Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bak is a pro-apoptotic member of the Bcl-2 family whose genes are involved in regulation of programmed cell death. Using in situ hybridization, immunohistochemistry, and Northern blot analysis, we studied the expression of Bak in specimens from 12 normal pancreata and 26 primary pancreatic cancers, and correlated the findings with the clinical and histopathologic data of the patients. By comparison with normal pancreas, Northern blot analysis demonstrated a 2.5-fold increase of Bak messenger RNA expression in the tumor samples (P <0. 001). Elevated levels were found in 15 of the 26 pancreatic cancer tissue specimens. In these samples Bak expression was increased 4.3 fold (P <0.001). No association was detected between Bak expression and tumor stage. In situ hybridization and immunohistochemistry revealed that the tumor cells themselves and the stroma cells expressed only low levels of Bak. In contrast, in regions adjacent to the tumor, which showed chronic inflammation, there was always high expression in the acinar and inflammatory cells, explaining the increased Bak levels found in the tumor samples by means of Northern blot analysis. In the normal pancreas the expression of Bak was generally moderate in the acinar cells and low in the ductal and islet cells. In situ analysis using the terminal deoxynucleotidyl transferase method further showed that there was extensive cell death in the peritumorous areas with chronic inflammation. Taken together, these results suggest that in pancreatic cancer Bak expression and programmed cell death are present in cells that are localized in regions of chronic inflammation surrounding the pancreatic cancer cells but not in the tumor cells themselves, a situation that may facilitate tumor growth and spread.
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PMID:Bak expression and cell death occur in peritumorous tissue but not in pancreatic cancer cells. 1045 28

Adenocarcinoma of the pancreas generally remains an incurable disease by available treatment modalities, demanding the development of a suitable cell-culture/animal model and the discovery and evaluation of novel therapeutic agents. We report the clonal preservation of a human pancreatic cell line (KCI-MOH1) established from a 74-year-old African-American man diagnosed with pancreatic cancer. Initially the human primary tumor was grown as a xenograft in SCID mice and, subsequently, a cell line was established from tumors grown as a xenograft as reported in our earlier publication. The molecular characterization of the primary tumor, the tumors grown as xenograft, and the cell line all revealed similar genotypic properties. By using an automated DNA sequencer, a K-ras mutation (codon 12, GGT to CGT, Gly to Arg) was detected in the pancreatic tumor tissue taken from the patient, whereas no p53 mutation was detected. The same K-ras mutation and unaltered p53 was also found in the xenograft tumor and in the KCI-MOH1 cell line. Chromosome analysis of the cultured cells revealed: 42,XY,add(3)(p11.2),der(7)t(7;12) (p22;q12),-10,-12,add (14)(p11),-18,add (20)(q13),-22/84, idemx2, which is the same chromosome complement found in xenograft tumors. The KCI-MOH1 cell line grows well in tissue culture and forms tumors in the SCID mice when implanted subcutaneously, as well as in orthotopic sites. The KCI-MOH1 cell line-derived SCID mouse xenograft model was used for efficacy evaluation of bryostatin 1, auristatin-PE, spongistatin 1, and gemcitabine alone and in combination. Tumor growth inhibition (T/C expressed as percentage), tumor growth delay (T - C), and log 10 kill for these agents were 38%, 22 days, and 0.53; 15%, 30 days, and 0.80; 24%, 25 days, and 0.66; and 10%, 33 days, and 0.90, respectively. When given in combination, two of seven gemcitabine + auristatin-PE-treated animals were free of tumors for 150 days and were considered cured. Animals treated with a combination of bryostatin 1 and gemcitabine and a combination of spongistatin and gemcitabine produced remissions in only one of seven mice. From these results, we conclude that (a) this is the first study illustrating that clonal characteristics of primary pancreatic tumors remained unchanged when implanted in mice and as a permanent cell line grown in vitro; and (b) there is a synergistic effect between gemcitabine and selected marine products tested in this study, which is more apparent in the gemcitabine and auristatin-PE combination. The results of this preliminary study suggest that these agents should be explored clinically in the treatment of pancreatic cancer.
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PMID:Clonal preservation of human pancreatic cell line derived from primary pancreatic adenocarcinoma. 1054 95

