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Biomedical subjects

Takehiko Fujisawa

Publications and source records attributed to Takehiko Fujisawa.

At least 19 recordsLinked to original sources
PubMed2006

Methylation and gene silencing of the Ras-related GTPase gene in lung and breast cancers.

BACKGROUND: RRAD, a small Ras-related GTPase, is highly expressed in human skeletal muscle, lung, and heart. Although loss of expression of RRAD in breast cancer cells has been reported and it may act as an oncogene, the mechanism of silencing is unknown. METHODS: We examined (1) mRNA expression of RRAD in lung and breast cancer cell lines using RT-PCR and (2) methylation status of lung and breast cancers. RESULTS: Loss of RRAD expression was found in 14 of 20 (70%) NSCLC cell lines, 11 of 11 (100%) SCLC cell lines, and 8 of 10 (80%) breast cancer cell lines; expression was not affected in normal bronchial and mammary epithelial cells. Treatment of 23 expression-negative cell lines with a demethylating agent restored expression in all cases. We developed a methylation-specific assay from the analysis of bisulfite sequencing of the 5' region of RRAD in expression-negative and positive cell lines, which resulted in good concordance between methylation and expression. Primary lung and breast cancers showed hypermethylation in 89 of 214 (42%) and 39 of 63 (62%) cases, respectively. RRAD hypermethylation correlated with smoking history and poorer prognosis in lung adenocarcinomas. CONCLUSIONS: We conclude that epigenetic silencing of RRAD is a frequent event in lung and breast cancers, and analysis of it may provide novel opportunities for prognosis and therapy of these cancers.

Adenocarcinoma↗
PubMed2006

A phase I study of in vitro expanded natural killer T cells in patients with advanced and recurrent non-small cell lung cancer.

PURPOSE: Human Valpha24 natural killer T (Valpha24 NKT) cells bearing an invariant Valpha24JalphaQ antigen receptor are activated by a glicolipid ligand alpha-galactosylceramide (alphaGalCer; KRN7000) in a CD1d-dependent manner. The human Valpha24 NKT cells activated with alphaGalCer and interleukin-2 have been shown to produce large amounts of cytokines, such as IFN-gamma, and also exerting a potent killing activity against various tumor cell lines. We did a phase I study with autologous activated Valpha24 NKT cell therapy. EXPERIMENTAL DESIGN: Patients with advanced or recurrent non-small cell lung cancer received i.v. injections of activated Valpha24 NKT cells (level 1: 1 x 10(7)/m2 and level 2: 5 x 10(7)/m2) to test the safety, feasibility, and clinical response of this therapeutic strategy. Immunomonitoring was also done in all cases. RESULTS: Six patients were enrolled in this study. No severe adverse events were observed during this study in any patients. After the first and second injection of activated Valpha24 NKT cells, an increased number of peripheral blood Valpha24 NKT cells was observed in two of three cases receiving a level 2 dose of activated Valpha24 NKT cells. The number of IFN-gamma-producing cells in peripheral blood mononuclear cells increased after the administration of activated Valpha24 NKT cells in all three cases receiving the level 2 dose. No patient was found to meet the criteria for either a partial or a complete response. CONCLUSIONS: The clinical trial with activated Valpha24 NKT cell administration was well tolerated and carried out safely with minor adverse events even in patients with advanced diseases.

Adult↗
PubMed2006

Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis.

The distinction between pulmonary large cell neuroendocrine carcinoma and small cell carcinoma is difficult in some cases. Some propose that these carcinomas should be classified as one high-grade neuroendocrine carcinoma. We examined biological features of small cell carcinoma (n=23), large cell neuroendocrine carcinoma (n=17), and classic large cell carcinoma (n=12). The average ratio of nuclear diameter of the tumor cells to that of lymphocytes for small cell carcinoma was smaller than that for large cell neuroendocrine carcinoma (P<0.0001). The frequencies of the expressions of CD56, mASH1, TTF-1, and p16 were higher and that of NeuroD was lower in small cell carcinoma than in large cell neuroendocrine carcinoma. The frequency of loss of heterozygosity at 3p was higher in high-grade neuroendocrine carcinomas than in classic large cell carcinoma (P=0.0002). Allelic losses at D5S422 (5q33) were more frequent in small cell carcinoma than in large cell neuroendocrine carcinoma (P=0.0091). Mean fractional regional loss indices of the tumors were 0.38, 0.65, and 0.72 for patients with classic large cell carcinoma, large cell neuroendocrine carcinoma, and small cell carcinoma, respectively (P=0.0003). Five-year overall survivals of patients with classic large cell carcinoma, large cell neuroendocrine carcinoma and small cell carcinoma in stage I were 67, 73, 60%, respectively. Patients with NeuroD expression had better survivals, and those with p63 expression had poorer survivals in large cell neuroendocrine carcinoma. Patients with TTF-1 expression had poorer survivals in small cell carcinoma. Our data suggest that large cell neuroendocrine carcinoma and small cell carcinoma are different morphologically, phenotypically, and genetically, although there are some overlapping features. Although further studies are needed to analyze the biological behavior of high-grade neuroendocrine carcinomas including sensitivity to chemotherapy, the pathological distinction of large cell neuroendocrine carcinoma from small cell carcinoma may be necessary to treat the patients with neuroendocrine tumors.

