Plaque characterisation by Virtual Histology intravascular ultrasound analysis in patients with type 2 diabetes.

OBJECTIVES: To evaluate the in-vivo plaque composition and characteristics in patients with type 2 diabetes mellitus (DM) using Virtual Histology intravascular ultrasound (VH IVUS). METHODS: In 90 patients with stable angina pectoris, de novo target vessels were studied and plaque components were analysed. Patients were divided into two groups: a diabetic group (36 vessels) and a non-diabetic group (54 vessels). RESULTS: The percentage area of necrotic core and dense calcium were significantly larger in the DM group than the non-DM group (necrotic core: 11.0% (interquartile range (IQR): 7.2-15.2%) vs 7.6% (IQR 5.6-13.2%), p = 0.03; dense calcium: 5.6% (IQR: 2.3-7.3%) vs 2.9% (IQR: 1.7-4.9%), p = 0.01). The DM group presented with a significantly higher presence of at least one VH IVUS-derived thin-cap fibroatheroma (VHD-TCFA) (75% vs 41%, p = 0.001) and VH IVUS-derived fibrocalcific atheroma (VHD-FCA) (75% vs 40%, p = 0.001). In the DM group, 53% of the vessels had both VHD-TCFA and VHD-FCA, which was significantly higher than non-DM group (17%, p = 0.0004). CONCLUSIONS: Coronary plaque characteristics in DM patients showed an increased amount of dense calcium and necrotic core, as well as a higher frequency of VHD-TCFA and VHD-FCA. Atherosclerosis of the target vessel was more advanced in diabetic patients.

Serial six year quantitative angiographic follow up in asymptomatic patients following successful coronary angioplasty.

OBJECTIVE: To evaluate long term (six years) lumen changes after balloon angioplasty by using quantitative coronary angiography. METHODS: Complete serial quantitative coronary angiography (before and after angioplasty and at six months, three years, and six years) was performed in 100 patients with successful angioplasty and without subsequent repeated revascularisation. In all, 198 dilated segments were compared with 395 non-dilated segments that were obtained from non-target arteries of study patients. RESULTS: From six months to three years after angioplasty, minimum lumen diameter (MLD) increased significantly by 0.13 (0.28) (mean (SD)) mm in dilated segments and decreased significantly by 0.04 (0.27) mm in non-dilated segments. From three years to six years, MLD remained stable in dilated segments but decreased further (by 0.04 (0.28) mm) in non-dilated segments. Consequently, the DeltaMLD between six months and six years was larger in dilated segments than in non-dilated segments (0.12 (0.32) v -0.08 (0.34); p < 0.001). Further, DeltaMLD from six months to six years correlated positively with the percentage diameter stenosis (DS) at six months in each group (dilated segments r = 0.47, p < 0.0001; non-dilated segments r = 0.49, p < 0.0001). Multivariate analysis showed that the only independent predictor of DeltaMLD over six years for each group was the DS at six months. CONCLUSIONS: Lesion regression occurs within the first three years after angioplasty and reaches a plateau thereafter. Moreover, the stenosis severity at six months predicts the magnitude of late regression after angioplasty.

Acquisition of a gastric or duodenal phenotype on heterotropic transplantation of esophagus and bladder tissues in F344 rats.

Cell differentiation is very important but not well understood. In the present study the ability of various tissues to newly-differentiate when transplanted into the fundus or the duodenum in rats was tested. Pieces of esophagus, bladder, diaphragm and trachea from 8-week-old male F344 rats were transplanted into the gastric fundus or duodenum of females and examined after 3 or 6 months. While the diaphragm was not recognizable as a muscle layer in either the stomach or the duodenum, the esophagus and trachea persisted, the latter with the presence of cartilage. Esophagus grafts transplanted into the glandular stomach and duodenum, newly-differentiated into gastric and duodenal mucosa, respectively. Goblet cells with alcian-blue positive mucin appeared in bladder tissue implanted into the duodenum. Six months after the operation, their numbers had increased and cytoplasm alkaline phosphatase (ALP) positivity was noted. Gastrointestinal and also bladder stem cells may thus have multipotential ability for differentiation and may be able to newly-differentiate when transplanted into different environments in the gastrointestinal tract.

Prevention of the development of preneoplastic lesions, aberrant crypt foci, by a water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia in male F344 rats.

