Urethral metastasis from esophageal cancer: symptoms of dysuria and cystoscopic diagnosis.

Urethral malignant tumors are rare and can lead to stenosis, causing dysuria. We report a case of urethral metastasis secondary to esophageal cancer. At the time of diagnosis, a patient with esophageal squamous cell carcinoma presented with voiding difficulties, feeble stream, terminal dribbling and incomplete voiding. The urethral tumor was diagnosed using cystoscopy, and biopsy was thereafter performed. Histopathology of the urethral tumor microscopically resembled to that of esophageal cancer. On immunohistochemistry, the urothelium markers uroplakin 2 and GATA3 were negative in the carcinomatous component; however, GATA3 was detected on the lesion's surface. This case demonstrated that esophageal cancer metastasized to the urethra. Medical oncologists should consider this diagnosis in patients with cancer presenting with dysuria.

Investigation of a Novel S-1 Administration Schedule for Treating Metastatic and Recurrent Breast Cancer (KBCOG13).

BACKGROUND/AIM: S-1, a 5-fluorouracil(5-FU) oral anti-cancer drug, has been traditionally used with a schedule of 4-week oral administration followed by 2-week rest for breast cancer treatment. We, herein, aimed to investigate the clinical efficacy and safety of a schedule of 2-week oral administration followed by 1-week rest for patients with metastatic breast cancer. PATIENTS AND METHODS: We enrolled patients with HER2-negative metastatic breast cancer who had not received prior chemotherapy. S-1 was administered consecutively for 2-weeks followed by a 1-week rest. RESULTS: Between September 1, 2013 and August 31, 2016, 32 patients were enrolled. The median follow-up time was 32.1 months. The median progression-free survival (PFS) was 9.4 months. Overall survival (OS) was 41.0 months, time to treatment failure (TTF) was 7.8 months, response rate (RR) was 31.3%, and disease control rate (DCR) was 78.1%. The incidence of grade 3 side-effects was not high. CONCLUSION: The 3-week schedule of S-1 can be considered useful as a treatment for patients with metastatic breast cancer, helping in maintaining a high quality of life.

Decreased percentage of neutrophil is a predict factor for the efficacy of trifluridine and tipiracil hydrochloride for pretreated metastatic colorectal cancer.

BACKGROUND: The concentration of trifluridine in tumor DNA was strongly correlated with that of white blood cells in tumor-bearing nude mice administered trifluridine-tipiracil (TAS-102). Further, a phase I study of TAS-102 in patients with advanced solid tumors showed a significant correlation between decreased neutrophil count and the area under the concentration-time curve of trifluridine. Herein, we aimed to evaluate the association of decreased neutrophil count with the efficacy of TAS-102. METHODS: We retrospectively analyzed 40 patients with pretreated metastatic colorectal cancer who received TAS-102 at Yodogawa Christian Hospital between June 2014 and May 2018. To evaluate the association between the efficacy of TAS-102 and decreased neutrophil count, patients were grouped into 4 categories according to the decrease of neutrophil count during the first cycle of TAS-102 as follows: Category A, <25%; B, 25% to <50%; C, 50% to <75%; D, ≥75%. RESULTS: The rate of overall survival (OS) was significantly different between Category A and B (median: 4.1 vs. 10.1 months; P=0.04), between Category A and C (median: 4.1 vs. 10.5 months; P=0.04), and between Category A and D (median: 4.1 vs. 15.6 months; P=0.04). In the multivariate analyses, a ≥25% decrease of neutrophils [hazard ratio (HR): 0.28; 95% confidence interval (CI): 0.12-0.72; P=0.01] and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 (HR: 3.79, 95% CI: 1.04-11.2; P=0.04) were independent prognostic factors for OS. CONCLUSIONS: Decreased neutrophil count is a predict factor for the efficacy of TAS-102. TAS-102 treatment may be ineffective in patients with a decreased neutrophil count of <25%.

Risk Analysis for Chemotherapy-induced Nausea and Vomiting (CINV) in Patients Receiving FEC100 Treatment.