Basic Helix-Loop-Helix Proteins↗
PubMed2006

Natural killer T cell-mediated antitumor immune responses and their clinical applications.

A unique lymphocyte population, CD1d-restricted NKT cells, has been revealed to be a key player in both the innate and acquired immune responses, including antitumor effects. Recent studies revealed that at least two subsets of CD1d-restricted NKT cells exist: type I, having invariant Valpha14 receptor; and type II, having heterogeneous non-Valpha14 receptor. The specific glycolipid ligand, alpha-GalCer, effectively stimulates mouse and human type I NKT cells. The activation of type I NKT cells substantially influences function of other various cell types, particularly DC, NK cells, CD4 Th1 cells, and CD8 cytotoxic T cells, all contributing to the antitumor immune responses. Recent studies also indicated that, unlike type I NKT cells, type II NKT cells have a potential to repress antitumor immune responses. In this review, we summarize the characteristics of the antitumor immune responses mediated by both mouse and human CD1d-restricted NKT cells and discuss their potential in clinical applications against cancer.

Animals↗
PubMed2006

Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer.

BACKGROUND: Both genetic and epigenetic changes in nonsmall cell lung cancer (NSCLC) are known to be a common event. METHODS: Mutations in the epidermal growth factor receptor gene (EGFR), HER-2, and KRAS and the methylation profile of 9 genes for NSCLC were analyzed and correlated with clinical and histologic data. RESULTS: Thirty-nine EGFR, 4 HER-2, and 6 KRAS mutations were found in 150 NSCLC cases, with the methylation percentages of the genes ranging from 13% to 54%. Most mutations were present in adenocarcinomas, but mutations of the 3 genes were never found to be present in individual tumors. The frequency of methylation for all the genes was correlated with the Methylation Index, a reflection of the overall methylation pattern (all genes, P< or = .01), supporting the presence of the CpG island methylator phenotype (CIMP) in NSCLC. On the basis of the methylation profile, CRBP1 and CDH13 methylation were good indicators of CIMP in NSCLC, and were correlated with a poorer prognosis in adenocarcinomas. Mutations in EGFR, HER-2, and KRAS were found to be present exclusively, whereas methylation tended to be present synchronously. A comparison of mutation and methylation demonstrated that the EGFR mutation had an inverse correlation with methylation of SPARC (secreted protein acidic and rich in cysteine), an extracellular Ca2+-binding matricellular glycoprotein associated with the regulation of cell adhesion and growth, and the p16INK4A gene. CONCLUSIONS: The findings of the current study suggest that adenocarcinoma cases with CIMP have a poorer prognosis than adenocarcinoma cases without CIMP, and the EGFR mutation was shown to have an inverse correlation with methylation of SPARC and the p16INK4A gene in NSCLC.

Adult↗
PubMed2006

Does perioperative high-dose prednisolone have clinical benefits for generalized myasthenia gravis?

