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Chemical Compound Review

SureCN94807     6-[amino-(4-chlorophenyl)- (3...

Synonyms: AG-E-40372, AC1L3WMK, CTK4E0918, DNC001367, DNC001449, ...
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Disease relevance of R-115777


High impact information on R-115777

  • Because its activation was required for sensitization by an FTI, R115777 may be useful against pancreatic tumors expressing oncogenic Ki-Ras [5].
  • Recently we have found that disease stabilization was achieved in 64% of patients with advanced MM treated with the farnesyltransferase inhibitor R115777 (Zarnestra) in a phase 2 clinical trial [4].
  • R115777 synergized with paclitaxel to inhibit MM cell proliferation and to induce apoptosis [4].
  • In order to enhance R115777 antitumor activity in MM, we examined the combination of this novel agent with other anticancer drugs in MM cell lines [4].
  • Furthermore, flow cytometry analysis also showed that paclitaxel and R115777 synergized to induce G(2)/M cell-cycle arrest [4].

Chemical compound and disease context of R-115777


Biological context of R-115777

  • Farnesyltransferase inhibitor (FTI) treatment with R115777 before and after irradiation was used to determine the effect of Ki-Ras farnesylation on cell survival [5].
  • R115777 appears to be a potent inducer of apoptosis, and its effects depend on the status of Ras mutation in cloned myeloma cells but not on the status of N-Ras mutation in fresh myeloma cells [8].
  • R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid [3].
  • PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks [9].
  • Inhibition of H-Ras, N-Ras, and lamin B protein processing was observed at concentrations of R115777 that inhibited cell proliferation [10].

Anatomical context of R-115777

  • Weekly marrow samples demonstrated that R115777 accumulated in bone marrow in a dose-dependent fashion, with large increases in marrow drug levels beginning at 600 mg bid and with sustained levels throughout drug administration [3].
  • In a panel of 53 human tumor cell lines tested for growth inhibition, approximately 75% were found to be sensitive to R115777 [10].
  • While no cell survival modification was observed after RasN17 induction, the expression of RhoBN19 induced a radiosensitization of FGF2 radioresistant HeLa cells in the same range as the one observed after a 48 h treatment with the specific FTI, R115777 [11].
  • At the maximum tolerated dose, accumulation of prelamin A in buccal mucosa cells of patients was evaluated as a marker of farnesyl transferase inhibition by R115777 [12].
  • An increase in prelamin A was also observed in peripheral blood lymphocytes in a breast cancer patient who responded to R115777 [13].

Associations of R-115777 with other chemical compounds


Gene context of R-115777


Analytical, diagnostic and therapeutic context of R-115777

  • Our results provide the basis for combination therapy clinical trials with paclitaxel or docetaxel with R115777 in MM patients [4].
  • Given that RAS mutations are nearly universal in pancreatic cancer and R115777 demonstrated preclinical activity against pancreatic cell lines and xenografts, this phase II study was undertaken to determine its clinical activity and effect on target proteins in patients with measurable metastatic pancreatic adenocarcinoma [18].
  • Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer [19].
  • Chemoprevention of benzo(a)pyrene-induced lung tumors in mice by the farnesyltransferase inhibitor R115777 [20].
  • These combined effects on glioblastoma underline the interest of associating R115777 with radiotherapy as a new treatment of these tumors of catastrophic prognosis [21].


