Ras biochemistry and farnesyl transferase inhibitors: A literature survey

Anti-Cancer Drugs

Volumn 12, Issue 3, 2001, Pages 163-184

  Crul, M ^a,b,d   De Klerk, G J ^a   Beijnen, J H ^a,b,c   Schellens, J H M S ^a,c  

^a NETHERLANDS CANCER INSTITUTE   (Netherlands)

^b SLOTERVAART HOSPITAL   (Netherlands)

^c UTRECHT UNIVERSITY   (Netherlands)

^d ANTONI VAN LEEUWENHOEK HOSPITAL   (Netherlands)

Author keywords

Farnesyl transferase inhibition; Ras; Rho; Signal transduction

Indexed keywords

2 [[2 [[2 [(2 AMINO 3 MERCAPTOPROPYL)AMINO] 3 METHYLPENTYL]OXY] 1 OXO 3 PHENYLPROPYL]AMINO] 4 (METHYLSULFONYL)BUTANOIC ACID ISOPROPYL ESTER; 3 BENZYL 7 CYANO 2,3,4,5 TETRAHYDRO 1 (1H IMIDAZOL 4 YLMETHYL) 4 (2 THIENYLSULFONYL) 1H 1,4 BENZODIAZEPINE; 4 (8 CHLORO 5,6 DIHYDRO 11H BENZO[5,6]CYCLOHEPTA[1,2 B]PYRIDIN 11 YLIDENE) 1 (4 PYRIDYLACETYL)PIPERIDINE; BENZODIAZEPINE; BENZODIAZEPINE DERIVATIVE; BMS 186511; GEMCITABINE; L 704272; L 778123; LONAFARNIB; MANUMYCIN; N (8 AMINO 2 BENZYL 5 ISOPROPYL 9 MERCAPTO 3,6 NONADIENOYL)METHIONINE; N (8 AMINO 2 BENZYL 5 ISOPROPYL 9 MERCAPTO 3,6 NONADIENOYL)METHIONINE METHYL ESTER; N [2 [2 (2 AMINO 3 MERCAPTOPROPYLAMINO) 3 METHYLPENTYLOXY] 3 PHENYLPROPIONYL]METHIONINE SULFONE; N [2 [2 (2 AMINO 3 MERCAPTOPROPYLAMINO) 3 METHYLPENTYLOXY] 3 PHENYLPROPIONYL]METHIONINE SULFONE METHYL ESTER; N [[5 [(2 AMINO 3 MERCAPTOPROPYL)AMINO][1,1' BIPHENYL] 2 YL]CARBONYL]METHIONINE; N [[5 [(2 AMINO 3 MERCAPTOPROPYL)AMINO][1,1' BIPHENYL] 2 YL]CARBONYL]METHIONINE METHYL ESTER; PACLITAXEL; PROTEIN FARNESYLTRANSFERASE; PROTEIN FARNESYLTRANSFERASE INHIBITOR; RAS PROTEIN; RHOB GUANINE NUCLEOTIDE BINDING PROTEIN; SCH 54429; SCH 59228; TIPIFARNIB; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CANCER CELL; CANCER CHEMOTHERAPY; CLINICAL TRIAL; DOSE RESPONSE; ENZYME INHIBITION; GASTROINTESTINAL SYMPTOM; GENE EXPRESSION; GENE MUTATION; HEADACHE AND FACIAL PAIN; HUMAN; IC 50; NONHUMAN; ONCOGENE RAS; PRENYLATION; PRIORITY JOURNAL; PROTEIN MODIFICATION; SIGNAL TRANSDUCTION; SOLID TUMOR;

ALKYL AND ARYL TRANSFERASES; ANIMALS; ANTINEOPLASTIC AGENTS; ENZYME INHIBITORS; FARNESYLTRANSTRANSFERASE; GENES, RAS; GUANOSINE TRIPHOSPHATE; HUMANS; NEOPLASMS; RAS PROTEINS; RHO GTP-BINDING PROTEINS; SIGNAL TRANSDUCTION;

EID: 0035064177     PISSN: 09594973     EISSN: None     Source Type: Journal    
DOI: 10.1097/00001813-200103000-00001     Document Type: Article

References (185)