The modifying effects of a dietary water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi or Mannentake) mycelia (MAK) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. Rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for three weeks to induce ACF and fed on diets containing 0, 1.25, 2.5 and 5.0% MAK for five weeks, starting one week before the first dose of carcinogen. MAK significantly and dose-dependently prevented the development of ACF, decreasing the total number of AC and inhibiting cyst formation. MAK (2.5 and 5.0%) also significantly reduced the longitudinal-cross section areas of colon epithelium. MAK in all doses significantly reduced the PCNA positive index, area of the germinal region and number of cells per half crypt. In an additional in vitro experiment, MAK inhibited anchorage-independent growth of several colon carcinoma cell lines. The present results thus indicate that dietary MAK could act as a preventive agent for colon carcinogenesis.

[Pressure wire guide provisional coronary stent implantation].

OBJECTIVES: Whether coronary artery lesion successfully dilated by balloon angioplasty should be stented or not is unclear. The purpose of this study is to evaluate the provisional stent implantation method assessing residual ischemia by pressure wire. METHODS: Thirty-one patients with de-novo lesions suitable for stenting were enrolled in a pressure wire guided provisional stent study. The pressure wire was used to assess the fractional flow reserve(FFR) before and after balloon angioplasty. When the FFR after angioplasty was less than 0.75, stent implantation was planned. Patients with lesions consisting of an intermediate stenosis proximal to the target lesion, chronic total occlusion, bypass graft and left main lesion were excluded from the study. Stent implantation was permitted even if the FFR was more than 0.75 when the operator thought stenting was necessary. Medical treatment was given with aspirin 162 mg/day, cilostazol 200 mg/day for 6 months and additional ticlopidine 200 mg/day for a month after stenting the lesion. RESULTS: Target vessel was the left anterior descending coronary artery in 19 lesions, the right coronary artery in 3, and the circumflex coronary artery in 9. Stent implantation was performed in seven (23%) of 31 lesions and the other 24(77%) lesions were treated with only balloon angioplasty. The FFR before intervention was 0.58 +/- 0.16, and improved to 0.87 +/- 0.07 (p < 0.0001). Percentage diameter stenosis before intervention was 70.7 +/- 12.6% and improved to 20.1 +/- 13.3% (p < 0.0001) after intervention. There was no major cardiac event (death, coronary artery bypass grafting, myocardial infarction, stent thrombosis). Six months follow-up angiography was performed in 27 patients (87%). Angiographic restenosis (percentage diameter stenosis > or = 50%) was found in four patients (15%). A new lesion was found in two patients. Target vessel revascularization was performed in six patients (21%). CONCLUSIONS: Lesions successfully dilated by balloon angioplasty with FFR > or = 0.75 do not require stenting.

Successful thrombus removal using 6Fr hydrolyser thrombectomy catheter in acute myocardial infarction via radial artery.

The 6Fr Hydrolyser thrombectomy catheter for acute myocardial infarction (AMI) successfully removed a massive thrombus in the coronary artery in three patients. The 6Fr Hydrolyser catheter could be advanced into the right coronary artery with bare-wire methods via a 6Fr sheath at the radial artery. This approach suggests that the device can be an alternative method for thrombolysis in selected AMI patients with massive thrombus in the coronary artery.

Radioprotective effects of miso (fermented soy bean paste) against radiation in B6C3F1 mice: increased small intestinal crypt survival, crypt lengths and prolongation of average time to death.

The radioprotective effect of miso, a fermentation product from soy bean, was investigated with reference to the survival time, crypt survival and jejunum crypt length in male B6C3F1 mice. Miso at three different fermentation stages (early-, medium- and long-term fermented miso) was mixed in MF diet into biscuits at 10% and was administered from 1 week before irradiation. Animal survival in the long-term fermented miso group was significantly prolonged as compared with the short-term fermented miso and MF cases after 8 Gy of 60Co-gamma-ray irradiation at a dose rate of 2Gy min(-1). Delay in mortality was evident in all three miso groups, with significantly increased survival. At doses of 10 and 12 Gy X-irradiation at a dose rate of 4 Gy min(-1), the treatment with long-term fermented miso significantly increased crypt survival. Also the protective influence against irradiation in terms of crypt lengths in the long-term fermented miso group was significantly greater than in the short-term or medium-term fermented miso and MF diet groups. Thus, prolonged fermentation appears to be very important for protection against radiation effects.

