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ras Oncogene Inhibitors

  • Chapter
Cancer Chemoprevention

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

The mammalian ras genes, N-, Ha- and Ki-ras, encode four highly homologous 21-Kd proteins— N-and Ha-Ras, and the splice variants Ki4A- and Ki4B-Ras that function as molecular switches in the regulation of cell proliferation, survival, and differentiation. Situated at the inner surface of the plasma membrane, these proteins transmit extracellular signals from membrane-localized receptor tyrosine kinases to the nucleus. Typical of guanosine 5’ triphosphate (GTP)-binding proteins, Ras cycles between the active, GTP-bound and inactive, guanosine 5’ diphosphate (GDP)-bound states through the action of its intrinsic GTPase activity, together with the action of guanine nucleotide exchange factors and GTPase-activating proteins (GAPs). Constitutively activated forms of Ras with compromised GTPase activity that are capable of deregulated cell growth are encoded by ras genes with point mutations in codons 12, 13, or 61 (1). Activation of Ras by mutation is a frequent finding in human tumors, with an overall incidence of 30%.

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References

  1. Barbacid M. ras Genes. Annu Rev Biochem 1987;56:779–827.

    Article  PubMed  CAS  Google Scholar 

  2. Bos JL. The ras gene family and human carcinogenesis. Mutat Res 1988;195:255–271.

    Article  PubMed  CAS  Google Scholar 

  3. Bos JL. ras oncogenes in human cancer: a review. Cancer Res 1989;49:4682–4689.

    PubMed  CAS  Google Scholar 

  4. Shirasawa S, Furuse M, Yokoyama N, Sasazuki T. Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 1993;260:85–88.

    Article  PubMed  CAS  Google Scholar 

  5. Plattner R, Anderson MJ, Sato KY, et al. Loss of oncogenic ras expression does not correlate with loss of tumorigenicity in human cells. Proc Natl Acad Sci USA 1996;93:6665–6670.

    Article  PubMed  CAS  Google Scholar 

  6. Saison-Behmoaras T, Tocque B, Rey I, et al. Short modified antisense oligonucleotides directed against Ha-ras point mutation induce selective cleavage of the mRNA and inhibit T24 cells proliferation. EMBO J 1991;10:1111–1118.

    PubMed  CAS  Google Scholar 

  7. Georges RN, Mukhopadhyay T, Zhang Y, et al. Prevention of orthotopic human lung cancer growth by intratracheal instillation of a retroviral antisense K-ras construct. Cancer Res 1993;53:1743–1746.

    PubMed  CAS  Google Scholar 

  8. Kashani-Sabet M, Funato T, Florenes VA, et al. Suppression of the neoplastic phenotype in vivo by an anti-ras ribozyme. Cancer Res 1994;54:900–902.

    PubMed  CAS  Google Scholar 

  9. Aoki K, Yoshida T, Sugimura T, Terada M. Liposome-mediated in vivo gene transfer of antisense K-ras construct inhibits pancreatic tumor dissemination in the murine peritoneal cavity. Cancer Res 1995;55:3810–3816.

    PubMed  CAS  Google Scholar 

  10. Aoki K, Yoshida T, Matsumoto N, et al. Suppression of Ki-ras p21 levels leading to growth inhibition of pancreatic cancer cell lines with Ki-ras mutation but not those without Ki-ras mutation. Mol Carcinog 1997;20:251–258.

    Article  PubMed  CAS  Google Scholar 

  11. Johnson L, Mercer K, Greenbaum D, et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 2001;410:1111–1116.

    Article  PubMed  CAS  Google Scholar 

  12. Dorr- A, Bruce J, Monia B, et al. Phase I and pharmacokinetic trial of ISIS 2503, a 20-mer antisense oligonucleotide against H-RAS, by 14-day continuous infusion (CIV) in patients with advanced cancer. Proc Am Soc Clin Oncol 1999;18:157a.

    Google Scholar 

  13. Adjei AA, Erlichman C, Sloan JA, et al. A Phase I trial of ISIS 2503, an antisense inhibitor of H-ras in combination with gemcitabine in patients with advanced cancer. Proc Am Soc Clin Oncol 2000;19:186a.

