Phase II and Pharmacodynamic Study of the Farnesyltransferase Inhibitor R115777 as Initial Therapy in Patients With Metastatic Pancreatic Adenocarcinoma

Cohen, Steven J.; Ho, Linus; Ranganathan, Sulabha; Abbruzzese, James L.; Alpaugh, R. Katherine; Beard, Mary; Lewis, Nancy; McLaughlin, Susan; Rogatko, André; Pérez‐Ruixo, Juan José; Thistle, Amanda M.; Verhaeghe, Tom; Wang, Hao; Weiner, Louis M.; Wright, John J.; Hudes, Gary R.; Meropol, Neal J.

doi:10.1200/jco.2003.08.040

Cited by 162 publications

(92 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The maximal decrease in activity was estimated at 49%, indicating that FTase could not completely be inhibited. Similar inhibition values were found in studies with single FTase inhibitors (Cohen et al, 2003;Alsina et al, 2004;Cortes et al, 2005;Tabernero et al, 2005). In the Calu-6 xenograft model, inhibition of FTase by 66% was associated with a reduction of the tumour volume of 15% (unpublished data).…”

Section: Discussionsupporting

confidence: 65%

Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer

et al. 2008

View full text Add to dashboard Cite

AZD3409 is an orally active double prodrug that was developed as a novel dual prenyltransferase inhibitor. The formation of the active metabolite AZD3409 acid is mediated by esterases in plasma and cells. The aim of this phase I study was to determine the maximum tolerated dose, toxicities, pharmacokinetics and pharmacodynamics of AZD3409. AZD3409 was administered orally to patients with advanced solid malignancies using an interpatient dose-escalation scheme starting at 500 mg AZD3409 once daily. Twenty-nine patients were treated at seven dose levels. The MTD of part A was defined as 750 mg b.i.d. in the fasted state. Adverse events were mainly gastrointestinal and the severity was on average mild to moderate and reversible. The dose-limiting toxicities were vomiting, diarrhoea and uncontrolled nausea. Pharmacokinetic studies of the prodrug and the active metabolite indicated dose proportionality. Pharmacodynamic studies showed that farnesyltransferase (FTase) was inhibited at all dose levels. In conclusion, chronic oral dosing with AZD3409 is feasible and results in significant inhibition of FTase activity. Pharmacodynamic studies revealed that the maximal FTase inhibition, estimated at 49±11%, appeared to be reached at AZD3409 acid plasma concentrations at which the occurrence of drug-related toxicity was low. This study supports the rationale to implement biological effect studies in clinical trials with biologically active anticancer drugs to define optimal dosing regimens.

show abstract

Section: Discussionsupporting

confidence: 65%

Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Matrix metalloproteinase inhibitors, farnesyltransferase inhibitors, and tyrosine-kinase inhibitors and monoclonal antibodies against growth factors or their receptors are novel agents that have undergone phase II or III trials (33,48). Phase III studies of matrix metalloproteinase inhibitors, alone or in combination with gemcitabine (49), and phase III studies of farnesyltransferase inhibitors have produced disappointing results (50). Targeting of epidermal growth factor receptor and its family members with monoclonal antibodies has become possible with the recent introduction of chimeric and humanized antibodies (33,48).…”

Section: Discussionmentioning

confidence: 99%

Autocrine Motility Factor Signaling Enhances Pancreatic Cancer Metastasis

Tsutsumi

Yanagawa

Shimura

et al. 2004

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Autocrine motility factor (AMF)/phosphoglucose isomerase (PGI) is a ubiquitous cytosolic enzyme that plays a key role in glycolysis. AMF/PGI is also a multifunctional protein that acts in the extracellular milieu as a potent mitogen/cytokine. Increased expression of AMF/PGI and its receptor has been found in a wide spectrum of malignancies and is associated with cancer progression and metastasis. Recent studies indicated that AMF is induced by hypoxia and enhances the random motility of pancreatic cancer cells. In the present study, the role and regulation of AMF in the growth and metastasis of pancreatic cancer cells were determined.Experimental Design: In this study, we assessed whether overexpression of AMF in human pancreatic cancer cells enhances the liver metastasis using an orthotopic mouse tumor model. We also investigated the intracellular signal transduction pathways of AMF in human pancreatic cancer cell lines.Results: Overexpression of AMF stimulated in vitro invasion of MIA PaCa-2 cells. In vivo, after orthotopic implantation into the pancreas of nude mice, parental and empty vector-transfected MIA PaCa-2 cells produced locally relatively small tumors with no evidence of liver metastasis, whereas AMF-transfected MIA PaCa-2 cells produced the large tumors and liver metastases. In addition, over-expression of AMF leads to down-regulation of E-cadherin expression associated with the up-regulation of the zinc-finger transcription factor SNAIL expression.Conclusions: The data submitted here show that AMF expression significantly contributes to the aggressive phenotype of human pancreatic cancer and thus may provide a novel prognostic and therapeutic target.

show abstract

“…Determination of FTase activity is possible by measuring the amount of ex vivo added radioactive farnesyl pyrophosphate that is bound to a peptide derived from lamin B or K-Ras in a scintillation proximity assay or filter binding assay. It was shown that administration of tipifarnib to patients with pancreatic cancer inhibits FTase activity in PBMCs by 35%-50% [55]. No evidence of antitumor activity was found, however.…”

Section: Ftase Activitymentioning

confidence: 99%

Development of Farnesyl Transferase Inhibitors: A Review

2005

View full text Add to dashboard Cite

Learning Objectives After completing this course, the reader will be able to: Describe the potential mechanisms by which farnesyl transferases inhibit tumor growth. Explain possible mechanisms by which tumor cells may develop resistance to this class of agents. Discuss the scientific requirements for developing targeted cancer treatments that will actually be useful in patients. Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at http://CME.TheOncologist.com

show abstract

Phase II and Pharmacodynamic Study of the Farnesyltransferase Inhibitor R115777 as Initial Therapy in Patients With Metastatic Pancreatic Adenocarcinoma

Abstract: Although treatment with R115777 resulted in partial inhibition of FTase activity in mononuclear cells, it did not exhibit single-agent antitumor activity in patients with previously untreated metastatic pancreatic cancer.

Cited by 162 publications

References 18 publications

Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer

Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer

Autocrine Motility Factor Signaling Enhances Pancreatic Cancer Metastasis

Development of Farnesyl Transferase Inhibitors: A Review

Contact Info

Product

Resources

About