Linked Life Data

11751396

Source:http://linkedlifedata.com/resource/pubmed/id/11751396

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
24
pubmed:dateCreated
2001-12-25
pubmed:abstractText
Farnesyl:protein transferase (FPTase) inhibitors (FTIs) were originally developed as potential anticancer agents targeting the ras oncogene and are currently in clinical trials. Whereas FTIs inhibit the farnesylation of Ha-Ras, they do not completely inhibit the prenylation of Ki-Ras, the allele most frequently mutated in human cancers. Whereas farnesylation of Ki-Ras is blocked by FTIs, Ki-Ras remains prenylated in FTI-treated cells because of its modification by the related prenyltransferase, geranylgeranyl:protein transferase type I (GGPTase-I). Hence, cells transformed with Ki-ras tend to be more resistant to FTIs than Ha-ras-transformed cells. To determine whether Ki-ras-transformed cells can be targeted by combining an FTI with a GGPTase-I inhibitor (GGTI), we evaluated potent, selective FTIs, GGTIs, and dual prenylation inhibitors (DPIs) that have both FTI and GGTI activity. We find that in human PSN-1 pancreatic tumor cells, which harbor oncogenic Ki-ras, and in other tumor lines having either wild-type or oncogenic Ki-ras, treatment with an FTI/GGTI combination or with a DPI blocks Ki-Ras prenylation and induces markedly higher levels of apoptosis relative to FTI or GGTI alone. We demonstrate that these compounds can inhibit their enzyme targets in mice by monitoring pancreatic and tumor tissues from treated animals for inhibition of prenylation of Ki-Ras, HDJ2, a substrate specific for FPTase, and Rap1A, a substrate specific for GGPTase-I. Continuous infusion (72 h) of varying doses of GGTI in conjunction with a high, fixed dose of FTI causes a dose-dependent inhibition of Ki-Ras prenylation. However, a 72-h infusion of a GGTI, at a dose sufficient to inhibit Ki-Ras prenylation in the presence of an FTI, causes death within 2 weeks of the infusion when administered either as monotherapy or in combination with an FTI. DPIs are also lethal after a 72-h infusion at doses that inhibit Ki-Ras prenylation. Because 24 h infusion of a high dose of DPI is tolerated and inhibits Ki-Ras prenylation, we compared the antitumor efficacy from a 24-h FTI infusion to that of a DPI in a nude mouse/PSN-1 tumor cell xenograft model and in Ki-ras transgenic mice with mammary tumors. The FTI and DPI were dosed at a level that provided comparable inhibition of FPTase. The FTI and the DPI displayed comparable efficacy, causing a decrease in growth rate of the PSN-1 xenograft tumors and tumor regression in the transgenic model, but neither treatment regimen induced a statistically significant increase in tumor cell apoptosis. Although FTI/GGTI combinations elicit a greater apoptotic response than either agent alone in vitro, the toxicity associated with GGTI treatment in vivo limits the duration of treatment and, thus, may limit the therapeutic benefit that might be gained by inhibiting oncogenic Ki-Ras through dual prenyltransferase inhibitor therapy.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
61
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
8758-68
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:11751396-Alkyl and Aryl Transferases, pubmed-meshheading:11751396-Animals, pubmed-meshheading:11751396-Antineoplastic Combined Chemotherapy Protocols, pubmed-meshheading:11751396-Apoptosis, pubmed-meshheading:11751396-Drug Screening Assays, Antitumor, pubmed-meshheading:11751396-Drug Synergism, pubmed-meshheading:11751396-Enzyme Inhibitors, pubmed-meshheading:11751396-Farnesyltranstransferase, pubmed-meshheading:11751396-Female, pubmed-meshheading:11751396-Humans, pubmed-meshheading:11751396-Mice, pubmed-meshheading:11751396-Mice, Nude, pubmed-meshheading:11751396-Pancreatic Neoplasms, pubmed-meshheading:11751396-Protein Prenylation, pubmed-meshheading:11751396-Tumor Cells, Cultured, pubmed-meshheading:11751396-Xenograft Model Antitumor Assays, pubmed-meshheading:11751396-ras Proteins
pubmed:year
2001
pubmed:articleTitle
Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models.
pubmed:affiliation
Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. rob_lobell@merck.com
pubmed:publicationType
Journal Article, Comparative Study, Evaluation Studies