Activity In Pancreatic Cancer Research Articles

Total carboxypeptidase a (T-CPA) activity in pancreatic cancer

Total carboxypeptidase a (T-CPA) activity in pancreatic cancer

Phase II study of the multitargeted antifolate LY231514 (ALIMTA™, MTA, pemetrexed disodium) in patients with advanced pancreatic cancer

To determine the safety and activity of LY231514 (ALIMTA, MTA, pemetrexed disodium, Eli Lilly and Co., Indianapolis, IN) in chemotherapy-naïve patients with advanced pancreatic cancer. Patients with unresectable or metastatic pancreatic cancer received LY231514 600 mg/m2 as a 10-minute infusion every three weeks. Forty-two patients were enrolled in this phase II trial. The median age was 60.3 (range 37-77) years; 79% had metastatic disease. Neutropenia was common (40% of patients > or = grade 3) but infectious complications were rare. Significant anemia or thrombocytopenia occurred in < 20% of patients. Non-hematologic toxicities included grade 2 or 3 skin reaction which was ameliorated by dexamethasone. Elevations of bilirubin or transaminases were infrequent (< 25% of patients) and did not require dose reductions or treatment delays. Thirty-five patients received two cycles of therapy and were evaluable for response. One complete (duration 16.2 months) and one partial (duration 6.9 months) were observed resulting in an objective response rate of 5.7% for evaluable patients. In addition, 17 patients (40%) had stable disease that lasted > or = 6 months in 5 patients. The median survival was 6.5 months, with 28% of patients alive at one year. LY231514 is a well-tolerated agent with minimal objective antitumor activity in pancreatic cancer. The median and one year survival times, which may be important indicators in phase II trials of new agents, are of interest. Combination trials of LY231514 in pancreatic cancer are planned.

New agents in gastrointestinal malignancies: Part 2: Gemcitabine in clinical practice.

This is part two of the two-part series on new chemotherapy agents for gastrointestinal malignancies. The first article addressed the agent irinotecan hydrochloride (CAMPTOSAR Injection, Pharmacia & Upjohn Company, Kalamazoo, MI; also investigated under the name CPT-11) for use with metastatic colon cancer. This article discusses gemcitabine hydrochloride (GEMZAR for Injection, Eli Lilly and Company, Indianapolis, IN; also referred to as dFdC) for advanced pancreatic cancer. The article reviews the current clinical use, safety profile, and key patient management guidelines for the new and novel cytotoxic agent, gemcitabine, which was approved in 1996. This agent has demonstrated activity in pancreatic cancer, is generally well tolerated, and can safely be administered on an outpatient basis. Therapy-related side effects are manageable with appropriate monitoring and intervention, and reversible with dose modification or discontinuation. As clinical and investigational use of gemcitabine increases, the oncology nurse and other members of the health care team will need to anticipate potential treatment-associated toxicities and be knowledgeable in their early identification and management. As patient advocates, oncology nurses play a key role in treatment outcome and related quality of life through expert patient education, symptom recognition, and intervention according to individual patient tolerance.

Carboxypeptidase a activity in pancreatic cancer and acute pancreatitis

Carboxypeptidase a activity in pancreatic cancer and acute pancreatitis

Activation of Raf-1 in Human Pancreatic Adenocarcinoma

Point mutations in the Ras oncogene cause Ras to remain in its active GTP-bound state sending signals downstream continuously. Since 75 to 90% of all human pancreatic ductal adenocarcinomas harbor activating mutations at codon 12 of the K-ras oncogene it was our belief that Raf-1–;MEK–;MAPK will be activated in the majority of human pancreatic cancers. The aim of this study was to confirm activation of Raf-1 in K-ras mutant human pancreatic cancer. Additionally, we sought to determine if Raf-1 activation differed in K-ras mutant and nonmutant pancreatic cancer. Futhermore, we were interested in determining if Raf-1 activation in pancreatic cancer led to subsequent activation of downstream effectors such as MAP kinase. The presence of mutations in codon 12 of the K-ras oncogene in 14 human pancreatic adenocarcinoma cell lines was determined by use of mutant allele-specific PCR restriction fragment length polymorphism analysis. Raf-1 expression of quiescent cells was determined by immunoblotting using a rabbit anti-human polyclonal antibody and enhanced chemiluminescence. MAP kinase activity was determined by measuring the incorporation of phosphate into Myelin Basic Protein. Seven cell lines were noted to have mutations in codon 12 of K-ras while seven cell lines did not. There was no difference in expression of the 74 kDa-activated form of Raf-1 in K-ras mutant vs K-ras nonmutant cell lines. However, there was a significant increase in MAP kinase activity in the nonmutant cell lines compared to the cell lines with Ras mutations (P= 0.026). We conclude that Raf-1 is expressed in its active form in human pancreatic cancer regardless of K-ras status. However, signaling downstream of Raf-1 differs in cell lines with K-ras mutations compared to those cell lines without K-ras mutations.