OBJECTIVE: The purpose of this study was to clarify the clinical benefits of perioperative administration of high-dose prednisolone (PSL) combined with extended thymectomy on the long-term outcomes of 116 consecutive patients with generalized myasthenia gravis (MG). METHODS: A retrospective review was conducted on 116 patients diagnosed with generalized MG who received alternate-day oral administration of high-dose PSL (100 mg/alternate days) and had undergone transsternal extended thymectomy. Incidences of postoperative myasthenic crisis, adverse effects of steroid, long-term outcomes, such as complete stable remission (CSR), pharmacologic remission (PR) or improvement (Imp), and disease recurrence after CSR were evaluated. RESULTS: Six patients (5.2%) experienced post-thymectomy myasthenic crisis. Crude cumulative CSR and PR + CSR rates were 44.8 and 62.7%, respectively. Life table analysis showed that 41.8, 52.8 and 63.4% of the patients were in CSR at 3, 5 and 10 years, respectively. Multivariate analysis revealed that age and pretreatment classification according to the Myasthenia Gravis Foundation of America (MGFA) criteria tended to be independent predictors of CSR. There were 6.9% with compressive vertebral fracture, 13.8% with cataract, and 5.2% with steroid-induced diabetes. Life table analysis revealed that recurrence rates after CSR were 36.8 and 46.0% at 3 and 5 years, respectively. Patients with thymoma had a significantly higher rate of recurrence than those without thymoma (p = 0.001). CONCLUSIONS: Alternate-day administration of high-dose prednisolone reduced the risk of post-thymectomy myasthenic crisis. Presence of thymoma was a risk factor for MG recurrence after CSR.

Adult↗
PubMed2006

Spontaneous regression of bone metastasis from renal cell carcinoma; a case report.

BACKGROUND: Spontaneous regression of metastatic renal cell carcinoma is rarely observed. CASE PRESENTATION: Metastatic renal cell carcinoma was identified in a 70-year-old male using computed tomography-guided percutaneous needle biopsy. Two months after the diagnosis, a partial resection of the sternal bone was performed. Pathological examination revealed granulated tissue with bleeding and necrosis but no carcinogenic cells. CONCLUSION: We report a pathologically identified case in which a sternal bone metastasis that was noticed two years after radical nephrectomy regressed completely and spontaneously.

Aged↗
PubMed2006

Characteristics of tumor extension requiring bronchoplasty and pneumonectomy in patients with lung cancer and positive bronchoscopic findings.

PURPOSE: The characteristics of tumor extension determine whether pneumonectomy or lobectomy with bronchoplasty should be performed for central lung cancer. We investigated how the characteristics of tumor extension determined the operative methods and the surgical outcomes. METHODS: We conducted a retrospective chart review of 151 patients with positive bronchoscopic findings who underwent lung cancer operations between January 1995 and March 2002. Twenty-five patients underwent pneumonectomy, 88 underwent lobectomy/segmentectomy (Lob/Seg), and 38 underwent Lob/Seg with bronchoplasty. RESULTS: Pathologic staging was higher in the pneumonectomy group than in the Lob/Seg groups, with or without bronchoplasty (P = 0.002). Interlobar extension and hilar lymph node involvement were more frequent, and mucosal invasion was less frequent, in the pneumonectomy group than in the Lob/Seg with bronchoplasty group. The frequencies of all specific pulmonary complications and 30-day mortality were similar among the three groups. The 5-year overall survival rates were 23.7%, 51.5%, and 72.8% for the pneumonectomy, Lob/Seg, and Lob/Seg with bronchoplasty groups, respectively (P = 0.0004). There was a significant difference in survival between patients with mucosal and those with submucosal types of lung cancer (P = 0.0114). CONCLUSIONS: Lob/Seg with bronchoplasty was feasible without a higher risk of operative complications or poorer long-term survival. The nature of tumor extension was important in the selection of operative methods and in predicting survival.

Aged↗
PubMed2006

Dose-volume factors predicting radiation pneumonitis in patients receiving salvage radiotherapy for postlobectomy locoregional recurrent non-small-cell lung cancer.

BACKGROUND: The correlation between treatment-related factors and lung toxicity has not been sufficiently evaluated in salvage radiotherapy. METHODS: Twenty-one patients with recurrent non-small-cell lung cancer (NSCLC) after lobectomy received salvage radiotherapy to a total dose of 46-60 Gy. The effects of radiotherapy parameters on the development of radiation pneumonitis (RP) were examined using dose-volume histograms. RESULTS: Grade 1 RP was observed in 4, grade 2 in 2, and grade 3 in 1 patient. Patients who developed RP had a significantly higher value in V dose (V13, V20) parameters and mean lung dose (MLD) than those who did not develop RP. Concerning G2 or higher RP, 3 patients who developed > or = G2 RP had a significantly higher value in V20, V13, and MLD than the remaining patients with P values of 0.01, 0.015, and 0.016, respectively. The mean V20, V13, and MLD in these 3 patients were 27%, 29.3%, and 14.8 Gy, respectively, whereas the mean V20, V13, and MLD in the remaining 18 patients were 15.8%, 18.3%, and 8.8 Gy, respectively. Three of 6 patients with a V20 > or = 20% developed > or = G2 RP whereas this did not occur in the remaining patients (P = 0.015). Similarly, 3 of 6 patients with a V13 > or = 23% developed > or = G2 RP whereas this did not occur in the remaining patients (P = 0.015). CONCLUSIONS: These data suggest that a somewhat lower V dose value or MLD, as compared with the setting of definitive radiotherapy, could be a surrogate for RP in patients undergoing salvage radiotherapy for recurrent NSCLC.

