Linked Life Data

11350886

Source:http://linkedlifedata.com/resource/pubmed/id/11350886

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2001-5-14
pubmed:abstractText
Raf-1 is a serine/threonine kinase that functions as a critical effector of Ras-mediated signal transduction via the mitogen-activated protein kinase pathway. Constitutive activation of this pathway directly contributes to malignant transformation in many human tumors. A 20-base phosphorothioate oligonucleotide complementary to c-raf-1 mRNA (ISIS 5132; CGP 69846A) has been shown to specifically suppress Raf-1 expression both in vitro and in vivo. This Phase I trial, involving 22 patients with advanced cancer, was designed to evaluate the safety, feasibility, and maximum tolerated dose of ISIS 5132 administration as a weekly 24-h i.v. infusion. Pharmacokinetic analysis was performed, and c-raf-1 mRNA levels in peripheral blood mononuclear cells were assessed using quantitative reverse transcription-PCR. This trial defined a maximum tolerated dose of 24 mg/kg/week on this schedule. Two of four patients treated at 30 mg/kg/week had serious adverse events after the first dose of ISIS 5132, including acute hemolytic anemia and acute renal failure and anasarca. There were no major responses documented. Dose-dependent complement activation was demonstrated on this schedule, but not on previously evaluated schedules, of ISIS 5132 administration. In contrast to other trials of ISIS 5132, there appeared to be no consistent suppression of peripheral blood mononuclear cell c-raf-1 mRNA level on this schedule at any of the dose levels analyzed. These data suggest that the efficacy and toxicity profiles of antisense oligonucleotides may be highly dependent on the schedule of administration and support the analysis of the putative molecular target in the evaluation of novel therapeutics.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1078-0432
pubmed:author
pubmed:issnType
Print
pubmed:volume
7
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1214-20
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:11350886-Adult, pubmed-meshheading:11350886-Aged, pubmed-meshheading:11350886-Aged, 80 and over, pubmed-meshheading:11350886-Antineoplastic Agents, pubmed-meshheading:11350886-Blood Coagulation, pubmed-meshheading:11350886-Complement System Proteins, pubmed-meshheading:11350886-Drug Administration Schedule, pubmed-meshheading:11350886-Female, pubmed-meshheading:11350886-Humans, pubmed-meshheading:11350886-Infusions, Intravenous, pubmed-meshheading:11350886-Leukocytes, Mononuclear, pubmed-meshheading:11350886-Male, pubmed-meshheading:11350886-Middle Aged, pubmed-meshheading:11350886-Neoplasm Staging, pubmed-meshheading:11350886-Neoplasms, pubmed-meshheading:11350886-Oligodeoxyribonucleotides, Antisense, pubmed-meshheading:11350886-Proto-Oncogene Proteins c-raf, pubmed-meshheading:11350886-RNA, Messenger, pubmed-meshheading:11350886-Thionucleotides, pubmed-meshheading:11350886-Treatment Outcome
pubmed:year
2001
pubmed:articleTitle
Phase I Trial of ISIS 5132, an antisense oligonucleotide inhibitor of c-raf-1, administered by 24-hour weekly infusion to patients with advanced cancer.
pubmed:affiliation
Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois 60637-1470, USA. crudin@meecine.bsd.uchicago.edu
pubmed:publicationType
Journal Article, Clinical Trial, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't, Clinical Trial, Phase I