosa-associated lymphoid tissue [DLBCL(MALT)] and without MALT ('pure' DLBCL) can be resolved by Helicobacter pylori eradication (HPE). Gastric MALT lymphoma is an indolent lymphoma derived from memory B cells in the marginal zone. In the present study, we aimed to explore the origin of large cells in HPE-responsive gastric DLBCLs (complete remission after HPE). We investigated gastric lymphoma biopsies from 31 patients with HPE-responsive DLBCLs [15 'pure' DLBCLs, 16 DLBCL(MALT)s]. We used the Hans algorithm (CD10, BCL-6, and MUM1) to define the origins of germinal center B cell (GCB) and non-GCB. To further ascertain the cellular origin, 11 'pure' DLBCLs were examined using an Agilent whole-human genome microarray. Eleven DLBCLs [eight with 'pure' DLBCL and three with DLBCL(MALT)] were also assessed using Lymph2Cx. Specific GCB markers, including BACH2, AID, and BCL2 rearrangement and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) codon 641 mutations, were evaluated in 31 patients with HPE-responsive gastric DLBCLs. According to the Hans algorithm, 53% (8/15) of gastric 'pure' DLBCLs and 50% (8/16) of DLBCL(MALT)s were of the GCB phenotype. Gene expression assays revealed that five of six patients with 'Hans' GCB had GCB genetic signatures, whereas four of five patients with 'Hans' non-GCB had activated B-cell genetic signatures. The Lymph2Cx assay revealed the GCB subtype in seven of eight patients with 'Hans' GCB. The expression patterns of BACH2 (p = 0.005) and AID (p = 0.038) closely correlated with the 'Hans' GCB phenotype. BCL2 rearrangements and EZH2 codon 641 mutations were detected in 44% (7/16) and 13% (2/16) of patients with 'Hans' GCB, respectively. In another cohort of 29 HPE-unresponsive gastric DLBCLs [19 'pure' DLBCLs and 10 DLBCL(MALT)s], we found a close association between the 'Hans' GCB subtype and the GCB subtype as determined by the Agilent whole-human genome microarray and Lymph2Cx in lymphoma cells of these patients. In conclusion, more than half of HPE-responsive large cell lymphoma cases in the stomach were of GCB origin. © 2026 The Pathological Society of Great Britain and Ireland.

Humans↗

PubMed2006

Disseminated Mycobacterium kansasii infection in an HIV-negative patient presenting with mimicking multiple bone metastases.

We report a patient with disseminated Mycobacterium kansasii infection, but with no underlying disease, presenting with mimicking multiple bone metastases with cancer of unknown primary site. Disseminated M. kansasii infection is rare in HIV-negative patients without underlying diseases. This patient had disseminated M. kansasii infection manifested with vertebral osteomyelitis, sacroiliitis, psoas abscess, bone marrow granuloma, liver granuloma, and possible spleen abscesses. The clinical manifestations are described and discussed in details.

Adult↗

PubMed2005

A pathway for tumor necrosis factor-alpha-induced Bcl10 nuclear translocation. Bcl10 is up-regulated by NF-kappaB and phosphorylated by Akt1 and then complexes with Bcl3 to enter the nucleus.

Bcl10 overexpression and nuclear translocation were originally identified in mucosa-associated lymphoid tissue lymphoma with t(1;14)(p32;q32) chromosome translocation. DNA amplification of Bcl10 was also found in other solid tumors. We have recently shown that nuclear translocation of Bcl10 is a specific molecular determinant of Helicobacter pylori-independent mucosa-associated lymphoid tissue lymphoma (Kuo, S.-H., Chen, L. T., Yeh, K.-H., Wu, M. S., Hsu, H. C., Yeh, P. Y., Mao, T. L., Chen, C. L., Doong, S. L., Lin, J. T., and Cheng, A.-L. (2004) J. Clin. Oncol. 22, 3491-3497). However, the molecular mechanism of Bcl10 nuclear translocation remains unknown. In this study, we observed that tumor necrosis factor-alpha (TNFalpha) up-regulates the expression of Bcl10 and induces a fraction of Bcl10 nuclear translocation in human breast carcinoma MCF7 cells. Chromatin immunoprecipitation assays and electrophoretic mobility shift assays indicated that an NF-kappaB-binding site resides in the Bcl10 5 '-untranslated region. This study also demonstrates that Akt1, activated by TNFalpha, phosphorylates Bcl10 at Ser218 and Ser231 and that phosphorylated Bcl10 subsequently complexes with Bcl3 to enter the nucleus. Either inhibition of Akt1 or depletion of Bcl3 blocks Bcl10 nuclear translocation. In summary, these findings characterize a molecular linkage that directs Bcl10 nuclear translocation in response to TNFalpha treatment.