Betacellulin (BTC) was identified in mouse pancreatic beta cell tumors as a member of the epidermal growth factor (EGF) family, and was found to bind and activate the EGF receptor. BTC is also expressed in some human malignancies and may have an important role in tumor growth progression. We examined whether BTC and EGF have a growth stimulatory effect on human pancreatic cancer cell lines both in vitro and in vivo. We also investigated the BTC expression and autonomous induction of BTC in pancreatic cancer cells. in vitro, both BTC and EGF had almost the same proliferative effect on Panc-1, MIA PaCa-2 and AsPC-1. in vivo, in a Panc-1 inoculated athymic mice model, BTC-treated tumors grew approximately five times larger than in control. Immunocytochemistry showed that BTC expression occurred in three pancreatic cancer cell lines, with MIA PaCa-2 showing the strongest intensity. Semi-quantitative RT-PCR of MIA Paca-2 showed that mRNA levels of BTC gradually increased after treatment with 1 nM BTC. Immunocytochemistry also demonstrated that the intensity of BTC-like immunoreactivity was increased when treated with 1 nM BTC but was reduced after treatment with 100 nM of AG1478, an EGF receptor tyrosine kinase inhibitor. BTC has thus a significant growth stimulatory effect on pancreatic cancer cells and might function as an autocrine and paracrine growth factor. BTC expression in pancreatic cancer cells is, at least in part, controlled by an auto-induction mechanism.
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PMID:Auto-induction and growth stimulatory effect of betacellulin in human pancreatic cancer cells. 1060 46

In pancreatic cancer, the mutation of c-K-ras is a critical event of tumor growth and metastasis. We have previously demonstrated a dominant negative effect of N116Y on the growth of pancreatic cancer cells. To evaluate the potential of N116Y for suppressing the metastatic growth of pancreatic tumor cells, we made a replication-deficient recombinant N116Y adenovirus driven by the carcinoembryonic antigen (CEA) promoter (Ad CEA-N116Y). We demonstrated that the expression of N116Y, growth inhibition, and apoptotic death induction were all specific to pancreatic cancer cell lines (PCI-35 and PCI-43) that were promoter positive, whereas no growth retardation was observed in human embryonic pancreas-derived cell line 1C3D3 after Ad CEA-N116Y infection. We examined the effect of Ad CEA-N116Y on the metastatic growth of PCI-43 colonies in liver, which was generated by tumor injection into the spleen of nude mice. The results showed that Ad CEA-N116Y effectively reduced the number of metastatic colonies without any complication by injecting intrasplenically 5 days after tumor cell inoculation. Thus, N116Y can selectively suppress the metastatic growth of pancreatic tumor cell by using the CEA promoter-driven adenovirus vector indicating that N116Y gene therapy may be potentially useful for the treatment of pancreatic cancer patients with liver micrometastasis.
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PMID:The dominant negative H-ras mutant, N116Y, suppresses growth of metastatic human pancreatic cancer cells in the liver of nude mice. 1075 26

Interleukin 12 (IL-12) is a heterodimeric cytokine that exerts a potent antitumor effect through its pleiotropic actions. It was recently reported that IL-12 has also a potent antiangiogenic effect through the induction of IFN-gamma, which triggers the production of chemokines such as IP-10 that has been shown to have antiangiogenesis properties. In this study we transfected the IL-12 gene into a human pancreatic adenocarcinoma cell line (PK-1). PK-1 cells transfected with the green fluorescence protein (gfp) gene were used as positive controls. The in vitro growth curve and in vivo tumor growth of transfectants (IL-12/PK-1 and gfp/PK-1) were compared with those of parental cells. The SCID mice used in this study were administered antiasialo GM-1 Ab (100 microg, i.p., twice weekly) to deplete the remaining immunoeffector cells, NK cells. Using a skinfold chamber model, we observed and recorded tumor angiogenesis by intravital microscopy. In vitro growth of IL-12/PK-1 and gfp/PK-1 cells was not different from that of wild-type PK-1 cells (wt/PK-1). However, IL-12 transfected PK-1 cells did not develop into tumors as did the wt/PK-1 cells after subcutaneous inoculation in antiasialo GM-1 Ab administered SCID mice. The growth of IL-12/PK-1 tumors was restored in mice treated with anti-IL-12 antibody. We found that IL-12/PK-1, in contrast to gfp/PK-1 and wt/PK-1, failed to initiate an angiogenic response, as observed in the skinfold chamber model. These results indicate that the antiangiogenesis effect of IL-12 alone, without immune system involvement, is sufficient to block the growth of human pancreatic cancer.
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PMID:The antiangiogenesis effect of interleukin 12 during early growth of human pancreatic cancer in SCID mice. 1076 47