1. The war on cancer
2. Signal transduction therapy. A novel approach to disease mangement
3. Pharmaceutical research in molecular oncology
4. Molecular themes in carcinogenesis
5. The ras signal transduction pathway
6. Ras genes
7. Coexpression of MMTV/v-Ha-ras and MMTV/v-myc genes in transgenic mice: Synergistic action of oncogenes in vivo
8. Farnesyl-transferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton
9. Harvey murine sarcoma virus p21 ras protein: Biological and biochemical significance of the cysteine nearest the carboxy terminus
10. Isoprenoid addition to ras protein is the critical modification for its membrane association and transforming activity
11. Geranylgeranylated RhoB mediates suppression of human tumor cell growth by farnesyltransfemse inhibitors
12. Molecular medicine, oncogenes
13. Protein modules and signalling networks
14. Farnesyl protein transferase inhibitors as potential cancer chemopreventives
15. Function and regulation of ras
16. Essential role for nuclear phospholipase C betal in insulin-like growth factor I-induced mitogenesis
17. Integrin structure and function
18. Singaling by integrin receptors
19. Ras, hut not Src, transformation of RIE-1 epithelial cells is dependent on activation of the mitogen-activated protein kinase cascade
20. A raf-independent epidermal growth factor receptor autocrine loop is necessary for Ras transformation of rat intestinal epithelial cells
21. Increasing complexity of ras signal transduction: Involvement of rho family proteins
22. How does the G protein, Gi2 transduce mitogenic signals?
23. Involvement of ras p21 protein in signal-transduction pathways from interleukin 2, interleukin 3, and granulocyte/macrophage colony-stimulating factor, hut not from interleukin 4
24. P21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity hut not tyrosine phosphorylation of p21ras GTPase-activating protein
25. Differentiation factors, including nerve growth factor, fibrohlast growth factor, and interleukin-6, induce an accumulation of an active Ras. GTP complex in rat pheochromocytome PC12 cells
26. Cooperating oncogenes converge to regulate cyclin/cdk complexes
27. Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway
28. 1 progression
29. 1 cyclin-dependent kinases
30. Cancer cell cycles
31. cip 1 cyclin-dependent kinase inhibitor
32. Cip 1
33. Phosphatidylinositol-3-OH kinase as a direct target of Ras
34. cDNA cloning of the type 1 neurfibromatosis gene: Complete sequence of the NT1 gene product
35. Identification and characterization of the neurofibromatosis type 1 protein product
36. GAP as a ras effector or negative regulator?
37. Molecular cloning of two types of GAP complementary DNA from human placenta
38. GTPase activating proteins
39. + channel currents
40. Signal transduction by Ras-like GTPases: A potential target for anticancer drugs
41. Bcl-2 associates with the ras-related protein R-ras p23
42. Ras target proteins in eukaryotic cells
43. Ras-effector interactions, the problem of specificity
44. byr2, a Schizosaccharomyces pombe gene encoding a protein kinase capable of partial suppression of the rasl mutant phenotype
45. Protein kinase Byr2 is a target of Ras1 in the fission yeast Schizosaccharomyces pombe
46. Identification of AF-6 and canoe as putative targets for Ras
47. Complexes of Ras. GTP with Raf-1 and mitogen-activated protein kinase kinase
48. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane
49. Two distinct Raf domains mediate interaction with Ras
50. Critical role of Rho in cell transformation by oncogenic Ras
51. Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation
52. Rho GTPases and signaling networks
53. Signalling by rho family proteins
54. Cdc42 regulates anchorage-independent growth and is necessary for Ras transformation
55. A novel ras-related gene family
56. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia
57. Regulation of phosphorylation pathways by p21 GTPases. The p21 Ras-related Rho subfamily and its role in phosphorylating signalling pathways
58. The small GTP-binding proteins Racl and Cdc42 regulate the activity of the JNK/SAPK signaling pathway
59. Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42
60. Rho stimulates tyrosine phosphorylation of focal adhesion kinase, p130 and paxillin
61. The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF
62. waf1/cip1
63. A role for rho in ras transformation
64. Molecular cloning of cDNAs encoding the GAp-associated protein p190: Implications for a signaling pathway from ras to the nucleus
65. Purification of a novel ras GTPase-activating protein from rat brain
66. Specific detection of phospatidylinositol 3,4,5-triphosphate binding protein by the PIP3 analogue beads: An application for rapid purification of the PIP3 binding proteins
67. Prevalence of ras gene mutations in human colorectal cancers
68. Kras codon 12 mutations occur very frequently in pancreatic adenocarcinomas
69. Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung
70. Oncogenes in bladder cancer
71. Preferential and novel actvation of H-ras in human bladder carcinomas
72. The pattern of mutational involvement of RAS genes in human hematologic malignancies determined by DNA amplification and direct sequencing
73. Genetic alterations during colorectal-tumor development
74. A study of ras gene mutations in colonic adenomas from familial polyposis coli patients