    Google Scholar 

  14. Dang T, Johnson D, Kelly K, et al. Multicenter Phase II trial of an antisense inhibitor of H-ras (ISIS-2503) in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001;20:332a.

    Google Scholar 

  15. Ahmadian MR, Zor T, Vogt D, et al. Guanosine triphos-phatase stimulation of oncogenic Ras mutants. Proc Nat Acad Sci USA 1999;96:7065–7070.

    Article  PubMed  CAS  Google Scholar 

  16. Zor T, Bar-Yaacov M, Elgavish S, et al. Rescue of a mutant G-protein by substrate-assisted catalysis. Eur J Biochem 1997;249:330–336.

    Article  PubMed  CAS  Google Scholar 

  17. Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 1996;65:241–269.

    Article  PubMed  CAS  Google Scholar 

  18. Willumsen BM, Norris K, Papageorge AG, et al. Harvey murine sarcoma virus p21 ras protein: biological and biochemical significance of the cysteine nearest the carboxy terminus. EMBO J 1984;3:2581–2585.

    PubMed  CAS  Google Scholar 

  19. Hancock JF, Magee AI, Childs JE, Marshall CJ. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 1989;57:1167–1177.

    Article  PubMed  CAS  Google Scholar 

  20. Jackson JH, Cochrane CG, Boume JR, et al. Farnesol modification of Kirsten-ras exon 4B protein is essential for trans-formation. Proc Natl Acad Sci USA 1990;87:3042–3046.

    Article  PubMed  CAS  Google Scholar 

  21. Kato K, Cox AD, Hisaka MM, et al. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Nall Acad Sci USA 1992;89:6403–6407.

    Article  CAS  Google Scholar 

  22. Moores SL, Schaber MD, Mosser SD, et al. Sequence dependence of protein isoprenylation. J Biol Chem 1991;266:14,603–14,610.

    CAS  Google Scholar 

  23. James G, Goldstein JL, Brown MS. Resistance of K-RasB V 12 proteins to farnesyltransferase inhibitors in Rat 1 cells. Proc Natl Acad Sci USA 1996;93:4454–4458.

    Article  PubMed  CAS  Google Scholar 

  24. Zhang FL, Kirschmeier P, Carr D, et al. 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. J Biol Chem 1997;272:10,232–10,239.

    CAS  Google Scholar 

  25. Whyte DB, Kirschmeier P, Hockenberry TN, et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 1997;272:14,459–14,464.

    Article  CAS  Google Scholar 

  26. Rowell CA, Kowalczyk JJ, Lewis MD, Garcia AM. Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. J Biol Chem 1997;272:14,093–14,097.

    Article  CAS  Google Scholar 

  27. Reiss Y, Goldstein JL, Seabra MC, et al. Inhibition of purified p21 ras farnesyl:protein transferase by Cys-AAX tetrapeptides. Cell 1990;62:81–88.

    Article  PubMed  CAS  Google Scholar 

  28. Goldstein JL, Brown MS, Stradley SJ, et al. Nonfarnesylated tetrapeptide inhibitors of protein farnesyltransferase. J Biol Chem 1991;266:15,575–15,578.

    CAS  Google Scholar 

  29. Pompliano DL, Rands E, Schaber MD, et al. Steady-state kinetic mechanism of Ras farnesyl:protein transferase. Biochemistry 1992;31:3800–3807.

    Article  PubMed  CAS  Google Scholar 

  30. Omer CA, Kohl NE. CAAX-competitive inhibitors of famesyltransferase as anti-cancer agents. Trends Pharmacol Sci 1997;18:437–444.

    PubMed  CAS  Google Scholar 

  31. Koblan KS, Kohl NE. Famesyltransferase inhibitors: agents for the treatment of human cancer, in G Proteins, Cytoskeleton and Cancer. Maruta H, Kohama K, eds. RG Landes Co., Georgetown, TX, 1998, pp.291–302.

    Google Scholar 

  32. Garcia AM, Rowell C, Ackermann K, et al. Peptidomimetic inhibitors of Ras famesylation and function in whole cells. J Biol Chem 1993;268:18,415–18,418.

    CAS  Google Scholar 

  33. James GL, Goldstein JL, Brown MS, et al. Benzodiazepine peptidomimetics: potent inhibitors of Ras famesylation in animal cells. Science 1993;260:1937–1942.