BACKGROUND/AIM: Risk factors for chemotherapy-induced nausea and vomiting (CINV) with anthracycline-containing regimen for breast cancer patients remain unknown. The risk factors for CINV with FEC100 were investigated. PATIENTS AND METHODS: Data on CINV events and patient backgrounds of 180 patients were collected from the first cycle of FEC100 treatment. In this regimen, patients were administered various antiemetics (ADs). The combinations of ADs were classified into four categories, while body mass index (BMI) was stratified into three categories. Risk factors were selected based on patient characteristics and combination of ADs. Risks for CINV were analyzed by univariate and multivariate analyses. RESULTS: In the univariate analysis of nausea, BMI was a significant factor, while BMI and combination of ADs were significant in vomiting. In the multivariate analysis concerning nausea, BMI was a significant factor. In the analysis concerning vomiting, the combination of ADs and BMI were significant. CONCLUSION: BMI was the most important risk factor for nausea and vomiting, while the combination of ADs was for vomiting.

Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study).

PURPOSE: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT). METHODS: Asian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ) group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95) or the CTZ group (n = 93) from March 2010 to April 2012, and 180 patients were assessed. All patients received four cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2), followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg) was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR) rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug. RESULTS: This randomized controlled trial indicated that the rates of pCR in CTZ group (14.8%) was doubled to CT group (7.7%), respectively (one-sided chi-square test, p = 0.068), though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.071), and that in patients with triple-negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.112). Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and patients with triple-negative breast cancer. Further investigation is warranted. TRIAL REGISTRATION: University Hospital Medical Information Network. UMIN000003261.

Imatinib mesylate (STI571) enhances amrubicin-induced cytotoxic activity through inhibition of the phosphatidylinositol 3-kinase/Akt pathway in small cell lung cancer cells.

Small cell lung cancer (SCLC) is characterized by autocrine mechanisms. Stem cell factor (SCF) and its receptor c-kit can activate Akt and extracellular signal-regulated kinase (Erk) pathways. Imatinib mesylate (STI571) can inhibit c-kit tyrosine kinase activity, but clinical trials have resulted in failure. We investigated the possibility of SCF/c-kit-targeted therapy against SCLC. Using c-kit-positive SCLC cells (H209 and H69 cells) and SCF as a model of the autocrine mechanisms, the effects of SCF, LY294002, PD98059 or STI571 on Akt and Erk were assessed by Western blot analysis. The cell growth inhibitions of cisplatin, etoposide irinotecan and amrubicin (AMR) with or without SCF, LY294002, PD98059 or STI571 were evaluated by MTT assay. Treatment with SCF activated Akt and Erk and the activations were inhibited by STI571 in H209 but not in H69 cells. LY294002 and PD98059 inhibited SCF-induced Akt and Erk activation in H209 cells, respectively. STI571 alone did not exert growth inhibition in the SCF-treated cells. In H209 cells, SCF decreased the cytotoxicity of AMR, but not of other drugs. In H69 cells, SCF did not affect sensitivity to any drugs. LY294002 but not PD98059 restored or enhanced AMR-sensitivity in SCF-treated H209 or untreated H69 cells, respectively. STI571 restored the AMR-sensitivity of SCF-treated H209 cells to the basal level. If the SCF/c-kit contributes to Akt activation in vivo, the combination of STI571 and AMR may be effective against SCLC. Additionally, using a combination of AKT inhibitors and AMR may be a promising treatment in the future.

Expression of functional leukotriene B4 receptors on human airway smooth muscle cells.

BACKGROUND: Leukotriene B4 (LTB4) increases in induced sputum and exhaled breath condensate in people with asthma. Furthermore, the T(H)2-type immune response and airway hyperresponsiveness induced by ovalbumin sensitization is markedly suppressed in LTB4 receptor (BLT) 1 null mice. These studies suggest that LTB4 may contribute to asthma pathophysiology. However, the direct effects of LTB4 on human airway smooth muscle (ASM) have not been studied. OBJECTIVES: We sought to determine the expression of LTB4 receptors on human ASM and its functional role in mediating responses of human ASM cells, and the effect of LTB4 on these cells. METHODS: Immunohistochemistry, RT-PCR, Western blotting, and flow cytometry were used to determine the expression of LTB4 receptors. To determine the effect of LTB4 on human ASM cells, cell proliferation was assessed by counting cells, and chemokinesis was assessed by gold particle phagokinesis assay. RESULTS: We confirmed expression of both BLT1 and BLT2 in human ASM cells in bronchial tissue and in cell culture. LTB4 markedly induced cyclin D1 expression, proliferation, and chemokinesis of human ASM cells. LTB4 also induced phosphorylation of both p42/p44 mitogen-activated protein kinase (MAPK) and downstream PI3 kinase effector, Akt1. However, we observed no induction of c-Jun N-terminal kinase or p38 MAPK. Notably, LTB4-induced migration and proliferation of ASM cells were inhibited by the BLT1 specific antagonist, U75302, and by inhibitors of p42/p44 MAPK phosphorylation (U1026), and PI3 kinase (LY294002). CONCLUSIONS: These observations are the first to suggest a role for a LTB4-BLT1 signaling axis in ASM responses that may contribute to the pathogenesis of airway remodeling in asthma.