Aged↗
PubMed2006

Prediction of prognosis and surgical indications for pulmonary metastasectomy from colorectal cancer.

BACKGROUND: Treatment of pulmonary metastases from colorectal cancer by excision has increased rapidly, but reports on indications and prognostic factors are inconsistent. We sought to identify poor prognostic factors preoperatively and to retrospectively evaluate preoperative clinical indications for surgery. METHODS: A total of 75 patients with colorectal cancer had pulmonary metastases excised from 1986 to 2003. Tumor size, number, laterality, hilar or mediastinal lymphadenopathy, and carcinoembryonic antigen level were possible risk factors for metastatic tumors, with primary site of colorectal tumor, disease-free interval, and hepatectomy for liver metastasis possible risk factors for primary tumors. Prognostic factors in univariate and multivariate analyses also included age and sex. RESULTS: Five-year survival rates were 41.3% after pulmonary excision and 73.1% after primary colorectal resection. Three factors identified as significant by univariate log-rank test for overall survival after pulmonary resection were carcinoembryonic antigen (p < 0.0001), tumor laterality (p = 0.0205), and number of pulmonary metastases (p = 0.0028). Multivariate analysis found that carcinoembryonic antigen, tumor number, tumor size, and patient's age were also independent prognostic factors. In contrast, carcinoembryonic antigen, number of metastases, and disease-free interval predicted prognosis after primary colorectal resection. Prior hepatectomy for metastases did not influence prognosis after pulmonary metastasectomy. CONCLUSIONS: Elevated carcinoembryonic antigen level and multiple metastases are preoperative predictors of poor prognosis after resection of pulmonary metastases from colorectal cancer. Survival rate is sufficient to justify pulmonary metastasectomy if there is no local or distant metastatic lesion other than in the liver; if needed, sequential pulmonary and hepatic metastasectomy can be performed.

Adenocarcinoma↗
PubMed2006

Long-term management of polychondritis with serial tracheobronchial stents.

A 56-year-old woman was referred to our hospital for airway compromise. Relapsing polychondritis was diagnosed by bronchial cartilage biopsy. Bronchoscopy showed tracheobronchial malacia due to the disappearance of bronchial cartilage as a result of chondritis. Stent insertion using a Dynamic stent (Rüsch; Kernen, Germany), Ultraflex stent (Boston Scientific International, Colombes, France) and TM stent (Fuji Systems Corp, Tokyo, Japan) was repeated for more than 7 years. Dramatic improvement of dyspnea was obtained each time. The patient survived during this period without oxygen inhalation or mechanical ventilation before she suddenly died due to suffocation caused by difficulty of sputum discharge.

Airway Obstruction↗
PubMed2006

Prospective study of adjuvant chemotherapy for pulmonary large cell neuroendocrine carcinoma.

BACKGROUND: Patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) have a very poor prognosis, but the benefit of adjuvant chemotherapy for these patients has not been established. We performed a prospective analysis of adjuvant chemotherapy for patients with completely resected pulmonary LCNECs to assess the effect of adjuvant chemotherapy. METHODS: The adjuvant mixture consisted of cisplatin and VP-16 and was administered after surgery to 15 patients with LCNECs from 2000 to 2005. We compared patient survival with historical data for LCNEC patients treated without platinum-based adjuvant chemotherapy after surgery. RESULTS: There were no differences in age, gender, surgical methods, and staging between the adjuvant chemotherapy group and the control group. Median follow-up was 33 months for the adjuvant group and 42 months for the control group. Of the 15 patients in the adjuvant chemotherapy group, 2 patients had disease recurrence and 1 died of interstitial pneumonia. The overall survival rate at 2 and 5 years of patients with adjuvant chemotherapy was 88.9%. The overall survival rate between patients with adjuvant chemotherapy and the historical control group was significantly different. CONCLUSIONS: Adjuvant chemotherapy consisting of cisplatin and VP-16 after surgery appears promising for the improvement of the prognosis for patients with completely resected LCNECs, and it should be evaluated further in larger multi-institutional trials.

