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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic adenocarcinoma is a leading cause of cancer death in the United States and represents a challenging chemotherapeutic problem. The pharmacological control of angiogenesis might represent a novel approach to the management of pancreas cancer, since the pathological development of vascular supply is a critical step for tumor growth and may affect its prognosis. In order to test this hypothesis, SU5416 ([3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one]) a selective inhibitor of the vascular endothelial growth factor receptor-2 tyrosine kinase, and gemcitabine (2', 2'-difluorodeoxycytidine) were tested on endothelial (HUVEC) and pancreatic tumor cells (MIA PaCa-2) in vitro and in vivo alone and in simultaneous association. SU5416 inhibited HUVEC cells stimulated to proliferate by vascular endothelial growth factor but not MIA PaCa-2 cells; the drug concentration that decreased cell growth by 50% (IC50) was 0.14 microM. Furthermore, SU5416 reduced the development of microvessels from placental explants (IC50, 0.23 microM). Gemcitabine inhibited the growth of both HUVEC and MIA PaCa-2 cells with an IC50 of 0.08 and 0.1 microM, respectively. A synergistic effect (combination index <1 and dose reduction index >1) on anti-proliferative and pro-apoptotic activity was calculated with the simultaneous combination of the two drugs on endothelial cells. A marked in vivo antitumor effect on MIA PaCa-2 xenografts was observed with SU5416 at a protracted schedules, as well as with gemcitabine; furthermore, the combination between the two drugs resulted in an almost complete suppression of tumor growth and relapse. In conclusion, the present results provide the evidence of an effective anti-endothelial/antitumor activity of protracted administration of SU5416 on human pancreas cancer xenografts, which is comparable with the one obtained by gemcitabine; moreover, the synergistic combination between these drugs on endothelial cells and the promising association in pancreatic cancer xenografts could be used in future studies and translated into the clinical setting.
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PMID:Antiangiogenic versus cytotoxic therapeutic approaches to human pancreas cancer: an experimental study with a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor and gemcitabine. 1536 70

Gemcitabine sensitizes tumor cells to radiation and cisplatin and thereby enhances the cytotoxic effect of gemcitabine. Here we report the efficacy and toxicity of concurrent chemoradiation with gemcitabine and cisplatin in the treatment of patients with locally advanced, unresectable pancreatic cancer. A total of 47 patients (29 men, 18 women; median age 61 years) with histologically proven advanced pancreatic carcinoma were included in the study. They underwent chemotherapy with gemcitabine 300 mg/m2 and cisplatin 30 mg/m2 on days 1, 8, 22, and 29; concurrent radiation (45-50 Gy) was applied to the tumor and regional lymph nodes (1.8-2.0 Gy/fraction 5 days per week). Subsequent to chemoradiotherapy, treatment was continued with more two cycles of gemcitabine (1000 mg/m2) and cisplatin (50 mg/m2) applied on days 1 and 15 of a 4-week cycle. After completion of chemoradiotherapy, 9 patients (19.1%) achieved a complete response and 23 patients (48.9%) a partial response, for an overall response rate of 68%. The lesions were considered resectable in 27 patients, and 25 of the 27 patients underwent laparotomy. The other 20 patients underwent a definitive pancreatic resection. Altogether, 13 patients had negative surgical margins. With a median follow-up of 25.7 months (range 12.7-38.7 months) after completion of chemoradiation, distant metastasis had occurred in 23 patients and local recurrence in only 4 of 44 patients (8.5%). the median progression-free survival was 7.8 months (range 6.2-9.4 months). The median survival amounted to 10.7 months (range 8.4-13.0 months) for all patients, whereas it was prolonged to 24.2 months (range 6.8-41.7 months) for those undergoing R0 resection. The main toxicities associated with chemoradiation included grade 3/4 leukopenia (68% of patients) and thrombocytopenia (61%). Episodes of cholangitis were observed in 11 patients. We concluded that gemcitabine and cisplatin can safely be combined with external beam radiation. This preoperative treatment approach is highly effective and appears to improve survival in patients whose tumors are rendered completely resectable.
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PMID:Effect of chemoradiotherapy with gemcitabine and cisplatin on locoregional control in patients with primary inoperable pancreatic cancer. 1557 57