Active Transport, Cell Nucleus↗

PubMed2005

Effects of glucocorticoids on the growth and chemosensitivity of carcinoma cells are heterogeneous and require high concentration of functional glucocorticoid receptors.

AIM: To determine how glucocorticoids (GCs) may affect the growth and chemosensitivity of common carcinoma cells. METHODS: The effect of dexamethasone (DEX) on growth and chemosensitivity was assessed in 14 carcinoma cell lines. The function of GC receptors (GR) was assessed by MMTV reporter assay. Overexpression of GR was done by in vitro transfection and expression of a GR-expressing vector. Immunohistochemical stain of tissues and cells were done by PA1-511A, an anti-GR monoclonal antibody. RESULTS: DEX inhibited cell growth of four (MCF-7, MCF-7/MXR1, MCF-7/TPT300, and HeLa), increased cisplatin cytotoxicity of one (SiHa), and decreased cisplatin cytotoxicity of two (H460 and Hep3B) cell lines. The GR content of the seven cell lines affected by DEX was significantly higher than those of the seven cell lines unaffected by DEX (5.2+/-2.5 x 10(4) sites/cell vs 1.3+/-1.4 x 10(4) sites/cell, P = 0.005). Only two DEX-unresponsive cell lines (NPC-TW01 and NPC-TW04) contained high GR amounts in the range (1.9-8.1 x 10(4) sites/cell) of the seven DEX-responsive cell lines. The GR function of NPC-TW01 and NPC-TW04, however, was found to be impaired. The importance of high cellular amount of GR in mediating DEX susceptibility of the cells was further exemplified by GR dose-dependent drug resistance to cisplatin of AGS, a cell line with low GR content and was unaffected by DEX before transfection of GR-expressing vector. Immunohistochemical studies of human cancer tissues showed that 5 of the 45 (11.1%) breast cancer and 43 of the 85 (50.6%) non-small cell lung cancer had high GR contents at the ranges of the GC-responsive carcinoma cell lines. CONCLUSION: The growth and chemosensitivity of human carcinomas with high GR contents may be affected by GC. However, in light of the heterogeneous and even contradictive effects of GC on these cells, routine examination of GR contents of human carcinoma tissues may not be clinically useful until other markers that help predict the ultimate effect of GC on individual patients are identified.

Anti-Inflammatory Agents↗

PubMed2005

Phase II study of weekly paclitaxel and 24-hour infusion of high-dose 5-fluorouracil and leucovorin in the treatment of recurrent or metastatic gastric cancer.

To investigate the efficacy and safety of combining weekly paclitaxel with weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV, folinic acid) in the treatment of patients with advanced gastric cancer. Patients with histologically confirmed recurrent or metastatic gastric cancer were studied. Paclitaxel 80 mg/m2 3-hour intravenous infusion was given on days 1, 8, and 15, and high-dose 5-FU 2,600 mg/m2 plus LV 300 mg/m2 24-hour intravenous infusion (HDFL) was given on days 2, 9, and 16, repeated every 4 weeks. Between August 1997 and August 2003, 30 patients were enrolled. The median age was 58 years (range: 37-70). Eighteen patients (60.0%) had recurrent or metastatic disease and 12 patients had de novo metastatic disease. Among the 27 patients evaluable for tumor response, 2 achieved complete response and 9 achieved partial response, with an overall response rate of 40.7% (95% confidence interval, CI: 22-61%). Eleven of the 21 patients without prior exposure to HDFL-containing regimens responded (response rate: 52.4%, 95% CI: 29-74%), while none of the 6 patients who had previously failed HDFL-containing regimens responded (p value = 0.054 by Fisher's exact test). All 30 patients were evaluated for survival and toxicities. Median time to progression and overall survival were 6 and 10 months, respectively. Major grade 3-4 toxicities were neutropenia in 12 patients (40.0%), diarrhea in 10 patients (33.3%), and stomatitis in 3 patients (10.0%). Grade 1-2 and 3-4 paclitaxel-related neuropathy developed in 16 (53.3%) and 2 (6.7%) patients, respectively. None of the patients discontinued protocol treatment because of paclitaxel-related neuropathy or developed HDFL-related hyperammonemic encephalopathy. This paclitaxel-HDFL regimen is effective and well tolerated in the treatment of advanced gastric cancer.