UFT plus vinorelbine in advanced non-small cell lung cancer: a phase I and an elderly patient-directed phase II study.

PURPOSE: The combination of tegafur-uracil (UFT) with vinorelbine has provided synergistic activity against non-small cell lung cancer (NSCLC) in experimental models. The recommended dose of UFT in combination with vinorelbine in NSCLC was determined in a phase I study. The phase II study evaluated efficacy and tolerability of this combination in elderly patients. METHODS: Vinorelbine was infused on days 1 and 8, and UFT was administered twice daily on days 2 to 6 and days 9 to 13 of a 3-week cycle. UFT and vinorelbine were increased during the phase I study from 400 to 600 mg/d and 20 to 25 mg/m(2), respectively, in 12 patients. In the phase II portion, previously untreated elderly patients were treated with 600 mg/d UFT and 20 mg/m(2) vinorelbine. RESULTS: At the dose level of 600 mg/d UFT and 25 mg/m(2) vinorelbine, dose-limiting toxicity of neutropenia or neutropenic fever was observed in two of three patients, determining the recommended dose of 600 mg/d UFT and 20 mg/m(2) vinorelbine. In 30 evaluable elderly patients of the phase II study, the response rate was 27% (8/30). The median survival and progression-free survival time was 11.8 (range 2.7-34.8) and 5.0 (range 0.5-32.5) months, respectively. Grade 3 or grade 4 neutropenia and grade 3 anemia occurred in 40% and 7% of phase II patients, respectively. Gastrointestinal toxicity was frequent but mild. As the most serious toxicity, pneumonitis was observed in three patients. CONCLUSION: This combination of UFT and vinorelbine is both feasible and active in the treatment of elderly patients with advanced NSCLC.

Synergistic cell growth inhibition by the combination of amrubicin and Akt-suppressing tyrosine kinase inhibitors in small cell lung cancer cells: implication of c-Src and its inhibitor.

Small cell lung cancer (SCLC) is one of the intractable malignancies. The goal of this study was to clarify whether Akt activity is involved with chemo-resistance and to improve the sensitivity of SCLC cells to the current standard chemotherapeutic drugs with agents that are expected to suppress Akt activity through tyrosine kinase inhibition. Although Akt activity seemed to be involved with the sensitivity of SCLC cells to chemotherapeutic agents (cisplatin, etoposide, SN38 and amrubicin), in Akt-activated N417 cells, only amrubicin exerted synergistic cell growth inhibition when combined with an Akt inhibitor, LY294002. A non-specific tyrosine kinase inhibitor, genistein, suppressed Akt and showed synergistic interaction in combination with amrubicin in N417 cells. Among tyrosine kinases (insulin-like growth factor I receptor, c-Kit and c-Src), only c-Src was activated in N417 cells compared with Akt-inactive H209 cells. A c-Src-specific inhibitor, PP2, and a clinically available multi-tyrosine kinase inhibitor, dasatinib, suppressed Akt activity in parallel with c-Src inhibition. Both PP2 and dasatinib exerted synergistic growth inhibition of N417 cells in the combination with amrubicin. In immunohistochemical analysis, c-Src was expressed in 17 of 19 of the SCLC tumor tissues. These observations suggested that Akt suppression enhances the cytotoxicity of amrubicin, and for the purpose of Akt suppression, c-Src is a promising target in SCLC.

Sequential treatment with SN-38 followed by 5-fluorouracil shows synergistic cytotoxic activity in small cell lung cancer cells.