Abnormalities of primitive myeloid progenitor cells expressing granulocyte colony-stimulating factor receptor in patients with severe congenital neutropenia.

To define the basis for faulty granulopoiesis in patients with severe congenital neutropenia (SCN), the expression of granulocyte colony-stimulating factor receptor (G-CSFR) in primitive myeloid progenitor cells and their responsiveness to hematopoietic factors were studied. Flow cytometric analysis of bone marrow cells based on the expression of CD34, Kit receptor, and G-CSFR demonstrated a reduced frequency of CD34(+)/Kit(+)/ G-CSFR(+) cells in patients with SCN. The granulocyte-macrophage colony formation of CD34(+)/Kit(+)/G-CSFR(+) cells in patients was markedly decreased in response to G-CSF alone and to the combination of stem cell factor, the ligand for flk2/flt3, and IL-3 with or without G-CSF in serum-deprived semisolid culture. In contrast, no difference in the responsiveness of CD34(+)/Kit(+)/G-CSFR(-) cells was noted between patients with SCN and subjects without SCN. These results demonstrate that the presence of qualitative and quantitative abnormalities of primitive myeloid progenitor cells expressing G-CSFR may play an important role in the impairment of granulopoiesis in patients with SCN. (Blood. 2000;96:4366-4369)

Grafting of stomach tissue into the duodenum in F344 rats results in chimeric crypts and tumor development.

Gastric tissue was transplanted from the fundic and pyloric mucosa of 8-week old female F344 rats into the duodenum of males. Autopsy, 12 months after the operation, revealed grafts associated with persistent stones in the duodenum and/or calcification in the tissue. Pepsinogen positive chimeric glands with goblet cells also appeared in the grafts which gave rise to tumors in 18 out of 45 animals (40%). In conclusion, stomach grafts re-differentiate into intestine with goblet cells in the duodenum and this process predisposes to tumor development.

Inhibitory effects of crude salts on the induction and development of colonic aberrant crypt foci in F-344 rats given azoxymethane.

The present study was designed to investigate the modifying effects of dietary exposure to NaCl and four kinds of crude salts on the induction and development of aberrant crypt foci in Fischer 344 rats. A total of 57 male rats were divided into five groups at six weeks of age, and all were given weekly injections of azoxymethane (15 mg/kg body wt s.c.) for three weeks. Group 1 was fed a normal diet throughout the experiment as control group. Groups 2, 3, 4, and 5 were fed diets containing 4.4% pure NaCl, 4.4% cooking salt, 4.4% rock salt, and 4.4% beach salt, respectively, from one week before the first azoxymethane dosing. The mean numbers of aberrant crypt foci and aberrant crypts per colon were significantly lower in Groups 3-5 than in Group 1 (p < 0.01). The present results suggest that the other mineral components (e.g., calcium and magnesium) of these crude salts, rather than pure NaCl, may be chemopreventive agents for colonic tumorigenesis.

Glutathione S-transferase-pi gene expression and platinum drug exposure in human lung cancer.

We examined the association between the gene expression levels of glutathione S-transferase-pi (GST-pi) and platinum drug exposure in human lung cancer. First we monitored GST-pi gene expression levels in two lung cancer cell lines and in peripheral mononuclear cells of ten previously untreated lung cancer patients after platinum drug exposure. Next we examined GST-pi gene expression levels in 40 lung cancer autopsy specimens. The GST-pi gene expression levels were assessed by the quantitative reverse transcription-polymerase chain reaction or Northern blot analysis. The GST-pi gene expression was not induced by platinum drugs either in vitro and in vivo within 24 h of exposure. In contrast, GST-pi gene expression levels in lung cancer tissues of patients who had been exposed to platinum drugs at least 1 month before death were significantly higher than that in those of patients who had not been exposed. These results suggest that GST-pi gene expression is associated with chronic exposure to platinum drugs in lung cancer and/or the stress response to xenobiotics.

Expression of drug resistance-related genes in head and neck squamous cell carcinomas and normal mucosa.