Addition of antioxidants to chemotherapy is an unresolved problem in oncology. It is still an issue of debate, whether antioxidants may reduce rough cellular toxicity and thereby the systemic side effects of the chemotherapy, without sacrificing the anti-tumor efficacy. Gemcitabine is a rather new anti-cancer agent, which is quite potent against a range of drug resistant tumors, particularly breast cancer. Tumor-sensitivity towards gemcitabine can be increased with COX inhibitory anti-inflammatory agents and ribonucleotide reductase (RR) inhibitor flavopiridol. Acetaminophen and DMSO are two unique anti-inflammatory and anti- oxidant agents with unrelated structures, yet both capable to block RR and COX, simultaneously. Using plating efficacy and 3H- thymidine labeling, we monitored efficacy of acetaminophen and DMSO to modulate growth and gemcitabine sensitivity in FM3A breast tumor cells, which is highly used to study thymineless death induced by nucleotide-metabolism hemming drugs. Peculiarly, acetaminophen alone stimulated S-phase, which was not accompanied with enhanced plating, rather resulting in 40.3% growth inhibition at the 96 hour. DMSO alone significantly diminished both the plating and S-phase, which resulted in 71.7% growth inhibition at the 96 hour. Gemcitabine drastically reduced S-phase and plating until 72 hours, yet at 96 hours it lost its efficacy to suppress the S-phase with concomitant 2-fold rise in cell numbers in comparison to 72 hour time point. Both DMSO and acetaminophen brought S-phase to around zero percent in combination with gemcitabine until 48 hours, yet they both reduced early cytotoxicity of gemcitabine at the same time interval. However, at the 96 hour, they both strongly augmented gemcitabine efficacy to block S-phase and prevented the rise in plating. Acetaminophen and DMSO should be tested in animal models, whether they could augment efficacy and reduce the toxicity of gemcitabine.
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PMID:Acetaminophen and DMSO modulate growth and gemcitabine cytotoxicity in FM3A breast cancer cells in vitro. 1564 Sep 56

Gemcitabine is pyrimidine analog which has demonstrated antitumoral activity in a variety of solid tumors. Laboratory studies demonstrating that gemcitabine is a potent radiosensitizer led to a variety of trials combining radiation and gemcitabine. In the clinic, phase I-II studies are still trying to determine the optimal dose and schedule which could be use in daily clinical practice. This review summarizes the mechanisms of interaction between radiotherapy and gemcitabine and presents several therapeutic schemes for each tumor location.
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PMID:[Concomitant use of radiotherapy and gemcitabine: preclinical findings and clinical practice]. 1567 55

Gemcitabine is a pyrimidine analog that is active in patients with aggressive lymphomas and Hodgkin disease. This study assessed tumor response in patients with previously treated follicular or small lymphocytic non-Hodgkin lymphoma. This was a 2-stage phase II trial with the first stage requiring 2 of 13 responses to proceed to the second stage. Gemcitabine was given as a single agent to patients with previously treated follicular or small lymphocytic lymphomas. Gemcitabine was administered at 1250 mg/m2 over 30 minutes on days 1 and 8 of a 21-day cycle for a maximum of 6 cycles. Thirteen patients were treated with 1 to 6 cycles of chemotherapy. Two patients experienced grade 4 toxicity with neutropenia. No grade 4 nonhematologic toxicity was seen. There was 1 partial response and 8 patients (61%) had either minimal response or stable disease. Single-agent gemcitabine administered at this dose and schedule produced 1 partial remission and half the patients had stable disease. However, the study had to be stopped early because of lack of meaningful response.
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PMID:A phase II study of single agent gemcitabine in relapsed or refractory follicular or small lymphocytic non-Hodgkin lymphomas: a Hoosier Oncology Group Study. 1580 12