    Article  PubMed  CAS  Google Scholar 

  34. Kohl NE, Mosser SD, deSolms SJ, et al. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science 1993;260:1934–1937.

    Article  PubMed  CAS  Google Scholar 

  35. Nagasu T, Yoshimatsu K, Rowell C, et al. Inhibition of human tumor xenograft growth by treatment with the famesyl transferase inhibitor B956. Cancer Res 1995;55:5310–5314.

    PubMed  CAS  Google Scholar 

  36. Manne V, Yan N, Carboni JM, et al. Bisubstrate inhibitors of farnesyltransferase: a novel class of specific inhibitors of Ras transformed cells. Oncogene 1995;10:1763–1779.

    PubMed  CAS  Google Scholar 

  37. Njoroge FG, Vibulbhan B, Rane DF, et al. Structure-activity relationship of 3-substituted N-(pyridinylacetyl)-4-(8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidine inhibitors of farnesyl-protein transferase: design and synthesis of in vivo active antitumor compounds. J Med Chem 1997;40:4290–4301.

    Article  PubMed  CAS  Google Scholar 

  38. Njoroge FG, Vibulbhan B, Pinto P, et al. Potent, selective, and orally bioavailable ticyclic pyridyl acetamide N-oxide inhibitors of farnesyl protein transferase with enhanced in vivo antitumor activity. J Med Chem 1998;41:1561–1567.

    Article  PubMed  CAS  Google Scholar 

  39. Ding CZ, Batorsky R, Bhide R, et al. Discovery and structureactivity relationships of imidazole-containing tetrahydrobenzodiazepine inhibitors of farnesyltransferase. J Med Chem 1999;42:5241–5253.

    Article  PubMed  CAS  Google Scholar 

  40. Rose WC, Lee FYF, Fairchild CR, et al. Preclinical antitumor activity of BMS-214662, a highly apoptotic and novel farnesyltransferase inhibitor. Cancer Res 2001;61:7507–7517.

    PubMed  CAS  Google Scholar 

  41. Cox AD, Garcia AM, Westwick JK, et al. The CAAX peptidomimetic compound B581 specifically blocks farnesylated, but not geranylgeranylated or myristylated, oncogenic Ras signaling and transformation. J Biol Chem 1994;269:19,203–19,206.

    CAS  Google Scholar 

  42. James GL, Brown MS, Cobb MH, Goldstein JL. Benzodiazepine peptidomimetic BZA-5B interrupts the MAP kinase activation pathway in H-Ras-transformed Rat-1 cells, but not in untransformed cells. J Biol Chem 1994;269:27,705–27,714.

    CAS  Google Scholar 

  43. Lerner EC, Qian Y, Blaskovich MA, et al. Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J Biol Chem 1995;270:26,802–26,806.

    CAS  Google Scholar 

  44. Sepp-Lorenzino L, Ma Z, Rands E, et al. A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res 1995;55:5302–5309.

    PubMed  CAS  Google Scholar 

  45. Prendergast GC, Davide JP, deSolms SJ, et al. Farnesyltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton. Mol Cell Biol 1994;14:4193–4202.

    PubMed  CAS  Google Scholar 

  46. End DW, Smets G, Todd AV, et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001;61:131–137.

    PubMed  CAS  Google Scholar 

  47. Kohl NE, Wilson FR, Mosser SD, et al. Farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc Natl Acad Sci USA 1994;91:9141–9145.

    Article  PubMed  CAS  Google Scholar 

  48. Patel DV, Gordon EM, Schmidt RJ, et al. Phosphinyl acidbased bisubstrate analog inhibitors of ras farnesyl protein transferase. J Med Chem 1995;38:435–442.

    Article  PubMed  CAS  Google Scholar 

  49. Hunt JT, Lee VG, Leftheris K, et al. Potent, cell active, non-thiol tetrapeptide inhibitors of farnesyltransferase. J Med Chem 1996;39:353–358.

    Article  PubMed  CAS  Google Scholar 

  50. Liu M, Bryant MS, Chen J, et al. Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and Wap-ras transgenic mice. Cancer Res 1998;58:4947–4956.