We examined the expression levels of mRNA for multidrug resistance 1 (MDR1), multidrug resistance-associated protein (MRP), human canalicular multispecific organic anion transporter (cMOAT), lung resistance-related protein (LRP), topoisomerase IIalpha, beta (Topo IIalpha, beta) and topoisomerase I (Topo I) genes in human head and neck squamous cell carcinoma (HNSCC) specimens and mucosa (HNM) specimens, to elucidate their roles in relation to the biological characteristics and drug resistance in vivo. Fifty-eight samples (45 head and neck carcinomas and 13 head and neck mucosa) obtained during surgical resection or biopsy from 38 patients were analyzed using the quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. MDR1, MRP, LRP, Topo IIalpha, Topo IIbeta, and Topo I gene transcripts were detected in all the samples tested, but cMOAT mRNA was not detected in them. Comparisons of the expression levels in HNSCC with those in HNM showed that the Topo IIalpha gene expression level was higher in HNSCC than in HNM (P=0.0298). Moreover, the Topo IIalpha mRNA level was significantly higher in metastatic lymph node samples of HNSCC than in HNM samples (P=0.0205). There were no significant differences in the six genes' expression levels between samples exposed to platinum drugs and those not exposed to platinum drugs. These results suggest that it may be effective in anticancer therapy to use topoisomerase-targetting drugs against HNSCC, especially metastatic neck tumors, and that the expression of these genes in HNSCC is not associated with platinum drug exposure.

Increased expression of the MRP5 gene is associated with exposure to platinum drugs in lung cancer.

To investigate the role of the multidrug resistance-associated protein (MRP1) homologue MRP5 in relation to platinum drug resistance, we examined the steady-state levels of the mRNAs for MRP5 in both lung cancer cell lines and peripheral mononuclear cells (PMN) after exposure to platinum drug and in normal lung and lung cancer tissue specimens. Firstly, we examined MRP5 gene expression levels in 80 autopsy samples (40 primary tumors and 40 corresponding normal lung tissues) from 40 patients who had died from lung cancer. Next, we monitored MRP5 gene expression levels within 24 hr in both lung cancer cell lines incubated with cisplatin and in PMN from 10 previously untreated lung cancer patients after carboplatin administration alone. The MRP5 gene expression levels were assessed by quantitative reverse transcription polymerase chain reaction or RNase protection assay. The MRP5 expression levels in normal lung tissues and in tumors from patients exposed to platinum drugs during their lifetime were significantly higher than those in tissues from non-exposed patients. On the other hand, the MRP5 expression levels were not rapidly induced by platinum drugs either in lung cancer cell lines or in PMN within 24 hr. Our results suggest that increased expression levels of the MRP5 gene are associated with exposure to platinum drugs in lung cancer in vivo and/or the chronic stress response to xenobiotics.

ZK7, a novel zinc finger gene, is induced by vascular endothelial growth factor and inhibits apoptotic death in hematopoietic cells.

Vascular endothelial growth factor (VEGF) inhibits radiation-induced apoptosis in the leukemia cell line, CMK86 (O. Katoh et al., Cancer Res., 55: 5687-5692, 1995). To elucidate the molecular mechanisms underlying this inhibitory effect of VEGF, we attempted to identify a transcription factor involved in the cellular response to VEGF stimulation. We cloned the cDNA of a novel Kruppel-type zinc finger (ZNF) gene, ZK7, from a cDNA library constructed from the human leukemia cell line CMK86 after incubation with VEGF. This cDNA encoded a protein of 289 amino acids, which contained a Kruppel-associated box A-box domain at the NH2 terminus and seven ZNF motifs at the COOH terminus. These ZNF motifs were identical to those of HZF16 (M. Saleh et al., Am. J. Hum. Genet., 52: 192-203, 1993). ZK7 and HZF16 genes appear to be the splice variants transcribed from the same gene. Northern blotting and quantitative reverse transcription-PCR analysis revealed that expression of ZK7 mRNA in CMK86 cells and human hematopoietic progenitor cells was increased after VEGF stimulation, whereas that of HZF16 mRNA remained unchanged. To examine the function of ZK7 protein, we generated clones of a human monocytoid leukemia cell line, U937, which were stably transfected with ZK7 or HZF16 cDNA. Importantly, ZK7-overexpressing cells had lower sensitivity to ionizing radiation and the chemotherapeutic agent etoposide than U937 parent cells or HZF16-overexpressing cells. Therefore, ZK7 protein may be involved in the inhibitory effect of VEGF on apoptotic cell death in human hematopoietic cells.

