sirolimus has been researched along with Carcinoma--Pancreatic-Ductal* in 16 studies
1 review(s) available for sirolimus and Carcinoma--Pancreatic-Ductal
1 trial(s) available for sirolimus and Carcinoma--Pancreatic-Ductal
15 other study(ies) available for sirolimus and Carcinoma--Pancreatic-Ductal
| Article | Year |
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Gα13 loss in Kras/Tp53 mouse model of pancreatic tumorigenesis promotes tumors susceptible to rapamycin.
Gα13 transduces signals from G-protein-coupled receptors. While Gα13 functions as a tumor suppressor in lymphomas, it is not known whether Gα13 is pro-tumorigenic or tumor suppressive in genetically engineered mouse (GEM) models of epithelial cancers. Here, we show that loss of Gα13 in the Kras/Tp53 (KPC) GEM model promotes well-differentiated tumors and reduces survival. Mechanistically, tumors developing in KPC mice with Gα13 loss exhibit increased E-cadherin expression and mTOR signaling. Importantly, human pancreatic ductal adenocarcinoma (PDAC) tumors with low Gα13 expression also exhibit increased E-cadherin expression and mTOR signaling. Treatment with the mTOR inhibitor rapamycin decreases the growth of syngeneic KPC tumors with Gα13 loss by promoting cell death. This work establishes a tumor-suppressive role of Gα13 in pancreatic tumorigenesis in the KPC GEM model and suggests targeting mTOR in human PDAC tumors with Gα13 loss. Topics: Animals; Cadherins; Carcinogenesis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Disease Models, Animal; GTP-Binding Protein alpha Subunits, G12-G13; Mice; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Sirolimus; TOR Serine-Threonine Kinases | 2022 |
Autophagy-mediated negative feedback attenuates the oncogenic activity of YAP in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy in humans, and new therapeutic targets are urgently needed. Yes-associated protein (YAP) plays a significant role in cancer progression. Autophagy is also closely associated with various human cancers. However, the interplay between YAP and autophagy in PDAC remains poorly understood. In this study, we found that YAP was upregulated and activated in PDAC. Further analysis revealed that there is a YAP-autophagy feedback loop in pancreatic cancer. Mechanistically, YAP activates autophagy by promoting Atg5 transcription via TEAD1-mediated binding, while autophagy negatively regulates YAP through autophagic degradation. The hyperactivation of YAP in PDAC unbalances the YAP-autophagy circuit and promotes cancer progression. Inhibition of autophagy enhances the oncogenic activity of YAP in PDAC. The autophagy activator rapamycin promotes the antitumor effect of verteporfin, a YAP inhibitor. Therefore, our study elucidated the interaction between YAP and autophagy in PDAC and our results suggest that targeting the YAP-autophagy circuit may be a new therapeutic strategy for pancreatic cancer. Topics: Animals; Antibiotics, Antineoplastic; Autophagy; Autophagy-Related Protein 5; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Feedback, Physiological; Female; Humans; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Photosensitizing Agents; Sirolimus; Verteporfin; Xenograft Model Antitumor Assays; YAP-Signaling Proteins | 2021 |
Targeting of the Hedgehog/GLI and mTOR pathways in advanced pancreatic cancer, a phase 1 trial of Vismodegib and Sirolimus combination.
