A case from South Korea: an occupational physician convicted of "interference with business".
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Air Pollutants, Occupational↗
Biomedical subjects
R Kim
Publications and source records attributed to R Kim.
A phase II trial of mitomycin C, 5'-deoxy-5-fluorouridine, etoposide and medroxyprogesterone acetate (McVD-MPA) as a salvage chemotherapy to anthracycline-resistant tumor in relapsed breast cancer and its mechanism(s) of antitumor action.
To assess the therapeutic efficacy in the combination of mitomycin C (MMC), 5'-deoxy-5-fluorouridine (5'-DFUR), etoposide (VP-16) and medroxyprogesterone acetate (MPA) (McVD-MPA) to anthracycline-resistant tumor as a salvage chemotherapy, a phase II trial was conducted in patients with relapsed breast cancer. Fifty-five patients were enrolled in this trial and 54 were assessable, who had all previously been treated with an anthracycline regimen. The treatment schedule was designed with the intravenous administration of MMC (6 mg/m2) on day 1 followed by peroral administration of VP-16 (75 mg/m2) on day 2, 4, 6 and the peroral administration of 5'-DFUR (600 mg/m2) and MPA (400 mg/m2) on day 1 through 21 in one cycle. The overall tumor response rate was 40.7% (22/54) including 16.6% (9 cases) in complete response and 24.0% (13 cases) in partial response, and the long no change (NC) was observed in 18.5% (10/54) out of 44.4% (24/54) in NC. Of the patients with primary resistance to anthracycline 30.0% responded to McVD-MPA therapy. Bone and liver metastases responded in 50.0% and 50.0%, whereas soft tissue and lung metastases responded in 36.8% and 35.2%, respectively. The mean time to response and response duration were 2.7 and 15.6 months, respectively. The overall survival of the patient treated with the McVD-MPA was superior to the non-treatment of second line therapy, and the median survival between McVD-MPA and non-treatment was 86 days and 50 days, respectively. The major adverse effect was observed in hematological toxicity (31.7%) such as leukopenia and thrombocytopenia and non-hematological toxicity of gastrointestinal events (31.7%), the toxicity was less than grade 2, and was tolerable during the treatment. In the experiment of MDA-MB-231 breast cancer cell line that was overexpressed with P-glycoprotein (P-gp) and multidrug resistance associated protein (MRP), the mechanism(s) by which McVD-MPA induces the antitumor effect to anthracycline-resistant tumor may be explained at least in part as follows: i) The treatment of MMC suppressed the expression of P-gp and MRP in a dose-and time-dependent manner, connecting the increase of the intracellular concentration of VP-16; ii) The treatment of MMC enhanced the expression of thymidine phosphorylase to increase the production of 5-FU from 5'-DFUR in the antiangiogenic effect of MPA. These results indicate that the combination chemotherapy of the McVD-MPA may be an effective regimen to anthracycline-resistant tumor as a salvage chemotherapy to prolong the survival in the patient with relapsed breast cancer.
ATP Binding Cassette Transporter, Subfamily B↗
Pharmacokinetic and biochemical analysis in the treatment of weekly paclitaxel in relapsed breast cancer.
The mechanism(s) by which weekly paclitaxel exerted more therapeutic efficacy than the triweekly schedule in relapsed breast cancer is still unclear. To assess the rationale in therapeutic efficacy of weekly paclitaxel in relapsed breast cancer, pharmacokinetic and biochemical analyses were examined in terms of the mean peak plasma concentration at 0 min (Cmax), 30 min, and 24 h after finishing the infusion, and the extracellular domain of HER-2 in response to the treatment with paclitaxel. Twenty-five patients treated with weekly 1 h infusion of paclitaxel in the dose range from 40 mg/m(2) to 80 mg/m(2) were studied. Eleven patients responded to the treatment including 4 cases of complete response (CR) and 7 cases of partial response (PR), while 14 patients did not respond including 12 cases of no change (NC) and 2 cases of progressive disease (PD). The plasma concentration of paclitaxel and extracellular domain of HER-2 in the patients were measured by high-pressure liquid chromatography and enzyme immunoassay, respectively. The peak concentration (Cmax) and the other peaks at 30 min and 24 h in 10 patients including 3 cases of 40 mg/m(2), 3 cases of 60 mg/m(2) and 4 cases of 80 mg/m(2) in the weekly paclitaxel were compared in proportion to the increase of dose escalation, and compared to their tumor response. Further, the plasma levels of extracellular domain of HER-2 in 17 patients treated with the weekly paclitaxel were measured, and also compared to their tumor response. The mean Cmax treated with 40 mg/m(2), 60 mg/m(2) and 80 mg/m(2) in the weekly paclitaxel was 1.94, 2.18 and 1.54 microM, respectively. The dose escalation of paclitaxel and the dose intensity were not correlated with the increase of plasma concentration of paclitaxel nor with the tumor response. In contrast, the plasma level of extracellular domain of HER-2 in responders was higher than that of non-responders in the weekly paclitaxel regimen(p=0.0512, Mann-Whitney's U-test). These results suggest that tumor response to the weekly 1 h infusion of paclitaxel was not associated with the plasma concentration and the dose intensity, rather the plasma level of extracellular domain of HER-2 protein may be a predictor of tumor response in the treatment of weekly paclitaxel in relapsed breast cancer.