75. Mechanism of activation of a human oncogene
76. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene
77. Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change
78. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants
79. ras proteins and their GTPase activating proteins
80. Tumorigenic transformation of mammalian cells induced by a normal human gene homologous to the oncogene of harvey murine sarcoma virus
81. Ras and human tumors
82. Ras oncogenes: Their role in neoplasia
83. Isolation of rsp-1, a novel cDNA capable of suppressing v-Ras transformation
84. The Ras suppressor RSU-1 localizes to lOp13 and its expression in the U251 glioblastoma cell line correlates with a decrease in growth rate and tumorigenic potential
85. Metabolic turnover of human c-rasHp21 protein of EJ bladder carcinoma and its normal cellular and viral homologs
86. Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules
87. The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity
88. Mutant ras oncogenes upregulate VEGF/VPF expression: Implications for induction and inhibition of tumor angiogenesis
89. Targeting farnesyltransferase: Is Ras relevant?
90. Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells
91. Signal transduction pathways regulated by the Rho family of small GTPases
92. Rho as a regulator of the cytoskeleton
93. Evidence that farnesyltransferase inhibitors suppress ras transformation by interfering with rho activity
94. rho proteins
95. Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB
96. Cell death: The significance of apoptosis
97. Programmed cell death: Concept, mechanism and control
98. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents
99. Susceptibility to apoptosis is differentially regulated by c-myc and mutated Ha-ras oncogenes and is associated with endonuclease availability
100. Mutant H-ras overexpression inhibits drug and UV induced apoptosis
101. Farnesyltransferase inhibitors induce dramatic morphological changes of KNRK cells that are blocked by microtubule interfering agents
102. Rodent fibroblast tumours expressing human myc and ras genes: Growth, metastasis and endogenous oncogene expression
103. Mutant Ha-ras overexpression inhibits a random apoptotic nuclease in myeloid leukemia cells
104. A farnesyl transferase inhibitor induces tumor regression in transgenic mice harboring multiple oncogenic mutations by mediating alterations in both cell cycle control and apoptosis
105. Farnesyl transferase inhibitors induce apoptosis of ras-transformed cells denied substratum attachment
106. Treatment with farnesyl protein transferase inhibitor induces regression of mammary tumors in transforming growth factor (TGF) alpha and TGF alpha/neu transgenic mice by inhibition of mitogenic activity and induction of apoptosis
107. Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects
108. Posttranslational modification of proteins by isoprenoids in mammalian cells
109. The prenylation of proteins
110. ras
111. A CAAX or a CAAL motif and a second signal are sufficient for plasma membrane targeting of ras proteins
112. Regulation of proliferation and Ras localization in transformed cells by products of mevalonate metabolism
113. Clinical evaluation of biologically targeted drugs: Obstacles and opportunities
114. Farnesyltransferase inhibitors and anti-Ras therapy
115. ras farnesyl:Protein transferase by Cys-AAX tetrapeptides
116. Mammalian protein geranylgeranyltrasferase. Subunit compostion and metal requirements
117. Purification of a mammalian protein geranylgeranyltransferase. Formation and catalytic properties of an enzyme-geranylgeranyl pyrophosphate complex
118. Protein farnesyltransferase and geranylgeranyltransferase share a common alpha subunit
119. Conformation of a heptapeptide substrate bound to protein farnesyltransferase
120. Photoaffinity-labeling peptide substrates for farnesylprotein transferase and the intersubunit location of the active site
121. Photoreactive analogues of prenyl diphosphates as inhibitors and probes of human protein farnesyltransferase and geranylgeranyltransferase type I
122. Sequence dependence of isoprenylation
123. Posttranslational modification of Ha-ras p21 by farnesyl versus geranylgeranyl isoprenoids is determined by the COOH-terminal amino acid
124. Characterization of Ha-Ras, N-Ras, Ki-Ras4A, and Ki-Ras4B as in vitro substrates for farnesyl protein transferase and geranylgeranyl protein transferase type I
125. Both farnesyl transferase and geranylgeranyl transferase I inhibitors are required for inhibition of oncogenic K-ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts
126. Crystal structure of protein farnesyltransferase at 2.25 Angstrom resolution
127. Nonidentical subunits of p21H-ras farnesyltransferase. Peptide binding and famesyl pyrophosphate carrier functions
128. Role of the carboxyterminal residue in peptide binding to protein farnesyltransferase and protein geranylgeranyltransferase
129. CAAX geranylgeranyl transferase transfers farnesyl as efficiently as geranylgeranyl to RhoB
130. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor
131. Selective inhibition of farnesyl protein transferase blocks ras processing in vivo
132. Benzodiazepine peptidomimetics: Potent inhibitors of ras farnesylation in animal cells