Adult↗

PubMed2005

Expression of CD86 and increased infiltration of NK cells are associated with Helicobacter pylori-dependent state of early stage high-grade gastric MALT lymphoma.

AIM: A high percentage of early-stage high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylori (H pylori)-dependent. However, unlike their low-grade counterparts, high-grade gastric MALT lymphomas may progress rapidly if unresponsive to H pylori eradication. It is mandatory to identify markers that may predict the H pylori-dependent status of these tumors. Proliferation of MALT lymphoma cells depends on cognate help and cell-to-cell contact of H pylori-specific intratumoral T-cells. To examine whether the expression of co-stimulatory marker CD86 (B7.2) and the infiltration of CD56 (+) natural killer (NK) cells can be useful markers to predict H pylori-dependent status of high-grade gastric MALT lymphoma. METHODS: Lymphoma biopsies from 26 patients who had participated in a prospective study of H pylori-eradication for stage I(E) high-grade gastric MALT lymphomas were evaluated. Tumors that resolved to Wotherspoon grade II or less after H pylori eradication were classified as H pylori-dependent; others were classified as H pylori-independent. The infiltration of NK cells and the expression of CD86 in pre-treatment paraffin-embedded lymphoma tissues were determined by immunohistochemistry. RESULTS: There were 16 H pylori-dependent and 10 H pylori-independent cases. CD86 expression was detected in 11 (68.8%) of 16 H pylori-dependent cases but in none of 10 H pylori-independent cases (P = 0.001). H pylori-dependent high-grade gastric MALT lymphomas contained significantly higher numbers of CD56 (+) NK cells than H pylori-independent cases (2.8+/-1.4% vs 1.1+/-0.8%; P = 0.003). CD86 positive MALT lymphomas also showed significantly increased infiltration of CD56 (+) NK cells compared to CD86-negative cases (2.9+/-1.1% vs 1.4+/-1.3%; P = 0.005). CONCLUSION: These results suggest that the expression of co-stimulatory marker CD86 and the increased infiltration of NK cells are associated with H pylori-dependent state of early-stage high-grade gastric MALT lymphomas.

Adult↗

PubMed2005

Survival outcome of inoperable non-small cell lung cancer patients receiving conventional dose epirubicin and Paclitaxel as first-line treatment.

OBJECTIVE: High-dose epirubicin was shown to be effective in the treatment of inoperable non-small cell lung cancer (NSCLC). Paclitaxel is synergistic to a conventional dose of anthracyclines in the treatment of advanced cancer. A phase II study was designed to test the effectiveness of combining paclitaxel with a conventional dose of epirubicin in inoperable NSCLC patients. METHODS: Eligibility criteria included inoperable stage IIIB or IV NSCLC patients, Eastern Cooperative Oncology Group performance status of 0-2, measurable or evaluable disease and adequate organ function. Epirubicin 70 mg/m2 intravenous infusion for 15 min was given on day 1. Paclitaxel 175 mg/m2 intravenous infusion for 3 h was given on day 2. Cycles were repeated every 21 days. Tumor response was evaluated every two cycles. Patients received treatment until disease progression, unacceptable toxicity or stable disease after cycle 6. RESULTS: Thirty-eight patients received a total of 185 cycles (median 6 cycles). Seventeen patients responded to treatment (response rate 44.7%). Twenty-six (68%) patients received second-line chemotherapy. All patients were followed until their death. Median survival was 11.9 months (95% confidence interval 9.0-14.9 months). Median time-to-treatment-failure was 4.6 months. CONCLUSION: Conventional dose epirubicin plus paclitaxel is effective as a first-line treatment for inoperable NSCLC patients.