Despite the high response rates of small cell lung cancer (SCLC) to first-line cisplatin-based chemotherapies, most patients with SCLC will eventually experience disease progression. Accordingly, novel chemotherapeutic regimens are desired. This in vitro study was carried out in order to develop novel chemotherapeutic regimens containing 5-fluorouracil (5-FU) or oral fluoropyrimidine for SCLC. 5-FU was combined with other standard drugs for SCLC (cisplatin, etoposide, an active metabolite of irinotecan and amrubicin) in different schedules. The combination effects were analyzed by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and an isobologram method using H69 SCLC cells. Among the examined combinations, synergistic growth inhibition was observed only when H69 cells were treated with 7-ethyl-10-hydroxycamptothecin (SN-38; an active metabolite of irinotecan) followed by 5-FU. The findings of a flow cytometric analysis were consistent with the enhancement of apoptotic cell death by this sequential treatment. This synergism was observed in 4 out of 5 SCLC cell lines tested. The effects of 5-FU and SN-38 on thymidylate synthase (TS) protein expression, an important determinant of 5-FU sensitivity, were assessed by Western blot analysis in H69 cells. Treatment with SN-38 for 24 h suppressed TS protein expression and this low level of TS was maintained for at least 72 h. Pretreatment with SN-38 inhibited the 5-FU-induced increase of TS protein. The synergistic effect induced by the combination of SN-38 and 5-FU may be attributable to the SN-38-induced suppression of TS protein. Furthermore, uracil and 5-chloro-2,4-hydroxypyridine, which are clinically available dihydropyrimidine dehydrogenase inhibitors, enhanced 5-FU-induced growth inhibition. These observations provide evidence supporting the clinical applications of the combination chemotherapy using irinotecan and 5-FU or oral fluoropyrimidines against SCLC.

Dexamethasone interferes with trastuzumab-induced cell growth inhibition through restoration of AKT activity in BT-474 breast cancer cells.

The combination of trastuzumab with paclitaxel (PTX) is an important option for the treatment of HER2-positive breast cancer. Dexamethasone (Dex) premedication is routinely used in the treatment with PTX. The interactions among Dex, PTX and trastuzumab were evaluated in BT-474 cells. Dex interfered with trastuzumab-induced cell growth inhibition without clear effects on PTX-induced cytotoxicity. Trastuzumab dephosphorylated retinoblastoma protein (pRB). Dex restored this trastuzumab-induced dephosphorylation of pRB and released trastuzumab-induced G1 arrest. Trastuzumab suppressed AKT activity without affecting ERK activity. A specific inhibitor for the phosphatidylinositol 3-kinase/AKT pathway, LY294002, inhibited cell growth and AKT and pRB phosphorylation. Dex restored the trastuzumab-induced suppression of AKT without affecting ERK activity. It was concluded that Dex interferes with trastuzumab-induced cell growth inhibition, at least partially, through the restoration of trastuzumab-induced AKT suppression and subsequent pRB dephosphorylation in BT-474 breast cancer cells. These observations support the development of new chemotherapeutic regimens without glucocorticoid premedication.

Severe toxicities after irinotecan-based chemotherapy in a patient with lung cancer: a homozygote for the SLCO1B1*15 allele.

Irinotecan is used widely in the treatment of several malignancies, but unpredictable severe toxicities such as myelosuppression and delayed-type diarrhea are sometimes experienced. Polymorphism of the UGT1A1 gene is one of the likely reasons for interindividual differences in irinotecan pharmacokinetics and severe toxicity. Also, polymorphic organic anion-transporting polypeptide 1B1 (OATP1B1, SLCO1B1) is reported to be involved in the hepatocellular uptake of SN-38. A 61-year-old man with lung cancer developed severe toxicities, including grade 3 diarrhea, grade 4 leukopenia, and grade 4 neutropenia, after the first cycle of irinotecan (60 mg/m) plus cisplatin chemotherapy. The irinotecan and SN-38 areas under the concentration-time curve from time zero to infinity in this patient were 43% and 87% higher than the corresponding mean values for 10 other patients with lung cancer treated with irinotecan (60-100 mg/m) normalized for the dose of irinotecan. Analysis of genetic variants in genes encoding the drug-metabolizing enzyme (UGT1A1) and transporter (SLCO1B1) involving irinotecan disposition revealed that this patient was homozygous for the SLCO1B1*15 allele, which may result in severe toxicities attributable to the extensive accumulation of SN-38. Screening of SLCO1B1*15 is suggested to be useful in irinotecan chemotherapy to avoid unpredicted severe toxicity, although the homozygous genotype is rare among the Japanese.