    PubMed  CAS  Google Scholar 

  51. Njoroge FG, Taveras AG, Kelly J, et al. (+)-4-[2-[4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] -pyridin-11(R)-yl)-1-piperidinyl] -2-oxo-ethyl] -1-piperidinecarboxamide (SCH-66336): a very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem 1998;41:4890–4902.

    Article  PubMed  CAS  Google Scholar 

  52. Hunt JT, Ding CZ, Batorsky R, et al. Discovery of (R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonly)-1 H-1,4-benzodiazepine (BMS-214662), a farnesyltransferase inhibitor with potent preclinical antitumor activity. J Med Chem 2000;43:3587–3595.

    Article  PubMed  CAS  Google Scholar 

  53. Bishop WR, Bond R, Petrin J, et al. Novel tricyclic inhibitors of farnesyl protein transferase. J Biol Chem 1995;270:30,611–30,618.

    CAS  Google Scholar 

  54. Sun J, Qian Y, Hamilton AD, Sebti SM. Ras CAAX peptidomimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-ras mutation and p53 deletion. Cancer Res 1995;55:4243–4247.

    PubMed  CAS  Google Scholar 

  55. Williams TM, Ciccarone TM, MacTough SC, et al. 2-Substituted piperazines as constrained amino acids. Application to the synthesis of potent, non carboxylic acid inhibitors of farnesyltransferase. J Med Chem 1996;39:1345–1348.

    Article  PubMed  CAS  Google Scholar 

  56. Leftheris K, Kline T, Vite GD, et al. Development of highly potent inhibitors of Ras farnesyltransferase possessing cellular and in vivo activity. J Med Chem 1996;39:224–236.

    Article  PubMed  CAS  Google Scholar 

  57. Liu M, Bryant MS, Chen J, et al. 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. Cancer Chemother Pharmacol 1999;43:50–58.

    Article  PubMed  CAS  Google Scholar 

  58. Mallams AK, Njoroge FG, Doll RJ, et al. Antitumor 8-chlorobenzocycloheptapyridines: a new class of selective, nonpeptidic, nonsulfhydryl inhibitors of Ras farnesylation. Bioorg Med Chem 1997;5:93–99.

    Article  PubMed  CAS  Google Scholar 

  59. Kelland LR, Smith V, Valenti M, et al. Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer. Clin Cancer Res 2001;7:3544–3550.

    PubMed  CAS  Google Scholar 

  60. Kohl NE, Omer CA, Conner MW, et al. Inhibition of famesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med 1995;1:792–797.

    Article  PubMed  CAS  Google Scholar 

  61. Barrington RE, Subler MA, Rands E, et al. A farnesyltrans-ferase inhibitor induces tumor regression in transgenic mice harboring multiple oncogenic mutations by mediating alterations in both cell cycle control and apoptosis. Mol Cell Biol 1998;18:85–92.

    PubMed  CAS  Google Scholar 

  62. Mangues R, Corral T, Kohl NE, et al. Antitumor effect of a farnesyl transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice. Cancer Res 1998;58:1253–1259.

    PubMed  CAS  Google Scholar 

  63. Omer CA, Chen Z, Diehl RE, et al. Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl:protein transferase inhibitor. Cancer Res 2000;60:2680–2688.

    PubMed  CAS  Google Scholar 

  64. Miguel K, Pradines A, Sun J, et al. GGTI-298 induces G0-G 1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells. Cancer Res 1997;57:1846–1850.

    Google Scholar 

  65. Ashar HR, James L, Gray K, et al. The farnesyl transferase inhibitor SCH 66336 induces a G2/M or G1 pause in sensitive human tumor cell lines. Exp Cell Res 2001;262:17–27.

    Article  PubMed  CAS  Google Scholar 

  66. Sepp-Lorenzino L, Rosen N. A farnesyl-protein transferase inhibitor induces p21 expression and G1 block in p53 wild type tumor cells. J Biol Chem 1998;273:20,243–20,251.

    Article  CAS  Google Scholar 

  67. Suzuki N, Urano J, Tamanoi F. Farnesyltransferase inhibitors induce cytochrome c release and caspase 3 activation preferentially in transformed cells. Proc Natl Acad Sci USA 1998;95:15,356–15,361.