Adult↗

PubMed2005

Nuclear expression of BCL10 or nuclear factor kappa B helps predict Helicobacter pylori-independent status of low-grade gastric mucosa-associated lymphoid tissue lymphomas with or without t(11;18)(q21;q21).

The t(11;18)(q21;q21) translocation is a specific marker for Helicobacter pylori-independent status of low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, there are no reliable markers to predict tumor response to H pylori eradication in patients without t(11;18)(q21;q21). Nuclear expression of BCL10 and nuclear factor kappa B (NF-kappaB) was recently found to be closely associated with H pylori-independent status of the high-grade counterpart of gastric MALT lymphoma, which usually lacks t(11;18)(q21;q21). This study examined whether these 2 markers can also predict H pylori-independent status of low-grade gastric MALT lymphomas without t(11; 18)(q21;q21). Sixty patients who underwent successful H pylori eradication for low-grade gastric MALT lymphomas were included. Forty-seven (78.3%) patients were negative for t(11;18)(q21;q21); among them, 36 (76.6%) were H pylori dependent and 11 (23.4%) were H pylori independent. Nuclear expression of BCL10 was significantly higher in H pylori-independent than in H pylori-dependent tumors (8 of 11 [72.7%] vs 3 of 36 [8.3%]; P < .001). Nuclear expression of NF-kappaB was also significantly higher in H pylori-independent than in H pylori-dependent tumors (7 of 11 [63.6%] vs 3 of 36 [8.3%]; P < .001). Further, nuclear translocation of BCL10 and NF-kappaB was observed in 12 of the 13 patients with t(11;18)(q21;q21), and all these 12 patients were H pylori independent. In summary, nuclear expression of BCL10 or NF-kappaB is predictive of H pylori-independent status of low-grade gastric MALT lymphoma with or without t(11;18)(q21; q21).

Active Transport, Cell Nucleus↗

PubMed2005

Somatic mutations in epidermal growth factor receptor underlying complete responsiveness to gefitinib in a Taiwanese female patient with metastatic adenocarcinoma of lung.

A 61-year-old never-smoker female suffered from adenocarcinoma of the lung with chest wall invasion and peri-adrenal lymph node metastases. After palliative resection of all clinically detectable primary and metastatic adenocarcinoma, she received cisplatin and gemcitabine combination chemotherapy for a total of 3 cycles. New metastatic lesions were found in spleen and para-aortic lymph nodes. Her tumor tissue was subjected to mutation analysis for epidermal growth factor receptor (EGFR) and had been shown to have a T-->G missense mutation in nucleotide 2819 of EGFR full-length cDNA (accession no. NM_005228.3), within exon 21 of the EGFR gene, resulting in amino acid substitutions from leucine to arginine at codon 858 (L858R) as expected. She received oral gefitinib 250 mg/day after mutation analysis. She had a very good tumor response with more than 90% tumor reduction shown by abdominal computed tomographic scan, normalization of previously elevated carcinoembryonic antigen level, and complete resolution of previous uptake signals in spleen and para-aortic lymph nodes shown by positron emission tomographic scan. She has been kept in clinical complete remission for 11+ months after the initiation of gefitinib treatment. Our patient supports the proposition that somatic mutation L858R in exon 21 of the EGFR gene accounts for complete responsiveness to gefitinib in a Taiwanese female patient with metastatic adenocarcinoma of lung.

Adenocarcinoma↗

PubMed2004

Nuclear expression of BCL10 or nuclear factor kappa B predicts Helicobacter pylori-independent status of early-stage, high-grade gastric mucosa-associated lymphoid tissue lymphomas.

