Farnesyltransferase inhibitors: Mechanism and applications

Expert Opinion on Investigational Drugs

Volumn 10, Issue 12, 2001, Pages 2105-2116

  Prendergast, G C ^a   Rane, N ^a  

^a DUPONT COMPANY   (United States)

Author keywords

Angiogenesis; Apoptosis; Cancer; FTI; Ras; Rho

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; AZD 3409; BIM 46228; CAPECITABINE; CELL PROTEIN; CP 609754; FTI 2148; GEMCITABINE; ISOPRENOID; L 778123; LONAFARNIB; ONCOPROTEIN; PACLITAXEL; PROTEIN FARNESYLTRANSFERASE INHIBITOR; RAS PROTEIN; TIPIFARNIB; UNCLASSIFIED DRUG;

ACUTE LEUKEMIA; ANIMAL CELL; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BLOOD TOXICITY; BONE MARROW SUPPRESSION; BREAST CANCER; CANCER CELL; CELL FUNCTION; CELL GROWTH; CONTROLLED STUDY; DIABETIC RETINOPATHY; DIARRHEA; DRUG DESIGN; DRUG MECHANISM; DRUG TARGETING; DRUG TOLERABILITY; GROWTH INHIBITION; HUMAN; HUMAN CELL; MALIGNANT TRANSFORMATION; MELANOMA; MOUSE; NEUTROPENIA; NONHUMAN; PRENYLATION; PROTEIN PROCESSING; RETINA MACULA DEGENERATION; REVIEW; SIGNAL TRANSDUCTION; SOLID TUMOR; TARGET CELL; THROMBOCYTOPENIA; TUMOR GROWTH;

ALKYL AND ARYL TRANSFERASES; ANGIOGENESIS INHIBITORS; ANIMALS; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS; ENZYME INHIBITORS; FARNESYLTRANSTRANSFERASE; HUMANS; NEOPLASMS; RHOB GTP-BINDING PROTEIN;

EID: 0035216833     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543784.10.12.2105     Document Type: Review

References (89)