Preclinical data indicated a functional and molecular interaction between Hedgehog (HH)/GLI and PI3K-AKT-mTOR pathways promoting pancreatic ductal adenocarcinoma (PDAC). A phase I study was conducted of Vismodegib and Sirolimus combination to evaluate maximum tolerated dose (MTD) and preliminary anti-tumor efficacy.. Cohort I included advanced solid tumors patients following a traditional 3 + 3 design. Vismodegib was orally administered at 150 mg daily with Sirolimus starting at 3 mg daily, increasing to 6 mg daily at dose level 2. Cohort II included only metastatic PDAC patients. Anti-tumor efficacy was evaluated every two cycles and target assessment at pre-treatment and after a single cycle.. Nine patient were enrolled in cohort I and 22 patients in cohort II. Twenty-eight patients were evaluated for dose-limiting toxicities (DLTs). One DLT was observed in each cohort, consisting of grade 2 mucositis and grade 3 thrombocytopenia. The MTD for Vismodegib and Sirolimus were 150 mg daily and 6 mg daily, respectively. The most common grade 3-4 toxicities were fatigue, thrombocytopenia, dehydration, and infections. A total of 6 patients had stable disease. No partial or complete responses were observed. Paired biopsy analysis before and after the first cycle in cohort II consistently demonstrated reduced GLI1 expression. Conversely, GLI and mTOR downstream targets were not significantly affected.. The combination of Vismodegib and Sirolimus was well tolerated. Clinical benefit was limited to stable disease in a subgroup of patients. Targeting efficacy demonstrated consistent partial decreases in HH/GLI signaling with limited impact on mTOR signaling. These findings conflict with pre-clinical models and warrant further investigations. Topics: Adult; Aged; Anilides; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Pancreatic Ductal; Drug Therapy, Combination; Female; Hedgehog Proteins; Humans; Immunosuppressive Agents; Male; Maximum Tolerated Dose; Middle Aged; Negative Results; Neoplasm Metastasis; Pancreatic Neoplasms; Pyridines; RNA, Neoplasm; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome | 2020 |
Metformin influences drug sensitivity in pancreatic cancer cells.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5-10% after diagnosis and treatment. Pancreatic cancer has been associated with type II diabetes as the frequency of recently diagnosed diabetics that develop pancreatic cancer within a 10-year period of initial diagnosis of diabetes in increased in comparison to non-diabetic patients. Metformin is a very frequently prescribed drug used to treat type II diabetes. Metformin acts in part by stimulating AMP-kinase (AMPK) and results in the suppression of mTORC1 activity and the induction of autophagy. In the following studies, we have examined the effects of metformin in the presence of various chemotherapeutic drugs, signal transduction inhibitors and natural products on the growth of three different PDAC lines. Metformin, by itself, was not effective at suppressing growth of the pancreatic cancer cell lines at concentration less than 1000 nM, however, in certain PDAC lines, a suboptimal dose of metformin (250 nM) potentiated the effects of various chemotherapeutic drugs used to treat pancreatic cancer (e.g., gemcitabine, cisplatin, 5-fluorouracil) and other cancer types (e.g., doxorubicin, docetaxel). Furthermore, metformin could increase anti-proliferative effects of mTORC1 and PI3K/mTOR inhibitors as well as natural products such as berberine and the anti-malarial drug chloroquine in certain PDAC lines. Thus, metformin can enhance the effects of certain drugs and signal transduction inhibitors which are used to treat pancreatic and various other cancers. Topics: Animals; Carcinoma, Pancreatic Ductal; Diabetes Mellitus, Type 2; Drug Interactions; Humans; Metformin; Pancreatic Neoplasms; Signal Transduction; Sirolimus | 2018 |
mTOR is a promising therapeutical target in a subpopulation of pancreatic adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease, unusually resistant against therapy. It is generally felt that stratification of patients for personalized medicine is the way forward. Here, we report that a subpopulation of PDACs shows strong activation of the mTOR signaling cassette. Moreover, we show that inhibition of mTOR in pancreatic cancer cell lines showing high levels of mTOR signaling is associated with cancer cell death. Finally, we show using fine needle biopsies the existence of a subpopulation of PDAC patients with high activation of the mTOR signaling cassette and provide evidence that inhibition of mTOR might be clinically useful for this group. Thus, our results define an unrecognized subpopulation of PDACs, characterized by high activation of mTOR and show that identification of this specific patient group in the early phase of diagnosis is feasible. Topics: Antibiotics, Antineoplastic; Autophagy; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Flow Cytometry; Humans; Immunohistochemistry; Molecular Targeted Therapy; Pancreatic Neoplasms; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases | 2014 |
Targeting mTOR dependency in pancreatic cancer.
Pancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease.. Activating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of Kras(G12D)-driven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition.. We found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours.. KRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future. Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Drug Administration Schedule; Gene Expression Regulation, Neoplastic; Humans; Injections, Intraperitoneal; Mice; Mice, Mutant Strains; Mutation; Pancreatic Neoplasms; Positron-Emission Tomography; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Tumor Suppressor Protein p53 | 2014 |
Use of a preclinical model of pancreas cancer to identify potential candidates for rapalogue therapy.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Humans; Pancreatic Neoplasms; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases | 2014 |
Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells.