Gemcitabine (2'2'-difluorodeoxycytidine [dFdC]) is a synthetic analog of deoxycytidine with two fluorine atoms at the 2' position of the carbohydrate. As a hydrophobic molecule, dFdC competes for intracellular access via membrane-associated nucleoside transporter proteins. Following intracellular transport, dFdC is phosphorylated sequentially by deoxycytidine kinase to gemcitabine triphosphate, which inhibits ribonucleotide metabolism, hinders DNA processing, and increases accumulation of intrastrand adducts and interstrand cross-links, thereby leading to a G1 block in the cell cycle. dFdC monotherapy has been extensively evaluated at doses of 800-1250 mg/m2. dFdC is generally well tolerated, with the most frequently occurring dose-limiting toxicities being hematologic, noncumulative, and easily managed by dose alteration. Several studies involving treatment of recurrent ovarian cancer patients with dFdC monotherapy, most of whom had platinum-resistant disease and/or prior exposure to paclitaxel, led to overall response rates of 14-22% and a median duration of response of 4.0-10.6 months. An additional one third of the participants experienced stable disease for an overall clinical benefit in approximately one half of the treated patients. Tumor cells with a multidrug resistance phenotype have increased sensitivity to dFdC (collateral sensitivity). As dFdC is unaffected by platinum resistance, and not susceptible to classic multidrug resistance, it could be particularly beneficial to administer following treatment with agents that induce multidrug resistance. Integration of dFdC with platinum and/or radiation should also be investigated.
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PMID:Gemcitabine monotherapy in recurrent ovarian cancer: from the bench to the clinic. 1583 53

Chemotherapy generates numerous adverse effects, but digital ischemia is usually associated with a paraneoplastic mechanism. In addition to thrombotic microangiopathy or hepatic or pulmonary venoocclusive disease gemcitabine appears to induce this type of complication. This study presents two cases of digital ischemia, which are very likely attributable to gemcitabine. The first case involved a 56-year-old female patient with lymph node metastatic squamous cell carcinoma, for which no primitive tumor could be identified. This carcinoma had been treated at a second stage with gemcitabine at a cumulative dose of 14 390 mg. Search for etiology revealed toxic vascularitis. Response was favourable after interruption of gemcitabine and prescription of a suitable medical treatment. The second case was a 74-year-old male patient with an infiltrating bladder urothelium carcinoma with lymph node metastasis. He had been treated by surgery and chemotherapy (gemcitabine and carboplatine). Gemcitabine-induced arterial thrombosis was diagnosed. Nine other cases of digital ischemia were identified in the literature. This rare adverse effect is probably underestimated. The other reported vascular side-effects are thrombotic microangiopathy, with an estimated occurrence of 1 per 6,000 patients and two cases of veno-occlusive disease. The pathogenic mechanisms have still not been fully elucidated. Precautions before use are necessary, especially in case of associated micro or macroangiopathy.
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PMID:[Digital ischaemia and gemcitabine. Two new cases]. 1592 70

Gemcitabine is the standard of care for advanced pancreatic neoplasia, and exerts its effect through inhibition of DNA synthesis. However, gemcitabine has limited survival benefits. Opioid growth factor (OGF) is an autocrine-produced peptide that interacts with the nuclear receptor, OGFr, to inhibit cell proliferation but is not cytotoxic or apoptotic. The present study was designed to examine whether a combination of chemotherapy with gemcitabine and biotherapy with OGF is more effective than either agent alone in inhibiting pancreatic cancer growth in vitro and in vivo. The combination of OGF (10(-6) M) and gemcitabine (10(-8) M) reduced MIA PaCa-2 cell number from control levels by 46% within 48 h, and resulted in a growth inhibition greater than that of the individual compounds. OGF in combination with 5-fluorouracil also depressed cell growth more than either agent alone. The action of OGF, but not gemcitabine, was mediated by a naloxone-sensitive receptor, and was completely reversible. OGF, but no other endogenous or exogenous opioids, altered pancreatic cancer growth in tissue culture. The combination of OGF and gemcitabine also repressed the growth of another pancreatic cancer cell line, PANC-1. MIA PaCa-2 cells transplanted into athymic mice received 10 mg/kg OGF daily, 120 mg/kg gemcitabine every 3 days; 10 mg/kg OGF daily and 120 mg/kg gemcitabine every 3rd day, or 0.1 ml of sterile saline daily. Tumor incidence, and latency times to tumor appearance, of mice receiving combined therapy with OGF and gemcitabine, were significantly decreased from those of the control, OGF, and gemcitabine groups. Tumor volumes in the OGF, gemcitabine, and OGF/gemcitabine groups were markedly decreased from controls beginning on days 14, 12, and 8, respectively, after tumor cell inoculation. Tumor weight and tumor volume were reduced from control levels by 36-85% in the OGF and/or gemcitabine groups on day 45 (date of termination), and the group of mice exposed to a combination of OGF and gemcitabine had decreases in tumor size of 70% and 63% from the OGF or the gemcitabine alone groups, respectively. This preclinical evidence shows that combined chemotherapy (e.g. gemcitabine) and biotherapy (OGF) provides an enhanced therapeutic benefit for pancreatic cancer.
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PMID:Combination chemotherapy with gemcitabine and biotherapy with opioid growth factor (OGF) enhances the growth inhibition of pancreatic adenocarcinoma. 1594 28