Dexamethasone inhibits paclitaxel-induced cytotoxic activity through retinoblastoma protein dephosphorylation in non-small cell lung cancer cells.

Paclitaxel is used frequently for the treatment of patients with non-small cell lung cancer. Hypersensitivity reactions remain one of the major adverse events in the clinical use of paclitaxel. Glucocorticoids are used to prevent these adverse events. This study was carried out in order to clarify the effect of glucocorticoids on paclitaxel-induced cytotoxity of cancer cells. Pretreatment with 10 microM of dexamethasone inhibited ERK activation and subsequent retinoblastoma protein (pRB) phosphorylation, and reduced sensitivity to paclitaxel in A549 cells. Then, we utilized ERK (PD98059) and AKT (LY294002) inhibitors. PD98059 and LY294002 effectively suppressed pRB phosphorylation in A549 cells. Dexamethasone (10 microM) suppressed ERK activity as well as PD98059, although it did not affect AKT activity. Furthermore, the combinations of paclitaxel with PD98059 or LY294002 were similarly antagonistic. Our observation in this study raised the possibility that dexamethasone pretreatment antagonizes paclitaxel-induced cytotoxicity through ERK suppression and pRB dephosphorylation. These observations support the development of new generation taxane-based chemotherapy without glucocorticoid premedication.

Lung cancer arising in association with middle lobe syndrome.

Middle lobe syndrome, caused mainly by benign inflammatory diseases, such as chronic bronchitis and bronchiectasis, is manifested clinically as a chronic cough with sputum production. The prognosis associated with this syndrome is considered good in most cases which are caused by chronic inflammatory diseases. A patient who developed lung cancer in the course of long-term treatment for right middle lobe syndrome is described. A 63-year-old woman was admitted to our hospital with complaints of right iliac bone pain. She had been treated for chronic bronchitis and bronchiectasis associated with middle lobe syndrome for 16 years before admission. Work-up of a lung adenocarcinoma originating from the right middle lobe disclosed bone metastasis to the illium. Tumorigenesis in association with middle lobe syndrome has not yet been reported, but this first reported case suggests the need to be alert to the possibility.

The influence of granisetron on the pharmacokinetics and pharmacodynamics of docetaxel in Asian lung cancer patients.

BACKGROUND: Docetaxel, which undergoes hepatic metabolism via cytochrome P450 3A4, is a promising anticancer agent. Toxicity is serious problem, however, because it is difficult to predict the cytochrome P450 3A4 activity of the drug. Moreover, drug-drug interactions involving cytochrome P450 3A4 enzymes are important. Granisetron, a selective antagonist of the 5-hydroxytryptamine3 receptor, also undergoes hepatic metabolism via cytochrome P450 3A4. In this study, we investigated the influence of granisetron on the pharmacokinetics and pharmacodynamics of docetaxel in Asian patients with lung cancer. METHODS: Six patients with advanced lung cancer were treated with doses of docetaxel (60 mg/m2). In the first course of treatment, no antiemetic agents were administered. In the second course, all patients received 3.0 mg of granisetron before 30-minute administration of docetaxel. In each of the treatment courses, blood samples (5 mL) were obtained for pharmacokinetic study at the following times: 0, 0.5, 1.5, 2.0, 3.0, 5.0, 8.0, and 24 hours after the start of the docetaxel infusion. RESULTS: Six patients were enrolled in this pharmacokinetics study. The mean +/- SD systemic clearance of docetaxel administered alone or in combination with granisetron was 32.9 +/ - 8.3 and 28.2 +/- 5.9, respectively. The area under the concentration-versus-time curve of plasma docetaxel (alone or in combination with granisetron) ranged from 1.355 to 2.773 and 1.647 to 3.079 microg x h/mL (mean +/- SD: 1.936 +/- 0.541 and 2.219 +/- 0.510 microg x h/mL), respectively. There was no significant difference in mean residence time (or invariance of residence time) between the single dose of docetaxel and the combination of docetaxel and granisetron. DISCUSSION: We found no significant difference in the pharmacokinetic and pharmacodynamic parameters of docetaxel between the single dose of docetaxel and the combination of docetaxel and granisetron. However, a wide interindividual variation existed in cytochrome P450 3A4 activity. It is clear that the results of the present study should be confirmed in a population study involving a larger number of subjects addressing the genetic variations of drug metabolizing enzymes, drug receptors, and drug transporters.

