Abstract
Treatment of chronic myelogenous leukemia with a specific inhibitor of the Bcr/Abl tyrosine kinase, imatinib, has shown great promise. However, acute lymphoblastic leukemias that express Bcr/Abl only transiently respond to imatinib. Therefore, alternative treatments for this type of leukemia are urgently needed. Here, we examined the activity of the farnesyltransferase inhibitor SCH66336 as a single chemotherapeutic agent in a nude mouse model representative of very advanced stage Bcr/Abl P190-positive lymphoblastic leukemia/lymphoma. Our results show that oral administration of the inhibitor was able to significantly increase the survival of these mice compared to controls treated with vehicle (P<0.005), and caused marked regression of the tumor burden in the treated mice. Upon prolonged treatment, lymphomas re-emerged and a subset of cells from two of such lymphomas tested was able to survive in the presence of increased concentrations of SCH66336. The same cells, however, remained sensitive towards imatinib. A combination of the two drugs, preceded by a therapy to reduce the initial tumor burden, could be very effective in the treatment of Ph-positive ALL. We conclude that SCH66336, on its own, is remarkably effective in eradicating large numbers of lymphoblastic lymphoma cells and causing visible reduction in tumor size, with minimal toxicity.
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References
Heisterkamp N, Groffen J . BCR/ABL gene structure and BCR function. In: Carella AM, Daley GQ, Eaves CJ, Goldman JM, Hehlman R (eds) Chronic Myeloid Leukemia: Biology and Treatment. London, UK: Martin Dunitz, 2001, pp 3–17.
Smith JM, Mayer BJ . Abl: mechanisms of regulation and activation. Front Biosci 2002; 7: d31–d42.
Shet AS, Jahagirdar BN, Verfaillie CM . Chronic myelogenous leukemia: mechanisms underlying disease progression. Leukemia 2002; 16: 1402–1411.
Faderl S, Garcia-Manero G, Thomas DA, Kantarjian HM . Philadelphia chromosome-positive acute lymphoblastic leukemia – current concepts and future perspectives. Rev Clin Exp Hematol 2002; 6: 142–160.
Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 2002; 100: 1965–1971.
Campbell LJ, Patsouris C, Rayeroux KC, Somana K, Januszewicz EH, Szer J . BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration. Cancer Genet Cytogenet 2002; 139: 30–33.
le Coutre P, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G et al. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 2000; 95: 1758–1766.
Druker BJ . Imatinib and chronic myeloid leukemia: validating the promise of molecularly targeted therapy. Eur J Cancer 2002; 38: S70–S76.
Schiffer CA, Hehlmann R, Larson R . Perspectives on the treatment of chronic phase and advanced phase CML and Philadelphia chromosome positive ALL. Leukemia 2003; 17: 691–699.
Cox AD . Farnesyltransferase inhibitors: potential role in the treatment of cancer. Drugs 2001; 61: 723–732.
Kelland LR . Farnesyltransferase inhibitors in the treatment of breast cancer. Expert Opin Investig Drugs 2003; 12: 413–421.
Cortes JE, Kurzrock R, Kantarjian HM . Farnesyltransferase inhibitors: novel compounds in the development for the treatment of myeloid malignancies. Semin Hematol 2003; 39: 26–30.
Le DT, Shannon KM . Ras processing as a therapeutic target in hematologic malignancies. Curr Poin Hematol 2002; 9: 308–315.
Haluska P, Dy GK, Adjei AA . Farnesyltransferase inhibitors as anticancer agents. Eur J Cancer 2002; 38: 1685–1700.
Choy E, Chiu VK, Silletti J, Feoktistov M, Morimoto T, Michaelson D et al. Endomembrane trafficking of Ras: the CAAX motive targets proteins to the ER and Golgi. Cell 1999; 98: 69–80.
Du W, Lebowitz PF, Prendergast GC . Cell growth inhibition by farnesyltransferase inhibitor is mediated by gain of geranylgeranylated RhoB. Mol Cell Biol 1999; 19: 1831–1840.
Norgaard P, Law B, Joseph H, Page DL, Shyr Y, Mays D et al. 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. Clin Cancer Res 1999; 5: 35–42.
Barrington RE, Subler MA, Rands E, Omer CA, Miller PJ, Hundley JE et al. A farnesyltransferase 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.
Crespo NC, Ohkanda J, Yen TJ, Hamilton AD, Sebti SM . The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells. J Biol Chem 2001; 276: 16161–16167.