PURPOSE: A high percentage of early-stage, high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylori dependent. t(11;18)(q21;q21), a genetic aberration highly predictive of H. pylori-independent status in low-grade gastric MALT lymphoma, is rarely detected in its high-grade counterpart. This study examined whether nuclear expression of BCL10 or nuclear factor kappa B (NF-kappaB) is useful in predicting H. pylori-independent status in patients with stage IE high-grade gastric MALT lymphomas. PATIENTS AND METHODS: Twenty-two patients who had participated in a prospective study of H. pylori eradication for stage IE high-grade gastric MALT lymphomas were studied. The expression of BCL10 and NF-kappaB in pretreatment paraffin-embedded lymphoma tissues was evaluated by immunohistochemistry and confocal immunofluorescence microscopy. The presence of t(11;18)(q21;q21) was identified by a multiplex reverse transcriptase polymerase chain reaction of the API2-MALT1 chimeric transcript. RESULTS: Aberrant nuclear expression of BCL10 was detected in seven (87.5%) of eight H. pylori-independent and in none of 14 H. pylori-dependent high-grade gastric MALT lymphomas (P <.001). All seven patients with nuclear BCL10 expression had nuclear expression of NF-kappaB, compared with only two of 15 patients without nuclear BCL10 expression (P =.002). As a single variable, the frequency of nuclear expression of NF-kappaB was also significantly higher in H. pylori-independent tumors than in H. pylori-dependent tumors (seven of eight [87.5%] v two of 15 [12.3%]; P =.002). The API2-MALT1 fusion transcript was detected in only one (12.5%) of eight H. pylori-independent lymphomas. CONCLUSION: Nuclear expression of BCL10 or NF-kappaB is highly predictive of H. pylori-independent status in high-grade gastric MALT lymphoma, and coexpression of these two markers in the nuclei is frequent.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Phosphorylation of p53 on Thr55 by ERK2 is necessary for doxorubicin-induced p53 activation and cell death.

We recently reported that exposure of human cervical carcinoma cells to doxorubicin results in extracellular signal-regulated kinase (ERK)2 activation, which in turn phosphorylates p53 on a previously uncharacterized site, Thr55. This study sought to clarify the biological significance of doxorubicin-induced Thr55 phosphorylation. In breast carcinoma MCF7 cells, doxorubicin (300 nM) activated ERK2 and induced phosphorylation of p53 on Thr55 residues. Pretreatment of MCF7 cells with an ERK2 chemical inhibitor, PD98059 or U0126, blocked doxorubicin-induced p53 activation and suppressed phosphorylation of p53Thr55. MCF55a cells were established by transfection of full-length p53 carrying Thr55 mutation (Thr to Ala) into MCF7 cells. Doxorubicin (500 nM) could not induce p53 activation in MCF55a cells, which showed significantly increased drug resistance toward doxorubicin. While the expression of the apoptotic protein, Bax, showed no difference between MCF7 and MCF55a cells, Bcl-2, an antiapoptotic protein, was constitutively expressed in MCF55a cells. The increase of Bcl-2 protein and/or Bcl-2/Bax ratio might at least partly contribute to the drug resistance of MCF55a cells. In summary, our results suggest that phosphorylation of p53Thr55 by ERK2 is important for doxorubicin-induced p53 activation and cell death.

Antibiotics, Antineoplastic↗

PubMed2004

Suppression of MEK/ERK signaling pathway enhances cisplatin-induced NF-kappaB activation by protein phosphatase 4-mediated NF-kappaB p65 Thr dephosphorylation.

We previously reported that suppression of the MEK/ERK pathway increases drug resistance of SiHa cells. In this study, we further characterized the underlying mechanism of this phenomenon. Pretreatment of SiHa cells with MEK/ERK inhibitor enhanced cisplatin-induced NF-kappaB activation. However, results of immunoblotting analysis showed that neither cisplatin nor MEK/ERK inhibitors induced marked IkappaBalpha degradation, suggesting that suppression of the MEK/ERK signaling pathway may enhance cisplatin-induced NF-kappaB activation via mechanisms other than the conventional pathway. Previous findings that protein phosphatase 4 (PP4), a nuclear serine/threonine phosphatase, directly interacts with and activates NF-kappaB led us to examine the phosphorylation status of NF-kappaB p65. Coincident with activation of NF-kappaB, cisplatin induced Ser phosphorylation but decreased Thr phosphorylation of NF-kappaB p65. Suppression of the MEK/ERK pathway further enhanced cisplatin-induced Thr dephosphorylation but did not affect cisplatin-induced Ser phosphorylation of NF-kappaB p65. Further, in parallel with Thr dephosphorylation, the protein level of nuclear PP4 was increased in cisplatin-treated cells and was further increased by suppression of the MEK/ERK pathway. SiHa cells were then transfected by a sense or an antisense PP4 gene. PP4-overexpressing cells showed a decrease in Thr phosphorylation of NF-kappaB p65 to nearly undetectable levels, and both basal and cisplatin-induced NF-kappaB activities were higher than those in parental cells. By contrast, cisplatin, either alone or with MEK/ERK inhibitors, induced little NF-kappaB activation in antisense PP4-transfected cells. Coprecipitated complex kinase assay revealed a fragment of NF-kappaB p65 (amino acids 279-444) to contain potential phosphorylation sites that directly interact with PP4. Further studies by site-directed mutagenesis suggested that Thr(435) was the major phosphorylation site.