    CAS  Google Scholar 

  68. Lebowitz PF, Sakamur D, Prendergast GC. Farnesyl transferase inhibitors induce apoptosis of ras-transformed cells denied substratum attachment. Cancer Res 1997;57:708–713.

    PubMed  CAS  Google Scholar 

  69. Du W, Liu A, Prendergast GC. Activation of the PI3’ K-AKT pathway masks the proapoptotic effects of farnesyltransferase inhibitors. Cancer Res 1999;59:4208–4212.

    PubMed  CAS  Google Scholar 

  70. Jiang K, Coppola D, Crespo NC, et al. The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol Cell Biol 2000;20:139–148.

    Article  PubMed  Google Scholar 

  71. Yan J, Roy S, Apolloni A, et al. Ras isoforms vary in their ability to activate raf-1 and phosphoinositide 3-kinase. J Biol Chem 1998:24,052–24,056.

    Google Scholar 

  72. Cox AD, Hisaka MM, Buss JE, Der CJ. Specific isoprenoid modification is required for function of normal, but not oncogenic, Ras protein. Mol Cell Biol 1992;12:2606–2615.

    PubMed  CAS  Google Scholar 

  73. Miyake M, Mizutani S, Koide H, Kaziro Y. Unfarnesylated transforming Ras mutant inhibits the Ras-signaling pathway by forming a stable Ras-Raf complex in the cytosol. FEBS Lett 1996;378:15–18.

    Article  PubMed  CAS  Google Scholar 

  74. Gibbs JB, Oliff A. The potential of farnesyltransferase inhibitors as cancer chemotherapeutics. Annu Rev Pharmacol Toxicol 1997;37:143–166.

    Article  PubMed  CAS  Google Scholar 

  75. Ashar HR, James L, Gray K, et al. Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F, and alter the association of CENP-E with the microtubules. J Biol Chem 2000;275:30,451–30,457.

    Article  CAS  Google Scholar 

  76. Adamson P, Marshall CJ, Hall A, Tilbrook PA. Post-translational modifications of p2lrho proteins. J Biol Chem 1992;267:20,033–20,038.

    CAS  Google Scholar 

  77. Du W, Lebowitz PF, Prendergast GC. Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB. Mol Cell Biol 1999;19:1831–1840.

    PubMed  CAS  Google Scholar 

  78. Du W, Prendergast GC. Geranylgeranylated RhoB mediates suppression of human tumor cell growth by farnesyltransferase inhibitors. Cancer Res 1999;59:5492–5496.

    PubMed  CAS  Google Scholar 

  79. Chen A, Sun J, Pradines A, et al. Both farnesylated and geranylgeranylated RhoB inhibit malignant transformation and suppress human tumor growth in nude mice. J Biol Chem 2000;275:17,974–17,978.

    CAS  Google Scholar 

  80. Bell IA. Inhibitors of protein prenylation 2000. Expert Opin Ther Patents 2000;10:1813–1831.

    Article  CAS  Google Scholar 

  81. Huber HE, Robinson RG, Watkins A, et al. Anions modulate the potency of geranylgeranyl-protein transferase I inhibitors. J Biol Chem 2001;276:24,457–24,465.

    CAS  Google Scholar 

  82. Kohl NE, Buser C, deSolms SJ, et al. L-778123 is an inhibitor of both farnesyl protein transferase and geranylgeranyl protein transferase type I that inhibits tumor growth in ras transgenic mice. Clin Cancer Res 2001;7:3829S.

    Google Scholar 

  83. Karp JE, Lancet JE, Kaufmann SH, et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a Phase 1 clinical-laboratory correlative trial. Blood 2001;97:3361–3369.

    Article  PubMed  CAS  Google Scholar 

  84. Johnston SR, Ellis PA, Houston S, et al. A Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced breast cancer. Proc Am Soc Clin Oncol 2000;19:83a.

    Google Scholar 

  85. Adjei AA, Erlichman C, Davis JN, et al. A Phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity. Cancer Res 2000;60:1871–1877.

    PubMed  CAS  Google Scholar 

  86. Britten CD, Rowinsky EK, Soignet S, et al. A Phase I and pharmacological study of the farnesyl protein transferase inhibitor L-778,123 in patients with solid malignancies. Clin Cancer Res 2001;7:3894–3903.