Adult↗
Introduction of gadd153 gene into gastric cancer cells can modulate sensitivity to anticancer agents in association with apoptosis.
Gadd 153 gene is known as one of the growth arrest and DNA damage inducible genes that may play an important role in signal transduction pathway(s) in response to DNA damage. We have investigated whether the introduction of gadd153 gene into gastric cancer cells could modulate the sensitivity to anticancer agents in association with apoptosis. The transfection of gadd153 gene into MKN45 gastric cancer cells (MKN45gadd153) increased the sensitivity to a variety of anticancer agents, compared to that of neo gene-transfected cells (MKN45neo). The sensitivity to CDDP and VP-16 was increased to a greater extent, whereas the sensitivity to 5-FU and taxotere was increased to a lesser extent. The increase of sensitivity to these drugs was associated with the increase of the formation of internucleosomal DNA ladders in apoptosis. The basal level of gadd153 mRNA was overexpressed in MKN45gadd153 cells, and its induction following the treatment of VP-16 and taxotere was found to a greater extent than that of MKN45neo cells. The analysis of mRNA expression in drug resistance-related genes including mdr1, mrp, topoisomerase II alpha showed that the increase of drug-sensitivity in MKN45gadd153 cells was not due to the changes in expression of drug resistance genes. These results suggest that the introduction of gadd153 gene into gastric cancer cells may modulate the sensitivity to certain anticancer agents by activating AP-1-associated signal transduction pathway(s) leading to apoptosis.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Expression and relationship between topoisomerase I and II alpha genes in tumor and normal tissues in esophageal, gastric and colon cancers.
DNA topoisomerases are known to be nuclear enzymes that are important targets of topoisomerase I (topo I) and topoisomerase II (topo II) inhibitors in cancer chemotherapy. We investigated the mRNA expression of topo I and topo II alpha genes as assessed by northern blot analysis in tumor and the adjacent normal tissues of esophageal, gastric and colon cancers. The surgical specimens consisted of 18 tumor tissues and the adjacent normal tissues including 6 esophageal cancers, 6 gastric cancers and 6 colon cancers. We found that the mRNA expression of topo I gene was not significantly different between tumor and normal tissues in 18 surgical specimens, whereas the mRNA expression of topo II alpha gene in the all types of tumors was significantly higher than that of the adjacent normal tissues. Furthermore, the mRNA expression of topo II alpha gene in tumor and adjacent normal tissues was correlated with the S-phase population in cell cycle. Of great importance was the significant relationship between mRNA expression of topo I and topo II alpha genes in tumor and normal tissues was found in esophageal and colon cancers (p < 0.05), except in gastric cancers. These results indicate that the rationale in tumor specific chemotherapy with topo II inhibitors was based on the finding of its higher expression of topo II alpha gene in tumors than that of normal tissues, an important target of topo II inhibitors, and suggest that the sequential chemotherapy targeting topo I and topo II enzymes by modulating topo II alpha expression by topo I inhibitors might be more effective in esophageal and colon cancers, in terms of their relationship between topo I and topo II alpha expression in tumor cells.
Antigens, Neoplasm↗
Taxotere activates transcription factor AP-1 in association with apoptotic cell death in gastric cancer cell lines.
We investigated whether a novel mitotic inhibitor, taxotere can activate the transcription factor AP-1 in association with apoptotic cell death in 8 gastric cancer cell lines. Apoptotic cell death was analyzed by DNA ladder formation assay, and AP-1 binding activity was assessed by gel mobility-shift assay. The activation of AP-1 binding was induced in accordance with the sensitivity to taxotere in gastric cancer cell lines. The relationship between the increase of AP-1 binding and the formation of internucleosomal DNA ladders induced by taxotere was significant (p < 0.05). Furthermore, the activation of AP-1 binding was induced following the treatment of taxotere in a dose and -time dependent manner. Although the sensitivity to taxotere was correlated with the formation of internucleosomal DNA ladders in apoptotic cell death, its sensitivity was not influenced by their p53 genomic states in gastric cancer cell lines. Rather, the activation of AP-1 binding was correlated with the induction of a growth arrest and DNA damage inducible gene, gadd153 (p < 0.05). These results indicate that the activation of AP-1 binding by taxotere seems to be an important factor in determining its sensitivity in association with internucleosomal DNA ladders, and suggest that the induction of gadd153 gene could be a downstream target of AP-1-regulated genes involved in signal transduction pathways leading to apoptosis in gastric cancer cells.