133. A peptidomimetic inhibitor of farnesylprotein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines
134. K- and N-ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors
135. Polylysine and CVIM sequences of K-rasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimetic in vitro
136. All ras proteins are polyisoprenylated but only some are palmitoylated
137. Pre-clinical development of farnesyltransferase inhibitors
138. The Ras-related protein Rheb is farnesylated and antagonizes ras signaling and transformation
139. PRL-1, a unique nuclear protein tyrosine phosphatase, affects cell growth
140. Prenylation of oncogenic human FTP(CAAX) protein tyrosine phosphatases
141. Unfarnesylated transforming Ras mutant inhibits the ras-signaling pathway by forming a stable Ras-Raf complex in the cytosol
142. Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones
143. Inhibition of growth and invasive activity of human pancreatic cancer cells by a farnesyltransferase inhibitor, manumycin
144. Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLOO320-DM human colon tumour cells
145. Steady-state kinetic mechanism of Ras farnesyl protein transferase
146. Nonfarnesylated tetrapeptide inhibitors of protein farnesyltransferase
147. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice
148. A peptidomimetic inhibitor of ras functionality markedly suppresses growth of human prostate tumor xenografts in mice. Prospects for long-term clinical utility
149. Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice
150. Ras Caax peptidomimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with k-ras mutation and p53 deletion
151. Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
152. Disruption of oncogenic K-Ras4B processing and signaling by a potent geranylgeranyltransferase I inhibitor
153. Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956
154. ras but does not affect their function or localization
155. Effects of SCH 59228, an orally bioavailable farnesyl protein transferase inhibitor, on the growth of oncogene transformed fibroblasts and a human colon carcinoma xenograft in nude mice
156. Farnesyltransferase inhibitor: Effect on ras activation
157. R115777, a selective farnesyl protein transferase inhibitor (FIT), induces anti-angiogenic, apoptotic and anti-proliferative activity in CAPAN-2 and in LoVo tumor xenografts
158. Bisubstrate inhibitors of farnesyltransferase: A novel class of specific inhibitors of ras transformed cells
159. Farnesyltransferase inhibitors block the neurofibromatosis type I (NF1) malignant phenotype
160. Monoterpenes as regulators of malignant cell proliferation
161. Inhibition of farnesyl protein transferase by monoterpene, curcumin derivates and gallotannin
162. Mevinolin: A highly potent competitive inhibitor of hyclroxymethylglutary-coenzyme A reductase and α cholesterol lowering agent
163. Lovastatin, a cholesterol-biosynthesis inhibitor, inhibits the growth of human H-ras oncogene transformed cells in nude mice
164. Organic acid, a potent inhibitor of Ras farnesyl-protein transferase
165. The potential of farnesyltransferase inhibitors as cancer chemotherapeutics
166. R115777 a novel imidazole farnesyl protein transferase inhibitor (FIT) with potent oral antitumor activity
167. Antitumor activity of SCH66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice
168. Phase I and pharmacologic study with the novel farnesyltransferase inhibitor (FTI) R115777
169. Phase 1 and pharmacokinetic study of farnesyl proten transferase inhibitor R115777 in advanced cancer
170. Use of farnesyl transferase inhibitor R115777 in relapsed and refractory acute leukemias: Preliminary results of a phase I trial
171. A phase I and pharmacokinetic study of the farnesyltransferase inhibitor, R115777 in combination with gemcitabine
172. Phase I trial of the farnesyl protein transferase inhibitor L-778123 on a 14- or 28-day dosing schedule
173. Phase I trial of the farnesyl transferase inhibitor L-778123 in combination with radiotherapy
174. A phase I and pk study of farnesyl transferase inhibitor L-778,123 administered as a seven day continuous infusion in combination with paclitaxel
175. Phase I and clinical trial of the farnesyl transferase inhibitor BMS-214462 in patients with advanced solid rumors
176. A phase 1 trial of the farnesyl transferase inhibitor SCH66336: Evidence for biological and clinical activity
177. Phase I pharmacokinetic trial of the farnesyl transferase inhibitor SCH66336 plus gemcitabine in advanced cancers
178. Phase I study of farnesyl transferase inhibitor SCH66336 with paclitaxel in solid rumors: Dose finding, pharmacokinetics, efficacy/safety
179. A phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced breast cancer
180. Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes
181. Both v-Ha-Ras and v-Raf stimulate expression of the vascular endothelial growth factor in NIH 3T3 cells
182. The up-regulation of vascular endothelial growth factor in mutated Ha-ras HaCaT cell lines is reduced by a farnesyl transferase inhibitor
183. Resistance of a variant ras-transformed cell line to phenotypic reversion by farnesyl transferase inhibition
184. Peptidomimetic inhibitors of ras farnesylation and function in whole cells
185. Benzodiazepine peptidomimetic BZA-5B interrupts the MAP kinase activation pathway in H-ras transformed Rat-1 cells but not in untransformed cells