The mTOR pathway is aberrantly stimulated in many cancer cells, including pancreatic ductal adenocarcinoma (PDAC), and thus it is a potential target for therapy. However, the mTORC1/S6K axis also mediates negative feedback loops that attenuate signaling via insulin/IGF receptor and other tyrosine kinase receptors. Suppression of these feed-back loops unleashes over-activation of upstream pathways that potentially counterbalance the antiproliferative effects of mTOR inhibitors. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic cancer cells with either rapamycin or active-site mTOR inhibitors suppressed S6K and S6 phosphorylation induced by insulin and the GPCR agonist neurotensin. Rapamycin caused a striking increase in Akt phosphorylation at Ser(473) while the active-site inhibitors of mTOR (KU63794 and PP242) completely abrogated Akt phosphorylation at this site. Conversely, active-site inhibitors of mTOR cause a marked increase in ERK activation whereas rapamycin did not have any stimulatory effect on ERK activation. The results imply that first and second generation of mTOR inhibitors promote over-activation of different pro-oncogenic pathways in PDAC cells, suggesting that suppression of feed-back loops should be a major consideration in the use of these inhibitors for PDAC therapy. In contrast, metformin abolished mTORC1 activation without over-stimulating Akt phosphorylation on Ser(473) and prevented mitogen-stimulated ERK activation in PDAC cells. Metformin induced a more pronounced inhibition of proliferation than either KU63794 or rapamycin while, the active-site mTOR inhibitor was more effective than rapamycin. Thus, the effects of metformin on Akt and ERK activation are strikingly different from allosteric or active-site mTOR inhibitors in PDAC cells, though all these agents potently inhibited the mTORC1/S6K axis. Topics: Antibiotics, Antineoplastic; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Feedback, Physiological; Gene Expression Regulation, Neoplastic; Humans; Hypoglycemic Agents; Indoles; Insulin; Metformin; Morpholines; Neurotensin; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Purines; Pyrimidines; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases | 2013 |
A genome-wide RNAi screen for polypeptides that alter rpS6 phosphorylation.
Mammalian target of rapamycin (mTOR) is a giant protein kinase that controls cell proliferation, growth, and metabolism. mTOR is regulated by nutrient availability, by mitogens, and by stress, and operates through two independently regulated hetero-oligomeric complexes. We have attempted to identify the cellular components necessary to maintain the activity of mTOR complex 1 (mTORC1), the amino acid-dependent, rapamycin-inhibitable complex, using a whole genome approach involving RNAi-induced depletion of cellular polypeptides. We have used a pancreatic ductal adenocarcinoma (PDAC) cell line, Mia-PaCa for this screen; as with many pancreatic cancers, these cells exhibit constitutive activation of mTORC1. PDAC is the most common form of pancreatic cancer and the 5-year survival rate remains 3-5% despite current nonspecific and targeted therapies. Although rapamycin-related mTOR inhibitors have yet to demonstrate encouraging clinical responses, it is now evident that this class of compounds is capable of only partial mTORC1 inhibition. Identifying previously unappreciated proteins needed for maintenance of mTORC1 activity may provide new targets and lead to the development of beneficial therapies for pancreatic cancer. Topics: Adenocarcinoma; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Fluorescent Antibody Technique; Genome, Human; Humans; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Pancreatic Neoplasms; Phosphorylation; Proteins; Ribosomal Protein S6; RNA Interference; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transfection | 2012 |
K-Ras mutation-mediated IGF-1-induced feedback ERK activation contributes to the rapalog resistance in pancreatic ductal adenocarcinomas.
Mammalian target of rapamycin complex 1 (mTORC1) is frequently activated in human cancers; however, clinical trials of rapalog (the mTORC1 inhibitors) have shown that pancreatic ductal adenocarcinomas (PDACs) resist to the treatment. Rapalog treatment activated the extracellular signal-regulated kinase (ERK) pathway in K-Ras mt PDAC cells. K-Ras knockdown abolished the insulin-like growth factor-1 (IGF-1)-induced ERK pathway in the K-Ras mt PDAC cells and enhanced the therapeutic efficacy of everolimus in treating K-Ras mt PDAC cells-derived mouse xenografts. The results indicate that targeting of K-Ras mutation may lead to the development of therapies that overcome rapalog resistance in PDAC. Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Benzenesulfonates; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Drug Resistance, Neoplasm; Enzyme Activation; Everolimus; Extracellular Signal-Regulated MAP Kinases; Feedback, Physiological; Female; Humans; Insulin-Like Growth Factor I; MAP Kinase Signaling System; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Mutation; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; Pyrroles; ras Proteins; Sirolimus; Sorafenib; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays | 2012 |
Rapamycin partially mimics the anticancer effects of calorie restriction in a murine model of pancreatic cancer.