Phytohemagglutinin-L (PHA-L) lectin surface binding of N-linked beta 1-6 carbohydrate and its relationship to activated mutant ras in human pancreatic cancer cell lines.

Alterations of the N-linked carbohydrate core structure of cell surface glycoproteins (beta 1-6 branching) can be detected by phytohemagglutinin (PHA-L) lectin binding and has been linked to tumor progression and K-ras activation in colon cancer. The purpose of this study was to determine the prevalence of this carbohydrate alteration and its relationship to K-ras activation in pancreatic cancer. Nine human pancreatic cancer cell lines and 4 colon lines as controls were grown under standard tissue culture conditions. K-ras genome analysis was performed by polymerase chain reaction amplification and sequencing. The proportion of cellular p21-ras bound to GTP (ras-GTP level) was determined using immunoprecipitation of 32P-labeled cell lysates followed by thin layer chromatography and phosphoimaging analysis. Lectin blot analysis was performed on crude membrane preparations. Sensitivity to lectins was assessed with cell culture thymidine incorporation. Of 9 pancreatic cancer lines tested, 3 had wild type K-ras, 2 had heterozygous and 4 had homozygous mutations in codon 12 of K-ras. These genotypes correlated strongly with the level of ras-GTP measured. K-ras mutants had increased levels of ras-GTP compared to wild-type cell lines. PHA-L binding to cell membranes correlated positively with ras-GTP levels in 7 out of 9 cell lines. PHA-L toxicity was greatest in cells with positive PHA-L reactivity on Western blotting. A positive correlation between the presence of K-ras mutation, increased ras-GTP level, and increased cell surface beta 1-6 N-linked carbohydrate exists in pancreatic cancer cell lines.

Coagulation inhibition and activation in pancreatic cancer. Changes during progress of disease.

To elucidate the disturbed hemostatic balance in patients with pancreatic cancer, the levels of plasma coagulation inhibition and coagulation activation were determined. Twenty-one patients with adenocarcinoma of the pancreas were followed from time of diagnosis until death, using plasma analyses of coagulation inhibitors and a molecular marker of coagulation activation (thrombin-antithrombin complex, TAT). TAT was increased significantly at the time of diagnosis of pancreatic cancer compared with age-adjusted healthy control subjects (mean, 6.2 +/- 4.6 micrograms/l [standard deviation] versus 2.0 +/- 0.7 micrograms/l). It increased with disease progression (mean in the terminal phase, 14.1 micrograms/l; P < 0.05). Plasma levels of tissue factor pathway inhibitor (TFPI) also were increased significantly at the time of diagnosis compared with the control group (mean, 176 +/- 80% versus 127 +/- 29%; P < 0.05). The TFPI decreased to normal levels (121 +/- 40%) after surgical removal of the pancreatic tumor (n = 4) or relief of the cholestasis using a bypass procedure (n = 6). The TFPI levels increased significantly as the malignant disease progressed (from 1-3 months postoperatively to the terminal phase of disease; mean, 114 +/- 52% versus 154 +/- 60%). There was a significant positive correlation between TFPI levels and bilirubin levels; the correlation coefficient at diagnosis was 0.70 (P < 0.001). The levels of the coagulation inhibitors antithrombin, heparin cofactor II, protein C, and free protein S decreased significantly with disease progression compared with the normal values found at diagnosis. The mechanism for TFPI increase in cancer is not known. It may be related to the preoperative cholestasis seen in this study, but the increased degree of coagulation activation also may contribute.

Overview of chemotherapy for pancreatic cancer

Of more than 30 anticancer drugs evaluated in advanced pancreatic cancer, only 5-FU has a response rate with 95% confidence intervals greater than 20%. Although mitomycin-C, streptozotocin, and doxorubicin are frequently used in combination regimens, their single-agent activity in pancreatic cancer is marginal. The improved response rates initially reported in some Phase II trials of drug combinations have not been confirmed in most cooperative group trials. When partial responses are obtained, they are brief and rarely associated with clinical benefit. Median survival for combination regimens range from 3 to only 6.5 mo and are probably no longer than those obtained with 5-FU. Radiotherapy combined with 5-FU prolongs survival in patients who undergo curative resection of tumor confined to the pancreas and in those with locally advanced disease. Radiation and imaging techniques that are more sophisticated than those available at the time of the initial randomized trials are now available. More effective treatments are needed for all disease stages and may evolve as understanding of the etiology, growth regulation, and drug resistance of pancreatic cancer increases. Since results of currently available treatment are poor, patients should be offered the opportunity to participate in clinical trials.