Aged↗
PubMed2006

Prognostic impact of large cell neuroendocrine histology in patients with pathologic stage Ia pulmonary non-small cell carcinoma.

BACKGROUND: Most patients with pathologic stage Ia non-small cell lung carcinoma have a good prognosis, and adjuvant chemotherapy is currently not being used in the management of this stage of the disease. However, if significant negative prognostic factors become evident in patients with pathologic stage Ia non-small cell lung carcinoma, patients with negative prognostic factors should have adjuvant treatment after surgery. METHODS: We analyzed 335 cases of pathologic stage Ia non-small cell lung carcinoma treated between 1988 and 2003 by complete resection. The pathologic stage Ia non-small cell lung carcinomas comprised 259 adenocarcinomas, 65 squamous cell carcinomas, and 11 large cell neuroendocrine carcinomas. The prognostic impact of various clinical variables was investigated by the Cox proportional hazards multivariable regression model. RESULTS: Univariate analysis showed that large cell neuroendocrine carcinoma histology, old age, large tumor size, male gender, and smoking predicted poorer overall survival. Large cell neuroendocrine carcinoma had a significantly poorer prognosis than other non-small cell carcinomas. Multivariate analysis revealed that large cell neuroendocrine carcinoma was predictive of poorer overall survival (P = .0200, hazard ratio 2.787). CONCLUSIONS: Large cell neuroendocrine histology has a significant adverse prognostic impact on pathologic stage Ia non-small cell carcinoma. Therefore, surgical resection alone represents insufficient treatment for large cell neuroendocrine carcinoma, even for pathologic stage Ia disease.

Adenocarcinoma↗
PubMed2006

Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer.

STUDY OBJECTIVES: To perform a prospective comparison of direct real-time endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA), positron emission tomography (PET), and thoracic CT for detection of mediastinal and hilar lymph node metastasis in patients with lung cancer considered for surgical resection. DESIGN: Prospective patient enrollment. SETTING: University teaching hospital. PATIENTS: One hundred two potentially operable patients with proven (n = 96) or radiologically suspected (n = 6) lung cancer were included in the study. INTERVENTIONS: CT, PET, and EBUS-TBNA were performed prior to surgery for the evaluation of mediastinal and hilar lymph node metastasis. The convex probe EBUS, which is integrated with a convex scanning probe on its tip, was used for EBUS-TBNA. Surgical histology was used as the "gold standard" to confirm lymph node metastasis unless patients were found inoperable for N3 or extensive N2 disease proven by EBUS-TBNA. MAIN RESULTS: EBUS-TBNA was successfully performed in all 102 patients (mean age, 67.8 years) from 147 mediastinal and 53 hilar lymph nodes. EBUS-TBNA proved malignancy in 37 lymph node stations in 24 patients. CT identified 92 positive lymph nodes, and PET identified 89 positive lymph nodes (4 supraclavicular, 63 mediastinal, 22 hilar). The sensitivities of CT, PET, and EBUS-TBNA for the correct diagnosis of mediastinal and hilar lymph node staging were 76.9%, 80.0%, and 92.3%, respectively; specificities were 55.3%, 70.1%, and 100%, and diagnostic accuracies were 60.8%, 72.5%, and 98.0%. EBUS-TBNA was uneventful, and there were no complications. CONCLUSION: Compared to CT and PET, EBUS-TBNA has a high sensitivity as well as specificity for mediastinal and hilar lymph node staging in patients with lung cancer. EBUS-TBNA should be considered for evaluation of the mediastinum early in the staging process of lung cancer.

Adult↗
PubMed2005

Dendritic cell maturation by CD11c- T cells and Valpha24+ natural killer T-cell activation by alpha-galactosylceramide.