1. Mechanism-based target identification and drug discovery in cancer research
2. Farnesyl protein transferase inhibitors and other therapies targeting the Ras signal transduction pathway
3. Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development
4. Biological effects and mechanism of action of farnesyl transferase inhibitors
5. Farnesyltransferase inhibitors: Antineoplastic properties, mechanisms of action, and clinical prospects
6. Farnesyltransferase inhibitors: Antineoplastic mechanism and clinical prospects
7. Blocking oncogenic Ras signalling for cancer therapy
8. Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: Lessons from mechanism and bench-to-bedside translational studies
9. Ras gene mutations and human cancer
10. Regulators and effectors of ras proteins
11. Regulators and effectors of Ras
12. Ras proto-oncogene activation in human malignancy
13. Tumourigenesis and male sterility in transgenic mice expressing a MMTV/N-ras oncogene
14. Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: Synergistic action of oncogenes in vivo
15. Mouse mammary tumour virus-Ki-RasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl: Protein transferase inhibitor
16. Essential role for oncogenic Ras in tumour maintenance
17. Altered growth of human colon cancer cell lines disrupted at activated Ki-Ras
18. Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic
19. The potential of farnesyltransferase inhibitors as cancer chemotherapeutics
20. Protein prenylation: A mediator of protein-protein interactions
21. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity
22. Protein prenyltransferases
23. Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase-I inhibitor in human tumour cell lines
24. K- and N-ras geranylgeranylated in cells treated with farnesyl protein transferase inhibitors
25. Characterisation of Ha-ras, N-ras, KiRas4A, Ki-Ras4B as in vitro substrates for farnesyl protein transferase and geranylgeranyl protein transferase Type I
26. Farnesyltransferase inhibitors and cancer treatment: Targeting simply Ras?
27. Non-Ras targets for farnesyltransferase inhibitors: Focus on Rho
28. Farnesyltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton
29. 2-M enrichment in A549 cells
30. A farnesyltransferase inhibitor induces tumour regression in transgenic mice harbouring multiple oncogenic mutations by mediating alterations in both cell cycle control and apoptosis
31. 1 block in p53 wild type tumour cells
32. Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB
33. Geranylgeranylated RhoB mediates inhibition of human tumour cell growth by farnesyltransferase inhibitors
34. 2/M cell cycle progression and apoptosis in human pancreatic ductal adenocarcinoma cells
35. The farnesyl transferase inhibitor SCH 66336 induces a G(2) → M or G(1) pause in sensitive human tumour cell lines
36. The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells
37. Farnesyltransferase inhibitors induce apoptosis in Rastransformed cells denied substratum attachment
38. Farnesyltransferase inhibitors induce cytochrome c release and caspase 3 activation preferentially in transformed cells
39. Activation of the PI3′K-AKT pathway masks the proapoptotic effect of farnesyltransferase inhibitors
40. The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis
41. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor
42. A peptidomimetic inhibitor of farnesyl: Protein transferase blocks the anchorage-dependent and -independent growth of human tumour cell lines
43. Isotype-specific Ras. GTP-levels predict the efficacy of farnesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status
44. Specific isoprenoid modification is required for function of normal, but not oncogenic, Ras function
45. Antitumour effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumours overexpressing N-ras in transgenic mice
46. Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumour growth in nude mouse xenografts
47. The CAAX peptidomimetic compound B581 specifically blocks farnesylated, but not geranylgeranylated or myristylated, oncogenic ras signalling and transformation
48. Evidence that farnesyl transferase inhibitors suppress Ras transformation by interfering with Rho activity
49. Targeting farnesyltransferase: Is Ras relevant?
50. Farnesyltransferase and geranylgeranyltransferase I inhibitors in cancer therapy: Important mechanistic and bench to bedside issues
51. Characterisation of the antitumour effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro
52. Treatment of Bcr/Abl-positive acute lymphoblastic leukaemia in P190 transgenic mice with the farnesyl transferase inhibitor SCH66336
53. Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukaemia and primary cells from patients with chronic myeloid leukaemia
54. Inhibition of human tumour cell growth in vivo by an orally bioavailable inhibitor of human farnesyltransferase, BIM-46228
55. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice
56. Antitumour activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumour xenograft models and wap-ras transgenic mice
57. The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumour activity in vivo
58. Antitumour efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: Combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine
59. Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones
60. Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines
61. The farnesyltransferase inhibitor FTI-277 radiosensitizes H-ras-transformed rat embryo fibroblasts
62. Inhibiting Ras prenylation increases the radiosensitivity of human tumour cell lines with activating mutations of ras oncogenes
63. A Phase I trial of the farnesyl transferase inhibitor SCH66336: Evidence for biological and clinical activity
64. Suppression of tumorigenicity in Rastransformed fibroblasts by alpha 2(I) collagen
65. Gene trapping identifies inhibitors of oncogenic transformation: The tissue inhibitor of metalloproteinases-3 (TIMP3) and collagen Type I-alpha-2 (COL1A2) are epidermal growth factor-regulated growth repressors
66. Elevation of α2(I) collagen, a suppressor of Ras transformation, is required for stable phenotypic reversion by farnesyltransferase inhibitors
67. RhoB alteration is required for the apoptotic and antineoplastic responses to farnesyltransferase inhibitors
68. Post-translational modification of p21 rho proteins
69. Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB
70. Actin' up: RhoB in cancer and apoptosis
71. rhoB encoding a UV-inducible ras-related small GTP-binding protein is regulated by GTPases of the rho family and independent of JNK, ERK, and p38 MAP kinase
72. RhoB is dispensable for mouse development, but it modifies susceptibility to tumour formation as well as cell adhesion and growth factor signalling in transformed cells
73. RhoB is required for the apoptotic response of neoplastically transformed cells to DNA damage
74. Both farnesylated and geranylgeranylated RhoB inhibit malignant transformation and suppress human tumour growth in nude mice
75. Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas
76. A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype
77. Genomic analysis of metastasis reveals an essential role for RhoC
78. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype
79. Transcriptional activation of the small GTPase gene rhoB by genotoxic stress is regulated via a CCAAT element
80. Geranylgeranylated RhoB is sufficient to mediate tissue-specific suppression of Akt kinase activity by farnesyltransferase inhibitors
81. Ras-related GTPase RhoB represses NF-kappaB signalling
82. Rho GTPases are overexpressed in human tumours
83. An essential part for Rho-associated kinase in the transcellular invasion of tumour cells
84. Rho-like GTPases: Their role in cell adhesion and invasion
85. Overexpression of small GTP-binding protein RhoA promotes invasion of tumour cells
86. Mode of action of farnesyltransferase inhibitors
87. Mutant ras oncogenes upregulate VEGF/vPF expression: Implications for induction and inhibition of tumour angiogenesis
88. Effect of novel CAAX peptidomimetic farnesyltransferase inhibitor on angiogenesis in vitro and in vivo