We examined the antitumor effect of locally secreted interleukin (IL)-12 or IL-15 on human pancreatic cancer cells (AsPC-1). We subcutaneously inoculated AsPC-1 cells retrovirally transduced with IL-12 or IL-15 cDNA into nude mice. Tumors derived from these cells showed retarded growth compared with those from wild-type (wt) cells. Nude mice inoculated intraperitoneally with the cytokine producers survived longer than those injected with wt cells. These cytokine producers were also tested for their tumor growth in severe combined immunodeficient mice. The tumor growth of IL-12 producers was similarly suppressed as found in nude mice, but the average tumor volumes of IL-15 producers were not statistically different from those of wt tumors. In nude mice that were administered anti-asialo GM1 antibody before the inoculation of the tumor cells, growth retardation of tumors of IL-12 producers remained the same as in untreated animals, but that of IL-15 producers was markedly reduced. Immunohistochemical analysis revealed that CD11b+ cells migrated into the tumors of cytokine producers and that the number of CD31+ endothelial cells within the tumors was not different between IL-12 producers and wt cells. Taken together with other data, it is possible that granulocytes are candidate cells for the IL-12-mediated antitumor effect, and that natural killer cells and gammadelta T cells are involved in the IL-15-induced antitumor effect. We did not observe synergistic effects of these cytokines to suppress subcutaneous tumors.
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PMID:Impaired tumorigenicity of human pancreatic cancer cells retrovirally transduced with interleukin-12 or interleukin-15 gene. 1077 Jun 43

There is a great need for new therapeutic agents for patients with advanced pancreatic cancer. The new dioxolane analogue troxacitabine was evaluated in two human pancreatic cancer xenograft models. The models used included the Panc-01 and MiaPaCa pancreatic cancer cell lines. Whereas there is certainly no absolute evidence that either of the in vivo models is predictive for clinical activity, there is at least some evidence that they may be helpful in selecting agents for clinical trials in patients with pancreatic cancer. Troxacitabine was administered i.v. to the animals at doses of 10 and 25 mg/kg on a daily x 5 regimen. Gemcitabine was used as a positive control. The end points for the study included tumor growth inhibition (TGI), final weight, and the number of partial and complete tumor responses in the animals. Troxacitabine was highly active against the Panc-01 model (n = 8), with TGI levels of 88.5% and 84.3% at the 10 and 25 mg/kg doses, respectively. The mean final tumor weights for animals given troxacitabine were also significantly smaller (P < 0.001) compared with vehicle controls. At the 10 mg/kg dose, there were three partial tumor shrinkages and one complete tumor shrinkage, whereas at the 25 mg/kg dose, there were three partial tumor shrinkages. Troxacitabine had less activity against the MiaPaCa model (n = 10) and, by traditional response criteria, would be considered inactive, with TGIs of 4% and 22.7% at the 10 and 25 mg/kg dose level, respectively. Of note is that in comparison with gemcitabine, troxacitabine was more efficacious against Panc-01 and was equally active against MiaPaCa. These in vivo results are encouraging and support the prospect of performing Phase II and perhaps Phase III trials with troxacitabine in patients with advanced pancreatic cancer.
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PMID:The new dioxolane, (-)-2'-deoxy-3'-oxacytidine (BCH-4556, troxacitabine), has activity against pancreatic human tumor xenografts. 1077 91