Human invariant Valpha24+ natural killer T (NKT) cells display potent antitumor activity upon stimulation. Activation of endogenous Valpha24+ NKT cells would be one strategy for the treatment of cancer patients. For example, dendritic cells (DCs) loaded with a glycolipid NKT cell ligand, alpha-galactosylceramide (alphaGalCer, KRN7000), are a possible tool for the activation and expansion of functional Valpha24+ NKT cells in vivo. In this report, we demonstrate that the levels of expansion and the ability to produce IFN-gamma of Valpha24+ NKT cells induced by alphaGalCer-loaded whole PBMCs cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs) were superior to those of cells induced by monocyte-derived CD11c+ DCs (moDCs) developed with IL-4 and GM-CSF. Interestingly, CD11c+ cells in the IL-2/GM-CSF-cultured PBMCs showed a mature phenotype without further stimulation and exerted potent stimulatory activity on Valpha24+ NKT cells to enable them to produce IFN-gamma preferentially at an extent equivalent to mature moDCs induced by stimulation with LPS or a cytokine cocktail. Cocultivation with CD11c- cells in the IL-2/GM-CSF-cultured PBMCs induced maturation of moDCs. In particular, CD11c-CD3+ T cells appeared to play important roles in DC maturation. In addition, TNF-alpha was preferentially produced by CD11c-CD3+ T cells in IL-2/GM-CSF-cultured PBMCs and was involved in the maturation of moDCs. Thus, the maturation of DCs induced by CD11c- T cells through TNF-alpha production appears to result in the efficient expansion and activation of Valpha24+ NKT cells to produce IFN-gamma preferentially.

Antigens, CD↗
PubMed2005

Endobronchial ultrasound guided transbronchial needle aspiration for staging of lung cancer.

During the staging process of lung cancer, accurate mediastinal lymph node staging is one of the important factors which affect patient management. The purpose of the current study was to evaluate the usefulness of direct real-time endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) for staging and diagnosis of lung cancer in patients with mediastinal lymph nodes suspected of malignancy and to assess the impact of this method in patient management. One hundred and eight patients with mediastinal lymph nodes with known or suspected lung cancer were included. The convex probe EBUS integrated with a convex scanning probe on its tip was used in all cases. Final diagnosis was based on cytology, surgical results, and/or clinical follow-up. In 105 patients, EBUS-TBNA was successfully performed to obtain samples from 163 lymph nodes. With respect to the correct prediction of lymph node stage, EBUS-TBNA had a sensitivity of 94.6%, specificity of 100%, positive predictive value of 100%, negative predictive value of 89.5%, and diagnostic accuracy rate of 96.3%. In the 20 suspected lung cancer cases, mediastinal lymph node was used for tissue diagnosis of malignancy as well as staging. As a result of EBUS-TBNA, 29 mediastinoscopies, 8 thoracotomies, 4 thoracoscopies, and 9 CT-guided PCNB were avoided. The procedure was uneventful without complications. EBUS-TBNA is a safe and sensitive method for lymph node staging in patients with lung cancer. It spares invasive staging procedures which has a major impact on patient management.

Adenocarcinoma↗
PubMed2005

Expression of IL-27 in murine carcinoma cells produces antitumor effects and induces protective immunity in inoculated host animals.

A novel cytokine interleukin-27 (IL-27), composed of p28 and Epstein-Barr virus-induced gene 3 (EBI3), is produced from activated dendritic cells and is involved in an early phase of T-helper type I differentiation. We examined whether Colon 26 murine colon carcinoma cells that were retrovirally transduced with the p28-linked EBI3 gene (Colon 26/IL-27) could produce antitumor effects in inoculated mice. Although proliferation in vitro of Colon 26/IL-27 cells was not different from that of parent cells, syngeneic BALB/c mice rejected Colon 26/IL-27 tumors inoculated and subsequently acquired tumor-specific protective immunity. In contrast, mice inoculated with Colon 26 cells transduced with either the p28 or EBI3 gene developed tumors and survival of the mice remained the same as that of the mice inoculated with parent cells. Syngeneic nude mice developed Colon 26/IL-27 tumors, but the growth was retarded compared to that of parent tumors. Depletion of natural killer cells from nude mice with anti-asialo GM(1) antibody diminished the growth retardation of Colon 26/IL-27 tumors. Survival of severe combined immunodeficient mice that received subcutaneous inoculation of Colon 26/IL-27 cells was not different from that of the immunodeficient mice inoculated with parent cells. Interferon-gamma was produced from CD4(+) and CD8(+) T, and natural killer cells of the mice that rejected Colon 26/IL-27 tumors and cytotoxic activity against Colon 26 cells were also detected from the mice. These data collectively suggest that expressed IL-27 in tumors produces T cell-dependent and-independent antitumor effects and is a possible therapeutic strategy for cancer.

Animals↗