  1. Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting. Kurzrock, R., Kantarjian, H.M., Cortes, J.E., Singhania, N., Thomas, D.A., Wilson, E.F., Wright, J.J., Freireich, E.J., Talpaz, M., Sebti, S.M. Blood (2003) [Pubmed]
  2. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Cortes, J., Albitar, M., Thomas, D., Giles, F., Kurzrock, R., Thibault, A., Rackoff, W., Koller, C., O'Brien, S., Garcia-Manero, G., Talpaz, M., Kantarjian, H. Blood (2003) [Pubmed]
  3. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Karp, J.E., Lancet, J.E., Kaufmann, S.H., End, D.W., Wright, J.J., Bol, K., Horak, I., Tidwell, M.L., Liesveld, J., Kottke, T.J., Ange, D., Buddharaju, L., Gojo, I., Highsmith, W.E., Belly, R.T., Hohl, R.J., Rybak, M.E., Thibault, A., Rosenblatt, J. Blood (2001) [Pubmed]
  4. Farnesyltransferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells. Zhu, K., Gerbino, E., Beaupre, D.M., Mackley, P.A., Muro-Cacho, C., Beam, C., Hamilton, A.D., Lichtenheld, M.G., Kerr, W.G., Dalton, W., Alsina, M., Sebti, S.M. Blood (2005) [Pubmed]
  5. Successful growth and characterization of mouse pancreatic ductal cells: functional properties of the Ki-RAS(G12V) oncogene. Schreiber, F.S., Deramaudt, T.B., Brunner, T.B., Boretti, M.I., Gooch, K.J., Stoffers, D.A., Bernhard, E.J., Rustgi, A.K. Gastroenterology (2004) [Pubmed]
  6. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. Van Cutsem, E., van de Velde, H., Karasek, P., Oettle, H., Vervenne, W.L., Szawlowski, A., Schoffski, P., Post, S., Verslype, C., Neumann, H., Safran, H., Humblet, Y., Perez Ruixo, J., Ma, Y., Von Hoff, D. J. Clin. Oncol. (2004) [Pubmed]
  7. Phase II trial of R115777 (NSC #70818) in patients with advanced colorectal cancer: a Southwest Oncology Group study. Whitehead, R.P., McCoy, S., Macdonald, J.S., Rivkin, S.E., Neubauer, M.A., Dakhil, S.R., Lenz, H.J., Tanaka, M.S., Abbruzzese, J.L. Investigational new drugs. (2006) [Pubmed]
  8. Effect of farnesyl transferase inhibitor R115777 on the growth of fresh and cloned myeloma cells in vitro. Ochiai, N., Uchida, R., Fuchida, S., Okano, A., Okamoto, M., Ashihara, E., Inaba, T., Fujita, N., Matsubara, H., Shimazaki, C. Blood (2003) [Pubmed]
  9. Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. Zujewski, J., Horak, I.D., Bol, C.J., Woestenborghs, R., Bowden, C., End, D.W., Piotrovsky, V.K., Chiao, J., Belly, R.T., Todd, A., Kopp, W.C., Kohler, D.R., Chow, C., Noone, M., Hakim, F.T., Larkin, G., Gress, R.E., Nussenblatt, R.B., Kremer, A.B., Cowan, K.H. J. Clin. Oncol. (2000) [Pubmed]
  10. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. End, D.W., Smets, G., Todd, A.V., Applegate, T.L., Fuery, C.J., Angibaud, P., Venet, M., Sanz, G., Poignet, H., Skrzat, S., Devine, A., Wouters, W., Bowden, C. Cancer Res. (2001) [Pubmed]
  11. RhoB controls the 24 kDa FGF-2-induced radioresistance in HeLa cells by preventing post-mitotic cell death. Ader, I., Toulas, C., Dalenc, F., Delmas, C., Bonnet, J., Cohen-Jonathan, E., Favre, G. Oncogene (2002) [Pubmed]
  12. A Phase I trial of the farnesyl protein transferase inhibitor R115777 in combination with gemcitabine and cisplatin in patients with advanced cancer. Adjei, A.A., Croghan, G.A., Erlichman, C., Marks, R.S., Reid, J.M., Sloan, J.A., Pitot, H.C., Alberts, S.R., Goldberg, R.M., Hanson, L.J., Bruzek, L.M., Atherton, P., Thibault, A., Palmer, P.A., Kaufmann, S.H. Clin. Cancer Res. (2003) [Pubmed]
  13. Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer. Kelland, L.R., Smith, V., Valenti, M., Patterson, L., Clarke, P.A., Detre, S., End, D., Howes, A.J., Dowsett, M., Workman, P., Johnston, S.R. Clin. Cancer Res. (2001) [Pubmed]
  14. Cell cycle regulation in the G1 phase: a promising target for the development of new chemotherapeutic anticancer agents. Owa, T., Yoshino, H., Yoshimatsu, K., Nagasu, T. Current medicinal chemistry. (2001) [Pubmed]
  15. Clinical research in pancreatic cancer: the Radiation Therapy Oncology Group trials. Willett, C.G., Safran, H., Abrams, R.A., Regine, W.F., Rich, T.A. Int. J. Radiat. Oncol. Biol. Phys. (2003) [Pubmed]
  16. Relative importance of apoptosis and cell cycle blockage in the synergistic effect of combined R115777 and imatinib treatment in BCR/ABL-positive cell lines. Miyoshi, T., Nagai, T., Ohmine, K., Nakamura, M., Kano, Y., Muroi, K., Komatsu, N., Ozawa, K. Biochem. Pharmacol. (2005) [Pubmed]
  17. Farnesyl transferase inhibitor (R115777)-induced inhibition of STAT3(Tyr705) phosphorylation in human pancreatic cancer cell lines require extracellular signal-regulated kinases. Venkatasubbarao, K., Choudary, A., Freeman, J.W. Cancer Res. (2005) [Pubmed]
  18. Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. Cohen, S.J., Ho, L., Ranganathan, S., Abbruzzese, J.L., Alpaugh, R.K., Beard, M., Lewis, N.L., McLaughlin, S., Rogatko, A., Perez-Ruixo, J.J., Thistle, A.M., Verhaeghe, T., Wang, H., Weiner, L.M., Wright, J.J., Hudes, G.R., Meropol, N.J. J. Clin. Oncol. (2003) [Pubmed]
  19. Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer. Crul, M., de Klerk, G.J., Swart, M., van't Veer, L.J., de Jong, D., Boerrigter, L., Palmer, P.A., Bol, C.J., Tan, H., de Gast, G.C., Beijnen, J.H., Schellens, J.H. J. Clin. Oncol. (2002) [Pubmed]
  20. Chemoprevention of benzo(a)pyrene-induced lung tumors in mice by the farnesyltransferase inhibitor R115777. Gunning, W.T., Kramer, P.M., Lubet, R.A., Steele, V.E., End, D.W., Wouters, W., Pereira, M.A. Clin. Cancer Res. (2003) [Pubmed]
  21. The farnesyltransferase inhibitor R115777 reduces hypoxia and matrix metalloproteinase 2 expression in human glioma xenograft. Delmas, C., End, D., Rochaix, P., Favre, G., Toulas, C., Cohen-Jonathan, E. Clin. Cancer Res. (2003) [Pubmed]
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