We present here a new cell line, NOR-P1, established from a metastatic subcutaneous tumor of a patient with pancreatic cancer. The cells show rapid growth in culture with a doubling time of 16 h and high migration activity. Genetic and molecular analyses revealed high telomerase activity and a mutation in the K-ras oncogene. Of particular interest, the cells express markedly elevated mRNA levels of angiogenic factors, vascular endothelial growth factor and platelet-derived growth factor, as well as other tumor growth-related factors. Subcutaneous transplantation of the NOR-P1 cells into nude mice formed solid, hemorrhagic tumors which were histologically diagnosed as adenocarcinoma with dense blood vessels and severe extravasation of blood. Furthermore, when NOR-P1 cell suspension was injected directly into the pancreas of nude mice, the cells grew rapidly to form intra-pancreatic tumors associated with liver metastases and peritoneal dissemination that resulted in cachexia and subsequent death. These properties suggest that NOR-P1 is an aggressive pancreatic cancer cell line with a high metastatic potential and may serve as a useful experimental model for studying tumor angiogenesis and metastasis of pancreatic cancer.
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PMID:Establishment of a new human pancreatic cancer cell line, NOR-P1, with high angiogenic activity and metastatic potential. 1082 30

Because of the dismal prognosis of advanced ductal pancreatic adenocarcinoma, recent investigational strategies have focused on improved detection and therapeutic intervention in early-stage pancreatic cancer. The obvious cost constraints of screening populations at risk but with a low tumor yield will restrict screening protocols to only the highest risk groups (hereditary pancreatitis = age 50, certain hereditary pancreatic cancer kindreds). The vast majority of patients, either lacking or exhibiting an inherited predisposition to pancreatic cancer, will continue to present with disease not resectable for cure. The authors believe that the best hope for these patients lies in the further delineation of the integrative pathophysiology driving tumor growth; this would facilitate the future development of a computer program or other modality that would predict the dominant pathways driving the growth and spread of each tumor based on its "molecular profile." This article reviews the authors' current knowledge regarding the growth factors, receptors, and molecular alterations driving uncontrolled proliferation, local invasion, and metastatic spread of these tumors. The current and potential contributions of studies in cohorts with an inherited predisposition to pancreatic cancer to this pathophysiologic model are also discussed. The future strategy for incorporating this information into a working pathophysiologic road map with clinical relevance is subsequently outlined.
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PMID:Growth factors, receptors, and molecular alterations in pancreatic cancer. Putting it all together. 1087 26

Pancreatic cancer is one of the most incurable and lethal human cancers in the United States. To facilitate development of novel therapeutic agents, we previously established an orthotopic pancreatic tumor model that closely mimics the natural biological behavior of human pancreatic cancer. In this study, magnetic resonance imaging (MRI) techniques were developed to detect tumor formation noninvasively and monitor serially tumor growth kinetics in this orthotopic model used for experimental drug testing. By using an optimized T2-weighted imaging method, we were able to distinguish human pancreas cancer from normal mouse pancreas. Orthotopic tumor formation was detected as early as day 1 after tumor cell implantation with a tumor volume as small as 12 mm3. Mice with evidence of tumor were separated into four treatment groups: control, auristatin-PE, gemcitabine, and their combination. After treatment, the mice were imaged at least three times before termination of the experiment. Comparison between MRI tumor volume measurements and tumor weights made at biopsy resulted in a correlation coefficient of 0.98. The tumor growth curves constructed from serial magnetic resonance imaging (MRI) measurements clearly showed tumor growth inhibition in treated mice compared with the control group. As expected, the group treated with the combination had the highest response rate compared with either auristatin-PE or gemcitabine alone, and the data were statistically highly significant (p < 0.004). From these results, we conclude that noninvasive MRI can be used to monitor serially therapeutic response in this orthotopic human pancreatic tumor model and can be used in the future to evaluate novel antitumor agents before human studies.
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PMID:Magnetic resonance imaging to measure therapeutic response using an orthotopic model of human pancreatic cancer. 1088 35


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