    PubMed  CAS  Google Scholar 

  87. Patnaik A, Izbicka E, Eckhardt SG, et al. Inhibition of HDJ2 protein farnesylation in peripheral blood mononuclear cells as a pharmacodynamic endpoint in a Phase I study of R115777 and gemcitabine. Proc Am Assoc Cancer Res 2001;42:488.

    Google Scholar 

  88. Sonnichsen D, Damle B, Manning J, et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of the farnesyltransferase (FT) inhibitor BMS-214662 in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2000;19:178a.

    Google Scholar 

  89. Tabernero J, Sonnichsen D, Albanell J, et al. A Phase I pharmacokinetic (PK) and serial tumor and PBMC pharmacodynamic (PD) study of weekly BMS-214662, a farnesyltransferase (FT) inhibitor, in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2001;20:77a.

    Google Scholar 

  90. Holden SN, Echhardt S, Fisher S, et al. A Phase I pharmacokinetic (PK) and biological study of the farnesyl transferase inhibitor (FTI) R115777 and capecitabine in patients (PTS) with advanced solid malignancies. Proc Amer Soc Clin Oncol 2001;20:80a.

    Google Scholar 

  91. Hurwitz HI, Colvin OM, Petros WP, et al. Phase I and pharmacokinetic study of SCH66336, a novel FPTI, using a 2-week on, 2-week off schedule. Proc Am Soc Clin Oncol 1999;18:156a.

    Google Scholar 

  92. Hurwitz HI, Amado R, Prager D, et al. Phase I pharmacokinetic trial of the farnesyl transferase inhibitor SCH66336 plus gemcitabine in advanced cancers. Proc Am Soc Clin Oncol 2000;19:185a.

    Google Scholar 

  93. Kies MS, Clayman GL, El-Naggar AK, et al. Induction therapy with SCH 66336, a farnesyltransferase inhibitor, in squamous cell carcinoma (SCC) of the head and neck. Proc Amer Soc Clin Oncol 2001;20:225a.

    Google Scholar 

  94. Liebes L, Hochster H, Speyer J, et al. Enhanced myelosuppression of topotecan when combined with the farnesyl transferase inhibitor, R115777: a Phase I and pharmacodynamic study. Proc Am Soc Clin Oncol 2001;20:81a.

    Google Scholar 

  95. Mackay HJ, Hoekstra R, Eskens F, et al. A Phase I dose escalating study of BMS-214662 in combination with cisplatin (C) in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2001;20:80a.

    Google Scholar 

  96. Nakagawa K, Yamamoto N, Nishio K, et al. A Phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of the farnesyl transferase inhibitor (FTI) R115777 in Japanese patients with advanced non-hematological malignancies. Proc Am Soc Clin Oncol 2001;20:80a.

    Google Scholar 

  97. Schwartz G, Rowinsky EK, Rha SY, et al. A Phase I, pharmacokinetic, and biologic correlative study of R115777 and Trastuzumab (Herceptin) in patients with advanced cancer. Proc Am Soc Clin Oncol 2001;20:81a.

    Google Scholar 

  98. Widemann BC, Salzer WL, Arceci RJ, et al. Phase I trial of R115777, an oral farnesyltransferase (FTase) inhibitor, in children with refractory solid tumors and neurofibromatosis type I (NFI). Proc Am Soc Clin Oncol 2001;20:368a.

    Google Scholar 

  99. Zujewski J, Horak ID, Bol CJ, et al. Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 2000;18:927–941.

    PubMed  CAS  Google Scholar 

  100. Schellens J, Klerk Gd, Swart M, et al. Phase I and pharmacologic study with the novel farnesyltransferase inhibitor (FTI) R115777. Proc Am Soc Clin Oncol 2000;19:184a.

    Google Scholar 

  101. Moasser MM, Sepp-Lorenzino L, Kohl NE, et al. Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones. Proc Nall Acad Sci USA 1998;95:1369–1374.

    Article  CAS  Google Scholar 

  102. Sun J, Blaskovich MA, Knowles D, et al. Antitumor 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. Cancer Res 1999;59:4919–4926.

