Nuclear matrix targeting of the protein kinase CK2 signal as a common downstream response to androgen or growth factor stimulation of prostate cancer cells.
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Protein kinase CK2, a messenger-independent serine/threonine kinase, has been implicated in cell growth. Androgenic stimulus in rat prostate modulates its association with nuclear matrix (NM) and chromatin. Because the growth of human prostate carcinoma cells is influenced by androgens and/or growth factors, we determined the nature of CK2 signaling in the NM in response to androgen and growth factor stimuli. Androgen-sensitive LNCaP and androgen-insensitive PC-3 cells were cultured in media to regulate their growth in the presence of 5alpha-dihydrotestosterone (5alpha-DHT) or growth factors (epidermal growth factor, keratinocyte growth factor, and transforming growth factor alpha). The activity of CK2 was measured in the cytosolic and NM fractions isolated from these cells after treatment with growth stimuli. The changes in CK2 in various fractions were also confirmed by immunoblotting with a specific antibody. LNCaP cells responded to both 5alpha-DHT and growth factors for growth. The presence of these agents in the culture medium evoked a translocation of CK2 to the NM from the cytosol. The PC-3 cells did not respond to 5alpha-DHT for growth but did respond to growth factors. Under these conditions, there was also a translocation of CK2 to the NM concomitant with a decrease in the cytosolic fraction. These results suggest that CK2 translocation to the NM occurs in response to various growth stimuli in cells in culture. Thus, CK2 is a common downstream signal transducer in response to diverse growth stimuli that may relate to the pathobiology of prostate cancer cells. (+info)
Chemotherapy for advanced pancreatic cancer: it may no longer be ignored.
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Two case histories are reported here in which a chemotherapeutic approach improved the clinical conditions of patients with advanced pancreatic cancer. Until recently, chemotherapy was considered ineffective in pancreatic cancer, and most oncologists treated these patients with best-supportive-care only. Enthusiasm for systemic therapy of advanced pancreatic cancer is again growing, spurred by the advent of new drugs and new treatment endpoints such as life quality and symptom palliation. Gemcitabine, the most intensively-investigated new drug in pancreatic cancer, has shown an advantage in both survival and clinical benefit over that of 5-fluorouracil (5-FU). Other new drugs such as taxanes have shown interesting levels of activity, and are deserving of further evaluation. Although these results are far from conclusive and are only partially satisfactory, they represent a significant step forward in the treatment of advanced pancreatic cancer. (+info)
Up-regulated pyrimidine nucleoside phosphorylase in breast carcinoma correlates with lymph node metastasis.
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BACKGROUND: The clinical significance of pyrimidine nucleoside phosphorylase (PyNPase) activity in breast carcinomas has never been determined. MATERIALS AND METHODS: In 41 cases of breast carcinoma, the enzyme activity of PyNPase was determined by the high performance liquid chromatography (HPLC) assay and its value was analyzed with clinicopathologic variables. The expression level of mRNA was examined by the semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay and compared with the enzyme activity. RESULTS: The higher activity of PyNPase was significantly correlated not only with the presence of vascular permeation (P = 0.02) but of lymph node metastasis (P = 0.02). The mRNA expression correlated well with the enzyme activity (r = 0.74, P < 0.01). A multivariate analysis disclosed the PyNPase factor to be associated with lymph node metastasis. In addition, 17 (41%) showed positive staining only in the tumor stromal cells and 18 (44%) cases showed positive staining in both the tumor stromal cells and the carcinoma cells by immunohistochemical study. CONCLUSIONS: These findings suggest that PyNPase activity is a new marker predicting the malignant potential of breast carcinomas, especially with respect to lymph node metastasis, and that the RT-PCR assay is a more useful method than direct evaluation of PyNPase activity. (+info)
Response to neoadjuvant chemotherapy best predicts survival after curative resection of gastric cancer.
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OBJECTIVE: In Western populations, long-term survival rates after curative resection of gastric cancer remain extremely poor. The lack of effective adjuvant therapy has prompted the evaluation of neoadjuvant approaches. Since 1988, we have conducted three separate phase II trials using neoadjuvant chemotherapy to treat patients with potentially resectable gastric cancer. The present study was conducted to evaluate whether response to neoadjuvant chemotherapy is predictive of survival in patients with resectable gastric cancer. METHODS: Eighty-three patients with pathologically confirmed gastric adenocarcinoma were treated with neoadjuvant chemotherapy before planned surgical resection. Response was assessed by upper gastrointestinal series, endoscopy, computed tomography scan, and pathologic examination. RESULTS: For the three phase II trials, clinical response rates ranged from 24% to 38%. Three patients (4%) had a complete pathologic response. Sixty-one patients (73%) underwent a curative resection. Median follow-up was 26 months. Univariate analysis revealed T stage, number of positive nodes, and response to chemotherapy to be significant predictors of overall survival. However, on multivariate analysis, response to chemotherapy was found to be the only independent prognostic factor. CONCLUSIONS: Response to neoadjuvant chemotherapy is the single most important predictor of overall survival after neoadjuvant chemotherapy for gastric cancer. These findings support further evaluation of neoadjuvant approaches in the treatment of this disease. (+info)
Reexploration for periampullary carcinoma: resectability, perioperative results, pathology, and long-term outcome.
