Linked Life Data

18374183

Source:http://linkedlifedata.com/resource/pubmed/id/18374183

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:dateCreated
2008-3-31
pubmed:abstractText
Chronic activation of Ras proteins by mutational activation or by growth factor stimulation is a common occurrence in many human cancers and was shown to induce and be required for tumor growth. Even if additional genetic defects are present, "correction" of the Ras defect has been shown to reverse Ras-dependent tumorigenesis. One way to block Ras protein activity is by interfering with their spatiotemporal localization in cellular membranes or in membrane microdomains, a prerequisite for Ras signaling and biological activity. Detailed reports describe the use of this method in studies employing farnesylthiosalicylic acid (FTS, Salirasib), a Ras farnesylcysteine mimetic, which selectively disrupts the association of chronically active Ras proteins with the plasma membrane. FTS competes with Ras for binding to Ras-escort proteins, which possess putative farnesyl-binding domains and interact only with the activated form of Ras proteins, thereby promoting Ras nanoclusterization in the plasma membrane and robust signals. This chapter presents three-dimensional time-lapse images that track the FTS-induced inhibition of membrane-activated Ras in live cells on a real-time scale. It also describes a mechanistic model that explains FTS selectivity toward activated Ras. Selective blocking of activated Ras proteins results in the inhibition of Ras transformation in vitro and in animal models, with no accompanying toxicity. Phase I clinical trials have demonstrated a safe profile for oral FTS, with minimal side effects and promising activity in hematological malignancies. Salirasib is currently undergoing trials in patients with pancreatic cancer and with nonsmall cell lung cancer, with or without identified K-Ras mutations. The findings might indicate whether with the disruption of the spatiotemporal localization of oncogenic Ras proteins and the targeting of prenyl-binding domains by anticancer drugs is worth developing as a means of cancer treatment.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0076-6879
pubmed:author
pubmed:issnType
Print
pubmed:volume
439
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
467-89
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
The Ras inhibitor farnesylthiosalicylic acid (Salirasib) disrupts the spatiotemporal localization of active Ras: a potential treatment for cancer.
pubmed:affiliation
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't