1999

DOI: 10.1002/(sici)1097-0215(19990315)80:6<911::aid-ijc18>3.0.co;2-4

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Growth inhibition of ras-dependent tumors in nude mice by a potent ras-dislodging antagonist

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,

²

,

Mali Gana‐Weisz

³

et al.

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Fts (Salirasib) Inhibits Growth Of Lung Cancer Cells1

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Cited by 37 publications

(25 citation statements)

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“…In this study, we employed the specific Ras inhibitor salirasib, which was originally designed to compete with Ras for its binding sites, thereby causing it to become dislodged from the cell membrane and subsequently undergo rapid degradation (19). Salirasib was shown previously to be highly potent in cell culture systems (24 -27), in soft-agar assays (31,32), and in various in vivo murine models (32 -36). Promoter and biochemical analyses of glioblastoma cells treated with salirasib have disclosed that two important Ras-controlled transcription factors are down-regulated by the treatment.…”

Section: Discussionmentioning

confidence: 91%

Salirasib (farnesyl thiosalicylic acid) for brain tumor treatment: a convection-enhanced drug delivery study in rats

¹

,

Ocherashvilli²,

et al. 2008

Molecular Cancer Therapeutics

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Our aim was to assess the ability of convection-enhanced drug delivery (CED), a novel approach of direct delivery of drugs into brain tissue and brain tumors, to treat brain tumors using salirasib (farsnesyl thiosalicylic acid). CED was achieved by continuous infusion of drugs via intracranial catheters, thus enabling convective distribution of high drug concentrations over large volumes while avoiding systemic toxicity. Several phase II/III CED-based trials are currently in progress but have yet to overcome two major pitfalls of this methodology (the difficulty in attaining efficient CED and the significant nonspecific neurotoxicity caused by high drug doses in the brain). In this study, we addressed both issues by employing our previously described novel CED imaging and increased efficiency methodologies to exclusively target the activated form of the Ras oncogene in a 9L gliosarcoma rat model. The drug we used was salirasib, a highly specific Ras inhibitor shown to exert its suppressive effects on growth and migration of proliferating tumor cells in in vitro and in vivo models, including human glioblastoma, without affecting normal tissues. The results show a significant decrease in tumor growth rate in salirasibtreated rats relative to vehicle-treated rats as well as a significant correlation between CED efficacy and tumor growth rate with no observed toxicity despite drug concentrations an order of magnitude higher than previously detected in the brain. The results show that CED of salirasib is efficient and nontoxic for the treatment of glioblastoma in a rat model, thus suggesting that it may be considered for clinical application.

“…In this study, we employed the specific Ras inhibitor salirasib, which was originally designed to compete with Ras for its binding sites, thereby causing it to become dislodged from the cell membrane and subsequently undergo rapid degradation (19). Salirasib was shown previously to be highly potent in cell culture systems (24 -27), in soft-agar assays (31,32), and in various in vivo murine models (32 -36). Promoter and biochemical analyses of glioblastoma cells treated with salirasib have disclosed that two important Ras-controlled transcription factors are down-regulated by the treatment.…”

Section: Discussionmentioning

confidence: 91%

Salirasib (farnesyl thiosalicylic acid) for brain tumor treatment: a convection-enhanced drug delivery study in rats

¹

,

Ocherashvilli²,

et al. 2008

Molecular Cancer Therapeutics

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Our aim was to assess the ability of convection-enhanced drug delivery (CED), a novel approach of direct delivery of drugs into brain tissue and brain tumors, to treat brain tumors using salirasib (farsnesyl thiosalicylic acid). CED was achieved by continuous infusion of drugs via intracranial catheters, thus enabling convective distribution of high drug concentrations over large volumes while avoiding systemic toxicity. Several phase II/III CED-based trials are currently in progress but have yet to overcome two major pitfalls of this methodology (the difficulty in attaining efficient CED and the significant nonspecific neurotoxicity caused by high drug doses in the brain). In this study, we addressed both issues by employing our previously described novel CED imaging and increased efficiency methodologies to exclusively target the activated form of the Ras oncogene in a 9L gliosarcoma rat model. The drug we used was salirasib, a highly specific Ras inhibitor shown to exert its suppressive effects on growth and migration of proliferating tumor cells in in vitro and in vivo models, including human glioblastoma, without affecting normal tissues. The results show a significant decrease in tumor growth rate in salirasibtreated rats relative to vehicle-treated rats as well as a significant correlation between CED efficacy and tumor growth rate with no observed toxicity despite drug concentrations an order of magnitude higher than previously detected in the brain. The results show that CED of salirasib is efficient and nontoxic for the treatment of glioblastoma in a rat model, thus suggesting that it may be considered for clinical application.