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OBJECTIVE: This single-institution experience retrospectively reviews the outcomes of patients undergoing reexploration for periampullary carcinoma at a high-volume center. SUMMARY BACKGROUND DATA: Many patients are referred to tertiary centers with periampullary carcinoma after their tumors were deemed unresectable at previous laparotomy. In carefully selected patients, tumor resection is often possible; however, the perioperative results and long-term outcome have not been well defined. METHODS: From November 1991 through December 1997, 78 patients who underwent previous exploratory laparotomy and/or palliative surgery for suspected periampullary carcinoma underwent reexploration. The operative outcome, resectability rate, pathology, and long-term survival rate were compared with 690 concurrent patients who had not undergone previous exploratory surgery. RESULTS: Fifty-two of the 78 patients (67%) undergoing reexploration underwent successful resection by pancreaticoduodenectomy; the remaining 26 patients (34%) were deemed to have unresectable disease. Compared with the 690 patients who had not undergone recent related surgery, the patients in the reoperative group were similar with respect to gender, race, and resectability rate but were significantly younger. The distribution of periampullary cancers by site in the reoperative group undergoing pancreaticoduodenectomy (n = 52) was 60%, 19%, 15%, and 6% for pancreatic, ampullary, distal bile duct, and duodenal tumors, respectively. These figures were similar to the 65%, 14%, 16% and 5% for resectable periampullary cancers found in the primary surgery group (n = 460). Intraoperative blood loss and transfusion requirements did not differ between the two groups. However, the mean operative time was 7.4 hours in the reoperative group, significantly longer than in the control group. On pathologic examination, reoperative patients had smaller tumors, and the percentage of patients with positive lymph nodes in the resection specimen was significantly less. The incidence of positive margins was similar between the two groups. Postoperative lengths of stay, complication rates, and perioperative mortality rates were not higher in reoperative patients. The long-term survival rate was similar between the two resected groups, with a median survival of 24 months in the reoperative group and 20 months in those without previous exploration. CONCLUSIONS: These data demonstrate that patients undergoing reoperation for periampullary carcinoma have similar resectability, perioperative morbidity and mortality, and long-term survival rates as patients undergoing initial exploration. The results suggest that selected patients considered to have unresectable disease at previous surgery should undergo restaging and reexploration at specialized high-volume centers. (+info)
Isolation of DNA fragments associated with methylated CpG islands in human adenocarcinomas of the lung using a methylated DNA binding column and denaturing gradient gel electrophoresis.
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We have constructed a library of DNA fragments heavily methylated in human adenocarcinomas of the lung to permit the comprehensive isolation of methylated CpG islands in cancer. Heavily methylated genomic DNA fragments from tumors of nine male patients were enriched using a methylated DNA binding column and used for construction of the library. From this library, DNA fragments having properties of CpG islands were isolated on the basis of their reduced rate of strand dissociation during denaturing gradient gel electrophoresis. Approximately 1,000 clones, corresponding to 0.3% of the library were analyzed, and nine DNA fragments were identified as being associated with CpG islands that were methylated in tumor DNA. One CpG island was methylated specifically in tumor DNA, whereas the remaining eight CpG islands were methylated both in normal and tumor DNA derived from the same patients. Our results suggest that the number of CpG islands methylated specifically in tumors is not large. The library, which contains DNA fragments from methylated CpG islands comprehensively, is expected to be valuable when elucidating epigenetic processes involved in carcinogenesis. (+info)
Complementary adenoviral vectors for oncolysis.
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Replication-competent adenoviruses (Ads) were used for oncolytic virotherapy soon after they were discovered. Recently mutated and genetically engineered Ads have been shown to selectively lyse tumor cells. We have split the human Ad type 5 genome into two defective viruses that complement each other only in certain tumor cells. The genome of one of these vectors, GT5610, contains only the minimal viral elements required in cis for replication and packaging and the E1 viral genes with E1A under the control of the human alpha-fetoprotein promoter. This "controlled" vector has a capacity for 30 kilobases of foreign DNA. The supplemental vector, AdHbeta, contains all adenoviral genes except for E1. Both vectors were designed to carry heterologous reporter genes whose expression could be detected throughout the tumor. Coinfection of hepatocarcinoma cells that have the capacity to transcribe genes under the control of the alpha-fetoprotein promoter leads to cell lysis and copropagation. The oncolytic spread of these complementary vectors in vivo was demonstrated by the intratumoral injection of human hepatocarcinomas xenografted in severe combined immunodeficient (SCID) mice. This system presents safety and gene capacity features that could yield a therapeutic advantage over oncolysis by a single virus. (+info)
Induction of antitumor immunity by direct intratumoral injection of a recombinant adenovirus vector expressing interleukin-12.
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Direct intratumoral (i.t.) injection of adenoviruses (Ads) expressing specific immunostimulatory cytokines represents an attractive strategy for the clinical implementation of cytokine gene therapy of cancer. Interleukin-12 (IL-12) is a heterodimeric cytokine produced by antigen-presenting cells and promotes a T helper 1-like immune response. We have constructed an Ad vector (AdCMV-mIL-12) containing both chains of the murine IL-12 (mIL-12) gene linked by an internal ribosomal entry site sequence under the transcriptional control of the cytomegalovirus immediate-early gene promoter, which is able to mediate the transient expression of very high levels of biologically active mIL-12 both in vitro and in vivo. An i.t. injection of 4x10(8) plaque-forming units of AdCMV-mIL-12 resulted in a complete regression of day 7 established subcutaneous MC38 murine adenocarcinomas and MCA205 murine fibrosarcomas. Treated animals rejected a subsequent rechallenge with MC38 and MCA205, respectively, demonstrating the induction of long-lasting antitumor immunity. Specific antitumor cytotoxic T lymphocyte reactivity was detected in splenocytes harvested from treated animals. A significant increase in the numbers of both CD4+ and CD8+ T cells in the AdCMV-mIL-12-infected tumors was observed. Ad-mediated IL-12 gene therapy was also associated with measurable serum levels of mIL-12 and profound changes in the composition of splenic lymphocytes. Taken together, these results demonstrate the feasibility and efficacy of delivering IL-12 directly i.t. using a recombinant adenoviral vector. (+info)