Human EVI9, a homologue of the mouse myeloid leukemia gene, is expressed in the hematopoietic progenitors and down-regulated during myeloid differentiation of HL60 cells.

Evi9, a common site of retroviral integration in BXH2 murine myeloid leukemias, encodes a C2H2 zinc finger protein and is overexpressed in these leukemic cells. To investigate a possible role of EVI9 in the human hematopoietic system, we isolated the cDNA clone of the human homologue. Human EVI9, located on the chromosome 2p13 region, contains an open reading frame of 797 amino acids that is 98.7% identical to the mouse protein. RT-PCR analysis of purified human hematopoietic cells showed that EVI9 is expressed in CD34-positive myeloid precursors, B cells, monocytes, and megakaryocytes, but only weakly in T lymphocytes, suggesting that EVI9 may play an important role in hematopoiesis. Furthermore, EVI9 was down-regulated during myeloid differentiation of HL60 cells induced by all-trans-retinoic acid, whereas the expression remained during monocytic differentiation induced by phorbol 12-myristate 13-acetate. These results indicate a distinct role for EVI9 in human hematopoietic cells and suggest that EVI9 may cause leukemia through inhibition of myeloid differentiation.

Defective proliferation of primitive myeloid progenitor cells in patients with severe congenital neutropenia.

Although several mechanisms have been proposed to explain the pathophysiology of severe congenital neutropenia (SCN), the precise defect responsible for SCN remains unknown. We studied the responsiveness of primitive myeloid progenitor cells to hematopoietic factors in 4 patients with SCN. The number of granulocyte-macrophage (GM) colonies formed in patients was decreased in response to granulocyte colony-stimulating factor (G-CSF) in both serum-supplemented and serum-deprived culture. The polymerase chain reaction-single-strand conformational polymorphism analysis of the G-CSF receptor gene showed no variance in structure conformation between the 4 patients and the normal subjects. In patients with SCN, the nonadherent light density bone marrow cells and cells that were purified on the basis of the expression of CD34 and Kit receptor (CD34(+)/Kit(+) cells) showed the reduced response to the combination of steel factor (SF), the ligand for flk2/flt3 (FL), and interleukin-3 (IL-3) with or without G-CSF in serum-deprived culture. Furthermore, when individual CD34(+)/Kit(+) cells from patients were cultured in the presence of SF, FL, and IL-3, with or without G-CSF for 10 days, the number of clones proliferated and the number of cells per each proliferating clone was significantly less than those in normal subjects. These results suggest that primitive myeloid progenitor cells of patients with SCN have defective responsiveness to not only G-CSF, but also the early- or intermediate-acting hematopoietic factors, SF, FL, and IL-3.

Effects of adjunctive balloon angioplasty after intravascular ultrasound-guided optimal directional coronary atherectomy: the result of Adjunctive Balloon Angioplasty After Coronary Atherectomy Study (ABACAS).

OBJECTIVES: This study was conducted to evaluate: 1) the effect of adjunctive percutaneous transluminal coronary angioplasty (PTCA) after directional coronary atherectomy (DCA) compared with stand-alone DCA, and 2) the outcome of intravascular ultrasound (IVUS)-guided aggressive DCA. BACKGROUND: It has been shown that optimal angiographic results after coronary interventions are associated with a lower incidence ofrestenosis. Adjunctive PTCA after DCA improves the acute angiographic outcome; however, long-term benefits of adjunctive PTCA have not been established. METHODS: Out of 225 patients who underwent IVUS-guided DCA, angiographically optimal debulking was achieved in 214 patients, then theywere randomized to either no further treatment or to added PTCA. RESULTS: Postprocedural quantitative angiographic analysis demonstrated an improved minimum luminal diameter (2.88 +/- 0.48 vs. 2.6 +/- 0.51 mm; p = 0.006) and a less residual stenosis (10.8% vs.15%; p = 0.009) in the adjunctive PTCA group. Quantitative ultrasound analysis showed a larger minimum luminal diameter (3.26 +/- 0.48 vs. 3.04 +/- 0.5 mm; p < 0.001) and lower residual plaque mass in the adjunctive PTCA group (42.6% vs. 45.6%; p < 0.001). Despite the improved acute findings in the adjunctive PTCA group, six-month angiographic and clinical results were not different. The restenosis rate (adjunctive PTCA 23.6%, DCA alone 19.6%; p = ns) and target lesion revascularization rate (20.6% vs. 15.2%; p = ns) did not differ between the groups. CONCLUSIONS: With IVUS guidance, aggressive DCA can safely achieve optimal angiographic results with low residual plaque mass, and this was associated with a low restenosis rate. Although adjunctive PTCA after optimal DCA improved the acute quantitative coronary angiography and quantitative coronary ultrasonography outcomes, its benefit was not maintained at six months.