Etiologic factors for pancreatic cancer, the 4th deadliest malignant neoplasm in the United States, include obesity and abnormal glucose metabolism. Calorie restriction (CR) and rapamycin each affect energy metabolism and cell survival pathways via inhibition of mammalian target of rapamycin (mTOR) signaling. By using a Panc02 murine pancreatic cancer cell transplant model in 45 male C57BL/6 mice, we tested the hypothesis that rapamycin mimics the effects of CR on pancreatic tumor growth. A chronic regimen of CR, relative to an ad libitum-fed control diet, produced global metabolic effects such as reduced body weight (20.6 ± 1.6 g vs. 29.3 ± 2.3 g; P < 0.0001), improved glucose responsiveness, and decreased circulating levels of insulin-like growth factor (IGF)-1 (126 ± 8 ng/mL vs. 199 ± 11 ng/mL; P = 0.0006) and leptin (1.14 ± 0.2 ng/mL vs. 5.05 ± 1.2 ng/mL; P = 0.01). In contrast, rapamycin treatment (2.5 mg/kg intraperitoneal every other day, initiated in mice following 20 weeks of ad libitum control diet consumption), relative to control diet, produced no significant change in body weight, IGF-1 or leptin levels, but decreased glucose responsiveness. Pancreatic tumor volume was significantly reduced in the CR group (221 ± 107 mm(3); P < 0.001) and, to a lesser extent, the rapamycin group (374 ± 206 mm(3); P = 0.04) relative to controls (550 ± 147 mm(3)), and this differential inhibition correlated with expression of the proliferation marker Ki-67. Both CR and rapamycin decreased phosphorylation of mTOR, p70/S6K, and S6 ribosomal protein, but only CR decreased phosphorylation of Akt, GSK-3β, extracellular signal regulated kinase/mitogen-activated protein kinase, and STAT3(TYR705). These findings suggest that rapamycin partially mimics the anticancer effects of CR on tumor growth in a murine model of pancreatic cancer. Topics: Animals; Antibiotics, Antineoplastic; Blotting, Western; Body Weight; Caloric Restriction; Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Disease Models, Animal; Glucose; Glucose Tolerance Test; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Immunoenzyme Techniques; Insulin-Like Growth Factor I; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; STAT3 Transcription Factor; TOR Serine-Threonine Kinases; Tumor Cells, Cultured | 2011 |
Adenovirus-mediated eukaryotic initiation factor 4E binding protein-1 in combination with rapamycin inhibits tumor growth of pancreatic ductal adenocarcinoma in vivo.
Over-expression of eIF4E indicates a poor prognosis in different tumors. In the present study, we investigated the frequency of eIF4E, 4E-BP1 and phosphorylated 4E-BP1 expression in PDAC cell lines, gastric carcinoma (GC) cell lines and human embryonic pancreatic cells, as well as gene therapy using translation repressor gene 4E-BP1 in combination with the mTOR inhibitor rapamycin. We also assessed the significance of eIF4E expression in 80 PDAC cases. Combination therapy of adenovirus vector-delivered 4E-BP1 gene and rapamycin was administered to determine their growth inhibition effect in vitro and in vivo in mice. Our study revealed that all PDAC cell lines, GC cell lines and human embryonic pancreas-derived cells expressed the 25-kDa eIF4E protein (MIAPaca-2 cells also expressed the 13-kDa protein 4E-BP1). The 80 PDAC specimens showed a heterogeneous pattern of eIF4E staining. No significant correlation between eIF4E expression and TNM classification was found. Adenovirus vectors Ad-4E-BP1 and Ad-GFP efficiently showed transgenic expression with hyperphosphorylation of 4E-BP1; however, insignificant growth inhibition of the PDAC and GC cell lines was observed. Combination therapy with rapamycin significantly inhibited proliferation and tumor growth in vitro as well as in vivo. Therefore, combination of Ad 4E-BP1 and rapamycin may be a more effective adjuvant therapy. Topics: Adaptor Proteins, Signal Transducing; Adenoviridae; Adult; Aged; Aged, 80 and over; Animals; Antibiotics, Antineoplastic; Carcinoma, Pancreatic Ductal; Cell Cycle Proteins; Cell Proliferation; Combined Modality Therapy; Female; Genetic Therapy; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Pancreatic Neoplasms; Phosphoproteins; Sirolimus; Transduction, Genetic; Tumor Cells, Cultured; Xenograft Model Antitumor Assays | 2009 |
A combined, rational approach towards inhibition of the MEK-ERK and mTOR pathways in pancreatic ductal adenocarcinoma: promise or deja vu?