    PubMed  CAS  Google Scholar 

  103. Shi B, Yaremko B, Hajian G, et al. The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo. Cancer Chemother Pharmacol 2000;46:387–393.

    Article  PubMed  CAS  Google Scholar 

  104. Adjei AA, Davis JN, Bruzek LM, et al. Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines. Clin Cancer Res 2001;7:1438–1445.

    PubMed  CAS  Google Scholar 

  105. Bernhard EJ, Kao G, Cox AD, et al. The farnesyltransferase inhibitor FTI-277 radiosensitizes H-ras-transformed rat embryo fibroblasts. Cancer Res 1996;56:1727–1730.

    PubMed  CAS  Google Scholar 

  106. Bernhard EJ, McKenna WG, Hamilton AD, et al. Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes. Cancer Res 1998;58:1754–1761.

    PubMed  CAS  Google Scholar 

  107. Hahn SM, Kiel K, Morrison BW, et al. Phase I trial of the farnesyl protein transferase (FPTase) inhibitor L-778123 in combination with radiotherapy. Proc Am Soc Clin Oncol 2000;19:231a.

    Google Scholar 

  108. Lantry LE, Zhang Z, Yao R, et al. Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis 2000;21:113–116.

    Article  PubMed  CAS  Google Scholar 

  109. Bol DK, Dell J, Ho CP, et al. A comparison of the therapeutic and preventive efficacy of a novel Ras farnesyltransferase inhibitor in endogenous mouse carcinogenesis models. Proc Am Assoc Cancer Res 2000;41:220.

    Google Scholar 

  110. Lerner EC, Zhang T- T, Knowles DB, et al. 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 tumor cell lines. Oncogene 1997;15:1283–1288.

    Article  PubMed  CAS  Google Scholar 

  111. Sun J, Qian Y, Hamilton AD, Sebti SM. Both farnesyltransferase and geranylgeranyltransferase 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. Oncogene 1998;16:1467–1473.

    Article  PubMed  CAS  Google Scholar 

  112. Lobell RB, Omer CA, Abrams MT, et al. Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models. Cancer Res 2001;61:8758–8768.

    PubMed  CAS  Google Scholar 

  113. Prendergast GC, Davide JP, Lebowitz PF, et al. Resistance of a variant Ras-transformed cell line to phenotypic reversion by farnesyl transferase inhibitors. Cancer Res 1996;56:2626–2632.

    PubMed  CAS  Google Scholar 

  114. Villar KD, Urano J, Guo L, Tamanoi F. A mutant form of human protein farnesyltransferase exhibits increased resistance to farnesyltransferase inhibitors. J Biol Chem 1999;274:27,010–27,017.

    Google Scholar 

  115. Hudes GR, Schol J. Phase I trial of oral R115777 in patients with refractory solid tumors, in Farnesyltransferase Inhibitors in Cancer Therapy. Sebti SM, Hamilton AD, eds. Humana Press, Inc., Totowa, NJ, 2000, pp. 251–254.

    Chapter  Google Scholar 

  116. Punt CJ, van Maanen L, Bol CJ, et al. Phase I and pharmacokinetic study of the orally administered farnesyl transferase inhibitor R115777 in patients with advanced solid tumors. Anticancer Drugs 2001;12:193–197.

    Article  PubMed  CAS  Google Scholar 

  117. Adjei AA, Erlichman C, Marks RS, et al. A Phase I trial of the farnesyltransferase inhibitor R115777, in combination with gemcitabine and cisplatin in patients with advanced cancer. Proc Am Soc Clin Oncol 2001;20:81a.

    Google Scholar 

  118. Verslype C, Steenbergen WV, Humblet Y, et al. Phase I trial of 5-FU/LV in combination with the farnesyltransferase inhibitor (FTI) R115777. Proc Am Soc Clin Oncol 2001;20:171a.

    Google Scholar 

  119. Piccart-Gebhart MJ, Branle F, Valeriola DD, et al. A Phase I, clinical and pharmacokinetic (PK) trial of the farnesyl transferase inhibitor (FTI) R115777 + docetaxel: a promising combination in patients (PTS) with solid tumors. Proc Am Soc Clin Oncol 2001;20:80a.