Impact of tranilast on restenosis after coronary angioplasty: tranilast restenosis following angioplasty trial (TREAT).

BACKGROUND: Tranilast is an antiallergic drug that suppresses the release of cytokines such as platelet-derived growth factor, transforming growth factor-beta1, and interleukin-1beta and prevents keloid formation after skin injury. Treatment with this drug reduced the restenosis rate after percutaneous transluminal coronary angioplasty in a preliminary study. METHODS AND RESULTS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial. A total of 255 patients with 289 lesions were randomly assigned to treatment with the oral administration of 600 mg/d tranilast, 300 mg/d tranilast, or a placebo for 3 months after successful angioplasty. Angiographic follow-up was done at 3 months, and a clinical follow-up examination was performed at 12 months. Two hundred ten (72.7%) lesions of 188 (73.7%) of the patients met the criteria and were eligible for the assessment of restenosis. The restenosis rates defined as >/=50% loss of the initial gain were 14.7% in the 600 mg/d tranilast group, 35.2% in the 300 mg/d tranilast group, and 46.5% in the placebo group (P <. 0001 for 600 mg/d tranilast vs placebo). The restenosis rates defined as percent diameter stenosis of >/=50% at follow-up were 17. 6% in the 600 mg/d tranilast group, 38.6% in the 300 mg/d tranilast group, and 39.4% in the placebo group (P =.005 for 600 mg/d tranilast vs placebo). CONCLUSIONS: The oral administration of 600 mg/d of tranilast for 3 months markedly reduced the restenosis rate after percutaneous transluminal coronary angioplasty.

Influence of concomitant miso or NaCl treatment on induction of gastric tumors by N-methyl-N'-nitro-N-nitrosoguanidine in rats.

Six-week old male Sprague-Dawley (CD) rats were treated with 100 ppm N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 16 weeks in their drinking water with control, miso or sodium chloride (NaCl) supplemented diets. All animals were autopsied 12 months after the beginning of the MNNG treatment. Despite higher intake of MNNG in the high dose miso and NaCl groups, the total tumor incidences were decreased compared to middle and lowest values. The glandular stomach adenocarcinoma incidences in the 10% and 5% miso groups were significantly decreased as compared to those in the 2.2% or 1.1% NaCl groups, with the same concentration of NaCl.

Induction of gamma-glutamylcysteine synthetase gene expression by platinum drugs in peripheral mononuclear cells of lung cancer patients.

BACKGROUND: To investigate in vivo the roles of gamma-glutamylcysteine synthetase (gamma-GCS), multidrug resistance-associated protein (MRP), human canalicular multispecific organic anion transporter (cMOAT) and DNA topoisomerase I (topo I) in relation to platinum drug resistance, we monitored the changes of the steady-state levels of the mRNAs for these factors in peripheral mononuclear cells (PMN) after completing platinum drug administration. PATIENTS AND METHODS: PMN from 46 subjects were studied. We obtained PMN from 14 previously untreated lung cancer patients and 14 normal volunteers to measure the baseline gene expression levels. We then obtained PMN from 18 patients with previously untreated advanced lung cancer before and after they received platinum drug treatment. We analyzed the gene expression levels by using the quantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS: There were no differences in the baseline expression levels between normal volunteers and lung cancer patients in any of the genes. After platinum drug administration, the heavy subunit of gamma-GCS (gamma-GCSh) expression level increased 2.5-fold within 24 hours and the increase persisted for a month, whereas the light subunit of gamma-GCS (gamma-GCSl) expression level did not show an early response but had increased after a month. By contrast, the MRP, cMOAT and topo I expression levels were similar before, during and after chemotherapy. CONCLUSIONS: These results suggest that the gene expression levels of both subunits of gamma-GCS play an important in vivo role in platinum drug resistance.