Gemcitabine, oxaliplatin, leucovorin, and 5-fluorouracil (GOLF) is a novel multidrug regimen inducing high levels of necrosis and apoptosis in colon carcinoma cells. This regimen is also able to promote a process of Ag remodeling including up-regulation of immunotherapy targets like carcinoembryonic Ag (CEA), thymidylate synthase (TS). We have conducted a preclinical study aimed to investigate whether these drug-induced modifications would also enhance colon cancer cell immunogenicity. Several CTL lines were thus generated by in vitro stimulating human HLA-A(*)02.01(+) PBMCs, from normal donors and colon cancer patients, with autologous dendritic cells cross-primed with cell lysates of colon cancer cells untreated, irradiated, or previously exposed to different drug treatments including the GOLF regimen. Class I HLA-restricted cytolytic activity of these CTL lines was tested against colon cancer cells and CEA and TS gene transfected target cells. These experiments revealed that CTLs sensitized with GOLF-treated cancer cells were much more effective than those sensitized with the untreated colon carcinoma cells or those exposed to the other treatments. CTL lines sensitized against the GOLF-treated colon cancer cells, also expressed a greater percentage of T-lymphocyte precursors able to recognize TS- and CEA-derived peptides. These results suggest that GOLF regimen is a powerful antitumor and immunomodulating regimen that can make the tumor cells a suitable means to induce an Ag-specific CTL response. These results suggest that a rationale combination of GOLF chemotherapy with cytokine-based immunotherapy could generate a chemotherapy-modulated Ag-specific T-lymphocyte response in cancer patients able to destroy the residual disease survived to the cytotoxic drugs.
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PMID:Dendritic cell-mediated cross-presentation of antigens derived from colon carcinoma cells exposed to a highly cytotoxic multidrug regimen with gemcitabine, oxaliplatin, 5-fluorouracil, and leucovorin, elicits a powerful human antigen-specific CTL response with antitumor activity in vitro. 1600 79

Gemcitabine (dFdCyd) is an analog of cytosine arabinoside with anti-tumor activity in several human cancers. However, the efficacy of this compound in osteosarcoma has not been fully elucidated. Here we assessed the anti-tumor activity of gemcitabine using osteosarcome cell lines. In 9 human osteosarcoma cell lines (G292, HOS, MG63, NY, SaOS, HuO, HuO-3N1, HuO9, HuO9-N2), gemcitabine at the doses of >100 nM showed significant cytotoxicity. In HOS and MG63 cell lines, gemcitabine inhibited DNA synthesis as determined by IdU labeling assay and induced apoptosis as determined by DNA fragmentation assay and May-Giemsa staining. In C3H mice inoculated s.c. with a murine osteosarcoma cell line, LM8, treatment of the mice with gemcitabine showed reduced size of the primary tumor associated with increased apoptotic cells and a virtual absence of metastatic lesions in the lung. Gemcitabine thus had anti-tumor activity on osteosarcoma cell lines both in vitro and in vivo. The result would provide a cellular basis for application of gemcitabine to patients with osteosarcoma.
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PMID:Gemcitabine inhibits viability, growth, and metastasis of osteosarcoma cell lines. 1602 13


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