Prendergast GC, Oliff A . Farnesyltransferase inhibitors: antineoplastic properties, mechanisms of action and clinical properties. Semin Cancer Biol 2000; 10: 443–452.
Falugi C, Trombino S, Granone P, Margaritora S, Russo P . Increasing complexity of farnesyltransferase inhibitors activity: role in chromosome instability. Curr Cancer Drug Targets 2003; 3: 109–118.
Cox AD, Der CJ . Ras family signaling. Cancer Biol Ther 2002; 1: 599–600.
Reichert A, Heisterkamp N, Daley GQ, Groffen J . Treatment of Bcr/Abl-positive acute lymphoblastic leukemia in P190 transgenic mice with the farnesyltransferase inhibitor SCH66336. Blood 2001; 97: 1399–1403.
Peters DG, Hoover RR, Gerlach MJ, Koh EY, Zhang H, Choe K et al. Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia. Blood 2001; 97: 1404–1412.
Voncken J-W, Griffiths S, Greaves MF, Pattengale PK, Heisterkamp N, Groffen J . Restricted oncogenicity of BCR/ABL P190 in transgenic mice. Cancer Res 1992; 52: 4534–4539.
Adjei AA, Erlichman C, Davis JN, Cutler DL, Sloan JA, Marks RS et al. A Phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity. Cancer Res 2000; 60: 1871–1877.
Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P et al. Antitumor activity of SCH66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and Wap-ras transgenic mice. Cancer Res 1998; 58: 4946–4947.
le Coutre P, Mologni L, Cleris L, Marchesi E, Buchdunger E, Giardini R et al. In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. J Natl Cancer Inst 1999; 91: 163–168.
Dash AB, Williams IR, Kutok JL, Tomasson MH, Anastasiadou E, Lindahl K et al. A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc Natl Acad Sci USA 2002; 99: 7622–7627.
Wolff NC, Ilaria Jr RL . Establishment of a murine model for therapy-treated chronic myelogenous leukemia using the tyrosine kinase inhibitor STI571. Blood 2001; 98: 2808–2816.
Adjei AA, Davis JN, Erlichman C, Svingen PA, Kaufmann SH . Comparison of potential markers of farnesyltransferase inhibition. Clin Cancer Res 2000; 6: 2318–2325.
Karp JE, Lancet JE, Kaufmann SH, End DW, Wright JJ, Bol K 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.
Schmitt CA, Rosenthal CT, Lowe SW . Genetic analysis of chemoresistance in primary murine lymphomas. Nat Med 2000; 6: 1029–1035.
Voncken JW, Morris C, Pattengale P, Dennert G, Kikly C, Groffen J et al. Clonal development and karyotype evolution during leukemogenesis of BCR/ABL transgenic mice. Blood 1992; 79: 1029–1036.
Smith V, Rowlands MG, Barrie E, Workman P, Kelland LR . Establishment and characterization of acquired resistance to the farnesyl protein transferease inhibitor R115777 in a human colon cancer cell line. Clin Cancer Res 2002; 8: 2002–2009.
Hofmann W-K, Komor M, Wassmann B, Jones LC, Gschaidmeier H, Hoelzer D et al. Presence of the BCR-ABL mutation Glu255Lys prior to STI571 (imatinib) treatment in patients with Ph+ acute lymphoblastic leukemia. Blood 2003; 102: 659–661.
Hoover RR, Mahon F-X, Melo JV, Daley GQ . Overcoming STI571 resistance with the farnesyltransferase inhibitor SCH66336. Blood 2002; 100: 1068–1071.
Nakajima A, Tauchi T, Sumi M, Bishop WR, Ohyashiki K . Efficacy of SCH66336, a farnesyl transferase inhibitor, in conjunction with Imatinib against BCR-ABL-positive cells. Mol Cancer Ther 2003; 2: 219–224.
Acknowledgements
We thank Bianca Hemmeryckx for help in establishing culture conditions for PLC1 and for help with the figures and Jan Willem Voncken for establishing growth of the S2-3 cells. This study was supported by the Kenneth T and Eileen L Norris Foundation (SM, BZ, and JG) and PHS NIH grants CA50248 and CA90321 (NH).
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Mishra, S., Zhang, B., Groffen, J. et al. A farnesyltransferase inhibitor increases survival of mice with very advanced stage acute lymphoblastic leukemia/lymphoma caused by P190 Bcr/Abl. Leukemia 18, 23–28 (2004). https://doi.org/10.1038/sj.leu.2403203
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DOI: https://doi.org/10.1038/sj.leu.2403203
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