Antineoplastic Agents↗

PubMed2004

Down-regulation of thymidylate synthase expression and its steady-state mRNA by oxaliplatin in colon cancer cells.

Recently, evidence has accumulated that weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) with leucovorin (LV, folinic acid) biochemical modulation may improve the response rates compared with the bolus 5-FU regimens in colorectal cancer (CRC). Combining the infusional 5-FU/LV (iFL) regimens with oxaliplatin or irinotecan is widely adopted to further improve treatment efficacy. Either oxaliplatin-iFL or irinotecan-iFL may achieve an overall response rate of more than 50% in the first-line treatment. Intriguingly, in the salvage treatment for metastatic CRC patients who had failed iFL, only oxaliplatin-iFL may achieve a response rate of about 13-25%. In contrast, oxaliplatin alone or irinotecan-iFL had a very low response rate of 5% or less. To test if the oxaliplatin may reverse the iFL-related 5-FU resistance in CRC, we used DLD-1 colon adenocarcinoma cells as the in vitro study model. First, we revealed that oxaliplatin and 5-FU act synergistically on DLD-1 cells by MTT cytotoxicity assay and median drug effect analysis. Second, we treated the DLD-1 cells with serial concentrations of oxaliplatin (0.1-10 microM). Oxaliplatin treatment results in down-regulation of free thymidylate synthase (TS) protein expression by Western blotting. Further, we analyzed the TS mRNA level by reverse transcription and real-time quantitative polymerase chain reaction assay. Oxaliplatin treatment results in down-regulation of the TS mRNA level up to 40% (mean +/- SD of ratio to reference control = 0.60 +/- 0.21, range 0.42-0.84). In this study, our data provide important information explaining the reason why the combination of oxaliplatin and 5-FU results in a better objective response in 5-FU-resistant patients than oxaliplatin alone does. Our data also suggest that TS down-regulation happens at the transcriptional level. TS modulation and down-regulation had, thus, shed light on the useful potential strategy to achieve objective responses in 5-FU-resistant CRC patients.

Adenocarcinoma↗

PubMed2004

Recent advances in therapy for gastric cancer.

Gastric cancer is the fourth leading cause of death from cancer in Taiwan. Complete surgical resection is the only potentially curative treatment for gastric cancer. Randomized trials have failed to show the superiority of D2 over D1 dissection, and comparisons showing higher survival rates following more extensive surgery in Japan may have been influenced at least in part by the fact that D1 dissection underestimates disease stage in Western populations. No studies have shown convincing evidence of a survival benefit from adjuvant chemotherapy. A regimen of postoperative 5-fluorouracil (5-FU)-based chemoradiotherapy can improve disease-free and overall survival compared with surgery alone. Inadequate lymph node dissection for local control is a major concern. For advanced disease, HDFL (weekly 24-hour infusion of high-dose 5-FU and leucovorin)-based 'doublet' chemotherapy forms a cornerstone of combination chemotherapy in gastric cancer, but the effect on prolonged median survival is minimal. A 'sequential' non-cross-resistant strategy may be useful to prolong overall survival in patients with advanced gastric cancer. There are indications that preoperative neoadjuvant chemotherapy or chemoradiotherapy may increase the resectability of tumors and reduce the risk of postoperative recurrence. In the future, substantial improvements of treatment outcome will likely depend on the integration of novel, molecularly targeted agents into multimodality treatment strategies for all stages of gastric cancer. Further clinical research is mandatory to develop optimal therapies for gastric cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Involvement of nuclear transcription factor-kappa B in low-dose doxorubicin-induced drug resistance of cervical carcinoma cells.