Antineoplastic Agents, Phytogenic↗
Enhancement of chemotherapeutic agents induced-apoptosis associated with activation of c-Jun N-terminal kinase 1 and caspase 3 (CPP32) in bax-transfected gastric cancer cells.
Apoptois is an important determinant in the sensitivity to chemotherapeutic agents in gastric cancer cells. In this study, we examined whether the introduction of the bax gene into MKN45 gastric cancer cells could enhance the sensitivity to chemotherapeutic agents in association with apoptosis. Apoptosis in the bax-transfected gastric cancer cells was enhanced following the treatment of various chemotherapeutic agents including adriamycin (ADM), cisplatin (CDDP), etoposide (VP-16) and taxotere (TXT) as compared to those of neo gene-transfected cells. The enhancement of apoptosis was coincident with the increase of sensitivity in the ratio of IC50 value, that was 1.3-fold in ADM, 4.4-fold in CDDP, 4.6-fold in VP-16 and 2.5-fold in TXT, respectively. Further, the enhancement of apoptosis in the bax-transfected gastric cancer cells was associated with the activation of c-Jun N-terminal kinase 1 (JNK 1) and caspase 3 (CPP32). The increases of sensitivities to these agents in the bax-transfected cells were also demonstrated in in vivo experiments using the tumor cells transplanted into nude mice. The tumor growth in the bax-transfected cells was significantly suppressed following the treatment of CDDP or VP-16 compared to that of neo-transfected cells (p < 0.05). These results indicated that, the bax gene might play a critical role in determination of sensitivity to chemotherapeutic agent in gastric cancer cells in vivo, and that the activation of JNK 1 and CPP32 might be involved in the signal transduction pathways leading to apoptosis.
Adenocarcinoma↗
A pharmacoeconomic evaluation of amlodipine usage in patients undergoing PTCA in the US using results from the Coronary Angioplasty Amlodipine Restenosis Study (CAPARES).
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Amlodipine↗
Factors contributing to adriamycin sensitivity in human xenograft tumors: the relationship between expression of the MDR1, GST-pi and topoisomerase II genes and tumor sensitivity to adriamycin.
To study the factors contributing to tumor sensitivity to adriamycin (ADR) in vivo, the relationship between mRNA expression of the MDR1, GST-pi and topoisomerase II genes and tumor response to ADR was examined in six human xenograft tumors derived from two esophageal, two gastric and two colon cancers. A significant tumor response to ADR was observed in two esophageal xenograft tumors of six tumor lines, and one gastric tumor partially responded to ADR. mRNA expression of the MDR1 and GST-pi genes was elevated in five tumor lines including three ADR responsive tumors, whereas mRNA expression of the topoisomerase II gene was detected in all six tested tumor lines. Topoisomerase II mRNA expression levels in ADR responsive tumors were higher compared with those of ADR unresponsive tumors. No significant relationship between mRNA expression of the MDR1 and GST-pi genes and ADR sensitivity was found. In contrast, topoisomerase II mRNA expression was significantly correlated with tumor sensitivity to ADR (p less than 0.01). Moreover, topoisomerase II mRNA expression was significantly correlated with the growth fraction (S-phase fraction) in the cell cycle kinetics (p less than 0.01). These results indicate that topoisomerase II mRNA expression in association with the high growth fraction may be an important in vivo factor to contribute to ADR sensitivity in human tumors.
Animals↗
A role for plasma membrane potential in doxorubicin--induced cytotoxicity.
Using a modifier of membrane function, we have shown that plasma membrane potential plays an important role in doxorubicin (DOX) - induced cytotoxicity through its connection with cell metabolism and through its effect on drug accumulation. Membrane potential of K562 cells, measured using 3, 3'-dihexyl-oxacarbocyanine (DiOC6 (3)), was increased in the presence of non-toxic cepharanthin or N-1379 and decreased in the presence of non-toxic K252a. Correlated with the level of the potential, DOX efficacy was enhanced by cepharanthin or N-1379 and decreased by K252a associated with an increase or decrease of the percentage of cells in S-phase and of intracellular DOX accumulation.