    Google Scholar 

  120. Verweij J, Kehrer D, Planting A, et al. Phase I trial of irinotecan in combination with the farnesyl transferase inhibiitor (FTI) R115777. Proc Am Soc Clin Oncol 2001;20:81a.

    Google Scholar 

  121. Eskens FA, Awada A, Cutler DL, et al. Phase I and pharmacokinetic study of the oral farnesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors. J Clin Oncol 2001;19:1167–1175.

    PubMed  CAS  Google Scholar 

  122. Lersch C, Cutsem EV, Amado R, et al. Randomized Phase II study of SCH 66336 and gemcitabine in the treatment of metastatic adenocarcinoma of the pancreas. Proc Am Soc Clin Oncol 2001;20:153a.

    Google Scholar 

  123. Kim ES, Glisson BS, Meyers ML, et al. A Phase I/II study of the farnesyl transferase inhibitor (FTI) SCH66336 with paclitaxel in patients with solid tumors. Proc Am Assoc Cancer Res 2001;42:488.

    Google Scholar 

  124. Winquist E, Morre MJ, Chi K, et al. NCIC CTG IND.128: a Phase II study of a farnesyl transferase inhibitor (SCH 66336) in patients with unresectable or metastatic transitional cell carcinoma of the urothelial tract failing prior chemotherapy. Proc Am Soc Clin Oncol 2001;20:197a.

    Google Scholar 

  125. Rubin E, Abbruzzese JL, Morrison BW, et al. Phase I trial of the farnesyl protein transferase (FPTase) inhibitor L-778123 on a 14 or 28-day dosing schedule. Proc Am Soc Clin Oncol 2000;19:178a.

    Google Scholar 

  126. Sharma S, Britten C, Spriggs D, et al. A Phase I and PK study of farnesyl transferase inhibitor L-778,123 adminis-tered as a seven day continuous infusion in combination with paclitaxel. Proc Am Soc Clin Oncol 2000;19:185a.

    Google Scholar 

  127. Ryan DP, Eder JP, Supko JG, et al. Phase I clinical trial of the farnesyltransferase (FT) inhibitor BMS-214662 in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2000;19:185a.

    Google Scholar 

  128. Voi M, Tabernero J, Cooper MR, et al. A Phase I study of the farnesyltransferase (FT) inhibitor BMS-214662 adminis-tered as a weekly 1-hour infusion in patients (Pts) with advanced solid tumors: clinical findings. Proc Am Soc Clin Oncol 2001;20:79a.

    Google Scholar 

  129. Camacho LH, Soignet SL, Pezzulli S, et al. Dose escalation study of oral farnesyl transferase inhibitor (FTI) BMS-214662 in patients with solid tumors. Proc Am Soc Clin Oncol 2001;20:79a.

    Google Scholar 

  130. Kim KB, Shin DM, Summey CC, et al. Phase I study of farnesyl transferase inhibitor, BMS-214662 in solid tumors. Proc Am Soc Clin Oncol 2001;20:79a.

    Google Scholar 

  131. Bailey HH, Marnocha R, Arzoomanian R, et al. Phase I trial of weekly paclitaxel and BMS214662 in patients with advanced solid tumors. Proc Am Soc Clin Oncol 2001;20:79a.

    Google Scholar 

  132. Gibbs RA, Zahn TJ, Sebolt-Leopold JS. Non-peptidic prenyltransferase inhibitors: diverse structural classes and surprising anti-cancer mechanisms. Curr Med Chem 2001;8:1437–1465.

    Article  PubMed  CAS  Google Scholar 

  133. Prendergast GC, Rane N. Farnesyltransferase inhibitors: mechanism and applications. Expert Opin Invest Drugs 2001;10:2105–2116.

    Article  CAS  Google Scholar 

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Authors
  1. Nancy E. Kohl PhD
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  1. National Institutes of Health, Rockville, MD, USA

    Gary J. Kelloff MD  & Ernest T. Hawk MD, MPH  & 

  2. CCS Associates, Mountain View, CA, USA

    Caroline C. Sigman PhD

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Kohl, N.E. (2004). ras Oncogene Inhibitors. In: Kelloff, G.J., Hawk, E.T., Sigman, C.C. (eds) Cancer Chemoprevention. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-767-3_20

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  • DOI: https://doi.org/10.1007/978-1-59259-767-3_20

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