Administration of suboptimal doses of anticancer drugs not only fails to control tumor but often results in increased drug resistance of tumor cells. However, little is known about the effects of transient exposure to a minimally cytotoxic dose of chemotherapy on the development of drug resistance of the tumors. Previous studies have shown that upregulation of drug-exporter proteins (ATP-binding-cassette proteins) may be one of the key mechanisms involved in inducible drug resistance. In this study, we demonstrated that upregulation of NF-kappa B is another possible mechanism. SiHa cells were exposed to low-dose doxorubicin (100 nM; IC(30)) for 3 hr, and then were continuously cultured in drug-free culture media (designated as SiHa/DR cells). SiHa/DR cells at up to 9 passages showed increased resistance to doxorubicin and cross-resistance to cisplatin. Results of quantitative real-time PCR and flow cytometry assay indicated that the increased drug-resistance in SiHa/DR cells was not due to upregulation of drug-exporter proteins or to the decrease of intracellular concentration of anticancer drugs. Both the basal and drug-induced NF-kappa B activity were shown to be increased in SiHa/DR cells by EMSA and NF-kappa B-driven luciferase reporter gene assay. Suppression of NF-kappa B activation by transfection of a dominant negative I kappa B alpha prevented the development of drug resistance, indicating that the upregulated NF-kappa B activity was positively correlated with the low-dose doxorubicin-induced drug resistance. These results suggest that even a transient exposure to a small dose of anticancer drugs may induce drug resistance in some cancer cells via upregulation of NF-kappa B activity.

ATP-Binding Cassette Transporters↗

PubMed2002

High-frequency microsatellite instability predicts better chemosensitivity to high-dose 5-fluorouracil plus leucovorin chemotherapy for stage IV sporadic colorectal cancer after palliative bowel resection.

The influence of MSI on treatment outcome of colorectal cancers remains unclear and deserves further investigation. We recruited 244 patients with stage IV sporadic colorectal cancers for our study, based on appropriate eligibility criteria. Patients were nonrandomly allocated to 2 treatment groups of either with or without high-dose 5-FU plus leucovorin chemotherapy (HDFL, 5-FU 2,600 mg/m(2) leucovorin 300 mg/m(2) maximum 500 mg). Each treatment group was further divided into 2 subgroups according to high-frequency MSI (MSI-H) status. MSI-H was defined as the appearance of MSI in at least 2 of the 5 examined chromosomal loci (BAT-25, BAT-26, D5S346, D2S123, D17S250). We compared clinicopathologic parameters, p53 overexpression and overall survival between the groups. In addition, 4 subgroups were identified as follows: MSI-H(+)HDFL(+), n = 35; MSI-H(-)HDFL(+), n = 134; MSI-H(+)HDFL(-), n = 17; MSI-H(-)HDFL(-), n = 58. There was no significant difference of background clinicopathologic data between the HDFL(+) and HDFL(-) treatment groups (p > 0.05). Survival analyses indicated that the patients of subgroup MSI-H(+)HDFL(+) survived significantly longer than those of subgroup MSI-H(-)HDFL(+), with median survival times of 24 (95% CI 20.2-27.9) and 13 (95% CI 11.6-14.4) months, respectively (p = 0.0001, log-rank test). In contrast, in patients without chemotherapy, the prognosis was poor irrespective of MSI status, with median survival times of 7.0 (95% CI 4.6-9.4) and 7.0 (95% CI 6.1-7.9) months in the MSI-H(+)HDFL(-) and MSI-H(-)HDFL(-) subgroups, respectively (p = 0.8205, log-rank test). MSI-H cancers responded significantly better to HDFL (p = 0.001), with a mean response rate of 65.71% (95% CI 49.98-81.44%) in subgroup MSI-H(+)HDFL(+) compared to 35.07% (95% CI 26.99-43.15%) in subgroup MSI-H(-)HDFL(+). There appeared to be no preferential metastatic site where response to HDFL can be predicted based on the MSI status of the primary tumor. Toxicity to HDFL was similarly minimal between MSI-H(+) and MSI-H(-) patients (p > 0.05). Multivariate analysis of all patients further indicated that MSI-H and chemotherapy were independent favorable prognostic parameters (p < 0.05). Thus, the better prognosis of stage IV sporadic colorectal cancers with MSI-H may be associated with better chemosensitivity, rather than lower aggressiveness in biologic behavior.