Alkaloids↗
Expression of MDR1, GST-pi and topoisomerase II as an indicator of clinical response to adriamycin.
The usefulness of MDR1, GST-pi or topoisomerase II mRNA expression detected by dot blot analysis as an indicator of intrinsic resistance to adriamycin was investigated in 15 fresh human tumor specimens. MDR1 and GST-pi expression, which is known to be a marker for adriamycin resistance, was detected in six (66.7%) and seven (77.8%) of the nine clinically resistant tumors, respectively. However, in four of the six adriamycin responsive tumors, MDR1 and/or GST-pi expression were detected. Thus these two markers were not indicators of clinical response to adriamycin. In contrast, topoisomerase II mRNA expression was significantly correlated with clinical response (p less than 0.01, chi 2 test). The expression of topoisomerase II mRNA was detected at a high level in five (83.3%) of the 6 clinically responsive tumors, and the other nine tumors resistant to adriamycin treatment exhibited undetectable or low levels of topoisomerase II mRNA. We therefore suggest that the level of topoisomerase II mRNA expression is a useful marker of the clinical response to adriamycin.
Antineoplastic Combined Chemotherapy Protocols↗
Antitumor effect of KW2149, a new mitomycin derivative, administered by different modalities.
The effectiveness of a new mitomycin derivative, KW2149, against human tumors was evaluated by the 4 days subrenal capsule assay (SRCA) and the nude mice screening assay (NMSA). Evaluation by the SRCA showed a 50% response rate at a maximum dose of 3.8 mg/kg for 3 consecutive days. When evaluated by NMSA, the response rate was 100, 75 and 25% after the intermittent administration of 7.5, 5.6 and 4.5 mg/kg (q4dx3) respectively. Although the efficacy was reduced when mice were administered a single dose equivalent to the intermittent one, the new analog was along more effective than MMC administered by either modality.
Adenocarcinoma↗
Effect of C-reactive protein, PHA, PWM and choline phosphate in 3H-thymidine uptake of leukocytes of leprosy patients and normal individuals.
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Adolescent↗
Interlaboratory evaluation of an off-line supercritical fluid extraction/infrared spectrometric method for determination of petroleum hydrocarbons in solid matrixes.
A collaborative study was conducted, with 14 laboratories participating, to determine the method accuracy and precision of the proposed U.S. Environmental Protection Agency Methods 3560 and 8440. These methods involve the extraction of petroleum hydrocarbons from solid matrixes with supercritical carbon dioxide at 340 atm and 80 degrees C for 30 min (dynamic), collection of the extracted materials in tetrachloroethene (Method 3560), and analysis of the extracts by infrared (IR) spectrometry (Method 8440). The study design was based on the AOAC blind replicate design with balanced replicates. The study samples consisted of 4 solid matrixes that had petroleum hydrocarbon contents ranging from 614 to 32,600 mg/kg. Each of the 4 matrixes was extracted in triplicate, and the extracts were analyzed with 2 different IR spectrometers. In addition, each of the participating laboratories extracted a sample of unspiked clay soil, the same clay soil spiked with corn oil and reference oil at 1000 mg/kg each, and the same clay soil wetted to 30% water content and spiked with motor oil at 10,000 mg/kg (the latter 3 samples were extracted only once). Results indicated that the overall method accuracy for concentrations ranging from 614 to 32,600 mg/kg was 82.9%; the mean recoveries of petroleum hydrocarbons for each of the 4 solid matrixes ranged from 77.9 to 107% for analyses performed with the Perkin-Elmer Fourier transform IR spectrometer and from 75.9 to 101% for analyses performed with the Buck-Scientific IR spectrometer; the differences between the 2 instruments on a sample-by-sample basis were less than 17% for the total petroleum hydrocarbon determinations. The interlaboratory method precisions (RSDR) appeared to be matrix-dependent and ranged from 17.3 to 45.4% for analyses performed with the Perkin-Elmer Fourier transform IR spectrometer and from 16.7 to 47.9% for the Buck-Scientific IR spectrometer. The intralaboratory method precisions (RSDr) appeared to be less matrix-dependent and ranged from 11.5 to 17.0% for analyses performed with the Perkin-Elmer FTIR spectrometer and from 11.1 to 18.2% for the Buck-Scientific IR spectrometer. Method accuracy and precision data are also presented for the 5 laboratories that used Isco supercritical fluid extraction systems and for the 7 laboratories that used vessels with volumes of 3.5 mL or less with different supercritical fluid extraction systems.
Aluminum Silicates↗