Des-gamma-carboxy prothrombin (PIVKA-II)-producing mediastinal embryonal carcinoma with features of hepatoid differentiation.

The case of a 48-year-old man with primary nonseminomatous embryonal carcinoma at the posterior mediastinum is described. The patient displayed extremely high plasma levels of Des-gamma-carboxy prothrombin (PIVKA-II) (4040 mAU/ml). Ultrasonography and dynamic computed tomography ruled out hepatocellular carcinoma (HCC) or liver metastasis. After preoperative systemic chemotherapy, total tumor resection was performed. Postoperatively, the plasma levels of PIVKA-II returned to within the normal range (24 mAU/ml). An immnohistochemical study using anti-PIVKA-II monoclonal antibody revealed the cytoplasmic expression of PIVK4-II in the carcinoma cells. These results indicate that tumor cells, which are manifested as hepatoid differentiation, may produce PIVKA-II. This case seems to be the first case reported in which PIVKA-II was produced by nonseminomatous mediastinal embryonal carcinoma without HCC or liver metastasis.

Suppression of phosphatidylinositol 3-kinase/Akt signaling pathway is a determinant of the sensitivity to a novel histone deacetylase inhibitor, FK228, in lung adenocarcinoma cells.

A novel histone deacetylase inhibitor, FK228, is a promising anticancer agent and has been proposed to modulate intracellular signaling, in addition to regulating gene transcription. We evaluated the effect of this agent on Akt-mediated signaling in relation to its cytotoxic activity using lung adenocarcinoma cell lines. Based on MTT assay and the appearance of cleaved poly (ADP-ribose) polymerase (PARP), we regarded A549 and PC14 cells as relatively sensitive and resistant cell lines, respectively. In A549 cells, FK228 suppressed the phosphorylation of Akt at Ser-473 and glycogen synthase kinase-3 without affecting these protein levels, indicating inhibition of the Akt-mediated signaling pathway. On the other hand, in PC14 cells, these biochemical reactions were not detected after treatment with FK228. The combination of FK228 and a phosphatidylinositol 3-kinase (PI3K)/Akt pathway inhibitor, LY294002, was determined to be synergistically cytotoxic in PC14 cells by isobologram analysis. This synergistic effect was attributable to the enhancement of apoptosis, as judged by flow cytometric analysis, and the appearance of cleaved PARP. The combination of FK228 with UCN-01, another PI3K/Akt pathway inhibitor, also exerted a synergistic effect. We concluded that FK228 suppresses the PI3K/Akt signaling pathway in a cell-specific manner, and this effect is a determinant of sensitivity to FK228.

Loss of imprinting of PEG1/MEST in lung cancer cell lines.

Paternally expressed imprinted gene 1/mesoderm-specific transcript (PEG1/MEST) is an imprinted gene expressed from the paternal allele. Recently, frequent loss of imprinting (LOI) of PEG1/MEST has been reported in lung adenocarcinomas. It is suggested that the LOI may be involved in pathogenesis of lung adenocarcinoma. In the present study, incidence of LOI of PEG1/MEST was examined in lung cancer cell lines, including small cell lung cancer (SCLC). Among 50 cell lines tested, 20 cell lines were heterozygous for the AflIII site of the PEG1/MEST gene. In these heterozygotes, biallelic expression was observed in 9 cell lines (45%), monoallelic in 11 (55%). In cell lines of non-small cell lung cancer (NSCLC), 62% (8 of 13) exhibited biallelic expression. In SCLC, only 1 of 7 cell lines (14%) showed biallelic expression. LOI of PEG1/MEST in the NSCLC cell line is significantly frequent compared with that in SCLC cell lines (p=0.043). This result supports the possibility that LOI may be related to tumorigenesis and malignant transformation, especially in NSCLC.