Adult↗

PubMed2002

Increase of the resistance of human cervical carcinoma cells to cisplatin by inhibition of the MEK to ERK signaling pathway partly via enhancement of anticancer drug-induced NF kappa B activation.

In this study, we showed that suppression of the MEK-ERK transduction pathway by a selective inhibitor, 2'-amino-3'-methoxyflavone (PD98059), increased drug resistance of SiHa cells to cisplatin, but not to another common anticancer drug, doxorubicin. The downstream mechanism of this discrepant cellular response was investigated. Both cisplatin and doxorubicin activated nuclear ERK2 and nuclear transcription factor kappa B (NF kappa B) of SiHa cells. However, suppression of the MEK-ERK2 pathway by PD98059 resulted in a further enhancement of cisplatin-induced NF kappa B activation, while no further regulation of NF kappa B was noted in doxorubicin-treated cells. The activation of NF kappa B by cisplatin or doxorubicin was not due to the degradation of cytoplasmic I kappa B alpha, as demonstrated by western blotting. Transfection of a dominant negative I kappa B alpha resulted in a markedly diminished PD98059-induced cisplatin resistance in SiHa cells. Our results suggest that the MEK-ERK signaling pathway plays a role in the chemosensitivity of SiHa cells, and suppression of this pathway increases cisplatin resistance partly via an increase of NF kappa B activation. The mechanism responsible for the discrepant effect of PD98059 on NF kappa B activation and hence the chemosensitivity of SiHa cells towards cisplatin and doxorubicin remains to be investigated.

Antineoplastic Agents↗

PubMed2002

P53 overexpression predicts poor chemosensitivity to high-dose 5-fluorouracil plus leucovorin chemotherapy for stage IV colorectal cancers after palliative bowel resection.

Our study aims to further clarify the prognostic significance of p53 overexpression in stage IV colorectal cancer. Between January 1994 and June 1997, we recruited 144 patients with stage IV colorectal cancers for our study, based on appropriate eligibility criteria. The patients were nonrandomly allocated to 2 treatment groups of either with or without high-dose 5-fluorouracil plus leucovorin chemotherapy (HDFL: 5-Fu: 2,600 mg/m(2) leucovorin 300 mg/m maximum 500 mg). Each treatment group was further divided into 2 subgroups according to the status of p53 overexpression. Therefore, 4 subgroups were allocated in our study and were designated as p53 (overexpression) HDFL (+), n = 65; p53 (normal) HDFL (+), n = 37; p53 (overexpression) HDFL (-), n = 27; and p53 (normal) HDFL (-), n = 15, respectively. All patients were prospectively followed until April 2001. There was no significant difference of the background clinicopathologic data of these 4 allocated subgroups of patients (p > 0.05). Multivariate analysis of various clinicopathologic factors of the whole group of patients indicated that age > or = 60 years, poor differentiation, mucin production, CEA > 100 ng/ml, p53 overexpression and without chemotherapy were the significant independent poor prognostic factors (p < 0.05). Survival analyses indicated that the patients of subgroup p53 (normal) HDFL (+) survived significantly longer than those of subgroup p53 (overexpression) HDFL (+), with mean survival time (95% confidence interval [CI]) of 20.24 (16.24-24.25) and 13.29 (10.98-15.60) months, respectively (p = 0.0043, log-rank test). In contrast, in patients without chemotherapy, the prognosis was poor regardless of their p53 status, with mean survival time (95% CI) of 6.85 (5.47-8.23) and 5.87 (4.48-7.26) months in p53 (overexpression) HDFL (-) and p53 (normal) HDFL (-) subgroups of patients, respectively (p = 0.2820, log-rank test). Cancers of normal p53 expression responded significantly better to HDFL (p < 0.05), with mean response rate (95% CI) being 65.57% (52.18-82.96%) in subgroup p53 (normal) HDFL (+) as compared to 35.38% (23.52-47.24%) in subgroup p53 (overexpression) HDFL (+). The toxicity to HDFL was similarly minimal between p53-normal and p53-overexpression patients (p > 0.05). We thus concluded that the poorer prognosis of stage IV colorectal cancers with p53 overexpression was associated with their poorer chemosensitivity rather than the more biologic aggressiveness.

Adenocarcinoma↗