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Pancreatic Neoplasms; Protein Serine-Threonine Kinases; Ribosomal Protein S6; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays | 2009 |
In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer.
Mammalian target of rapamycin (mTOR) is considered to be a major effector of cell growth and proliferation that controls protein synthesis through a large number of downstream targets. We investigated the expression of the phosphatidylinositol 3'-kinase (PI3K)/mTOR signaling pathway in human pancreatic cancer cells and tissues, and the in vivo antitumor effects of the mTOR inhibitor CCI-779 with/without gemcitabine in xenograft models of human pancreatic cancer. We found that the Akt, mTOR and p70 S6 kinase (S6K1) from the PI3K/mTOR signaling pathway were activated in all of the pancreatic cancer cell lines examined. When surgically resected tissue specimens of pancreatic ductal adenocarcinoma were examined, phosphorylation of Akt, mTOR and S6K1 was detected in 50, 55 and 65% of the specimens, respectively. Although CCI-779 had no additive or synergistic antiproliferative effect when combined with gemcitabine in vitro, it showed significant antitumor activity in the AsPC-1 subcutaneous xenograft model as both a single agent and in combination with gemictabine. Furthermore, in the Suit-2 peritoneal dissemination xenograft model, the combination of these 2 drugs achieved significantly better survival when compared with CCI-779 or gemcitabine alone. These results demonstrate promising activity of the mTOR inhibitor CCI-779 against human pancreatic cancer, and suggest that the inhibition of mTOR signaling can be exploited as a potentially tumor-selective therapeutic strategy. Topics: Adenocarcinoma; Animals; Antimetabolites, Antineoplastic; Carcinoma, Pancreatic Ductal; Deoxycytidine; Female; Gemcitabine; Humans; Mice; Mice, Nude; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinases; Signal Transduction; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Transplantation, Heterologous | 2006 |
Inhibition of different intracellular signal cascades in human pancreatic cancer cells.
Pancreatic cancer is still a malignant disease with a poor prognosis. Except for surgery, no curative treatment has been found, albeit large research efforts. Agents, such as growth factors and hormones, have been shown to stimulate cell proliferation, whereas their receptor antagonists have been less efficient to inhibit cell proliferation. The aim of this study was to examine the effect of inhibitors of the intracellular signal cascades on pancreatic cancer cell number.. A cell line was developed from a patient with pancreatic cancer and subcloned to three generations. The four cell lines were grown in serum-free medium. The effects of PD98059, LY294002, rapamycin and its analogue CCI-779 were tested in dose-response experiments. The chemotherapeutic agent gemcitabine, with or without combination of the other potential inhibitor drugs in different concentrations, was also examined. The cell number was evaluated with the XTT method.. PD98059 reduced the cell number in all the cell lines tested. At a concentration of 10(-4) M the cell number was reduced by 50-90%. LY294002 reduced the cell number by 40-50% at the same concentration. Two of four cell lines had their cell number reduced by CCI-779 by 60%, whereas the other two cell lines were reduced by 30%. Rapamycin or gemcitabine alone had no or only moderate effect on single cell lines. Different combinations of CCI-779 and gemcitabine led to reduction of the cell number by about 50% in concentrations up to 10(-7) M.. Inhibitors of the intracellular signal cascades can reduce the cell number of human pancreatic cancer cell lines. Inhibitors of the mitogen-activated protein kinase downstream signalling cascades seem to be more efficient than the other inhibitors. PD98059 and CCI-779, in combination with gemcitabine, could be worth studying in clinical conditions. Topics: Antibiotics, Antineoplastic; Carcinoma, Pancreatic Ductal; Cell Division; Chromones; Culture Media, Serum-Free; Enzyme Inhibitors; Flavonoids; Humans; Morpholines; Pancreatic Neoplasms; Signal Transduction; Sirolimus; Tumor Cells, Cultured | 2005 |