“…On the other hand, when parasites were treated with FTS, a reduced signal was detected in anti-Ras immunoprecipitates of the schizont stages, and parasite development was arrested at this stage. FTS inhibits the development of the human pancreatic tumor by dislodging Ras from its membrane-anchoring domains and accelerating its degradation (14,16,19).…”

Section: Discussionmentioning

confidence: 99%

Terpenes Arrest Parasite Development and Inhibit Biosynthesis of Isoprenoids inPlasmodium falciparum

et al. 2004

Antimicrob Agents Chemother

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Development of new drugs is one of the strategies for malaria control. The biosynthesis of several isoprenoids in Plasmodium falciparum was recently described. Interestingly, some intermediates and final products biosynthesized by this pathway in mammals differ from those biosynthesized in P. falciparum. These facts prompted us to evaluate various terpenes, molecules with a similar chemical structure to the intermediates of the isoprenoids pathway, as potential antimalarial drugs. Different terpenes and S-farnesylthiosalicylic acid were tested on cultures of the intraerythrocytic stages of P. falciparum, and the 50% inhibitory concentrations for each one were found: farnesol, 64 M; nerolidol, 760 nM; limonene, 1.22 mM; linalool, 0.28 mM; and S-farnesylthiosalicylic acid, 14 M. All the terpenes tested inhibited dolichol biosynthesis in the trophozoite and schizont stages when [1-(n)-3 H]farnesyl pyrophosphate triammonium salt ([ 3 H]FPP) was used as precursor. Farnesol, nerolidol, and linalool showed stronger inhibitory activity on the biosynthesis of the isoprenic side chain of the benzoquinone ring of ubiquinones in the schizont stage. Treatment of schizont stages with S-farnesylthiosalicylic acid led to a decrease in intensity of the band corresponding a p21 ras protein. The inhibitory effect of terpenes and S-farnesylthiosalicylic acid on the biosynthesis of both dolichol and the isoprenic side chain of ubiquinones and the isoprenylation of proteins in the intraerythrocytic stages of P. falciparum appears to be specific, because overall protein biosynthesis was not affected. Combinations of some terpenes or S-farnesylthiosalicylic acid tested in this work with other antimalarial drugs, like fosmidomycin, could be a new strategy for the treatment of malaria.

“…1). This suggests that the effects of FTS on Rac͞Rho-dependent pathways, e.g., on membrane ruffles and stress fibers (52), would be mostly because of its effects on Ras. We cannot rule out, however, the possibility that FTS may interfere with the functions of Rac͞Rho or other prenylated proteins without an effect on their total amount.…”

Section: Discussionmentioning

confidence: 99%

Novel Ras antagonist blocks human melanoma growth

¹

,

Schlagbauer-Wadl

²

,

³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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During past decades, knowledge of melanoma biology has increased considerably. Numerous therapeutic modalities based on this knowledge are currently under investigation. Advanced melanoma, nevertheless, remains a prime example of poor treatment response that may, in part, be the consequence of activated N-Ras oncoproteins. Besides oncogenic Ras, wild-type Ras gene products also play a key role in receptor tyrosine kinase growth factor signaling, known to be of importance in oncogenesis and tumor progression of a variety of human neoplasms, including malignant melanoma; therefore, it is reasonable to speculate that a pharmacological approach that curtails Ras activity may represent a sensible approach to inhibit melanoma growth. To test this concept, the antitumor activity of S-trans, trans-farnesylthiosalicylic acid (FTS), a recently discovered Ras antagonist that dislodges Ras from its membrane-anchoring sites, was evaluated. The antitumor activity of FTS was assessed both in vitro and in vivo in two independent SCID mouse xenotransplantation models of human melanoma expressing either wild-type Ras (cell line 518A2) or activated Ras (cell line 607B). We show that FTS (5-50 M) reduces the amounts of activated N-Ras and wild-type Ras isoforms both in human melanoma cells and Rat-1 fibroblasts, interrupts the Rasdependent extracellular signal-regulated kinase in melanoma cells, inhibits the growth of N-Ras-transformed fibroblasts and human melanoma cells in vitro and reverses their transformed phenotype. FTS also causes a profound and statistically significant inhibition of 518A2 (82%) and 607B (90%) human melanoma growth in SCID mice without evidence of drug-related toxicity. Our findings stress the notion that FTS may qualify as a novel and rational treatment approach for human melanoma and possibly other tumors that either carry activated ras genes or rely on Ras signal transduction more heavily than nonmalignant cells.A dvanced human melanoma is the most malignant type of skin cancer and remains a paradigm of poor treatment response intrinsically linked to poor prognosis (1, 2). Although a multitude of factors have been suspected to play a role in melanoma growth and progression (1-4), the most common specific gene defects identified in this tumor are activating mutations in ras genes. The 15% incidence of ras gene mutations in human melanoma represents predominantly alterations in N-ras at codon 61 (3-6), whereas Ha-ras and K-ras mutations are rare (3-6). The high frequency of this particular mutational hotspot (codon 61) in the N-ras gene basically excludes the possibility of its incidental nature and suggests the involvement of the constitutively active N-Ras protein encoded by the mutated gene in the oncogenesis of human melanoma (6). More recent studies have shown that activated N-Ras confers chemoresistance to human melanoma because expression decreases chemotherapy-induced apoptosis in melanoma xenotransplantation models (7). Because Ras proteins are regulators of multiple signaling pathways that contro...

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