Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis

J. L. Liesveld, J. E. Lancet, K. E. Rosell, A. Menon, C. Lu, C. McNair, C. N. Abboud, Joseph D Rosenblatt

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Patients with acute myelogenous leukemia or myelodysplastic syndrome may respond to farnesyl transferase inhibitors (FTIs) with partial or complete response rates noted in about 30% of such patients. FTIs prevent the attachment of a lipid farnesyl moiety to dependent proteins prior to their insertion into the plasma membrane and thereby prevent activity of these prenylation-dependent proteins, but their mechanism of tumor suppression remains unknown. Many patients receiving FTIs do experience myelosuppression. In this work, the in vitro effects of the FTI, R115777 on normal and leukemic hematopoiesis have been examined as have its effects on apoptosis induction and cell cycle profile in both leukemic blasts and normal CD34+ cells. R115777 was inhibitory to normal CD34+ cell proliferation and to leukemic blast cells, but did not affect long-term culture initiating cell frequency nor NOD-SCID reconstituting capacity. No induction of apoptosis or cell cycle changes were noted in AML blasts. These data suggest that myelosuppression with R115777 occurs largely at the intermediate to late progenitor stage of hematopoiesis and that cyclic use might avoid long-term marrow suppression.

Original languageEnglish
Pages (from-to)1806-1812
Number of pages7
JournalLeukemia
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2003

Fingerprint

tipifarnib
Hematopoiesis
Transferases
Cell Cycle
Protein Prenylation
Apoptosis
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Cell Culture Techniques
Bone Marrow
Cell Proliferation
Cell Membrane
Lipids
Neoplasms
Proteins

Keywords

  • Farnesyl transferase inhibitors
  • Hematopoiesis
  • Myelodysplasia

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

Liesveld, J. L., Lancet, J. E., Rosell, K. E., Menon, A., Lu, C., McNair, C., ... Rosenblatt, J. D. (2003). Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis. Leukemia, 17(9), 1806-1812. https://doi.org/10.1038/sj.leu.2403063

Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis. / Liesveld, J. L.; Lancet, J. E.; Rosell, K. E.; Menon, A.; Lu, C.; McNair, C.; Abboud, C. N.; Rosenblatt, Joseph D.

In: Leukemia, Vol. 17, No. 9, 01.09.2003, p. 1806-1812.

Research output: Contribution to journalArticle

Liesveld, JL, Lancet, JE, Rosell, KE, Menon, A, Lu, C, McNair, C, Abboud, CN & Rosenblatt, JD 2003, 'Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis', Leukemia, vol. 17, no. 9, pp. 1806-1812. https://doi.org/10.1038/sj.leu.2403063
Liesveld JL, Lancet JE, Rosell KE, Menon A, Lu C, McNair C et al. Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis. Leukemia. 2003 Sep 1;17(9):1806-1812. https://doi.org/10.1038/sj.leu.2403063
Liesveld, J. L. ; Lancet, J. E. ; Rosell, K. E. ; Menon, A. ; Lu, C. ; McNair, C. ; Abboud, C. N. ; Rosenblatt, Joseph D. / Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis. In: Leukemia. 2003 ; Vol. 17, No. 9. pp. 1806-1812.
@article{19a4a39a405945098813273f2a105dde,
title = "Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis",
abstract = "Patients with acute myelogenous leukemia or myelodysplastic syndrome may respond to farnesyl transferase inhibitors (FTIs) with partial or complete response rates noted in about 30{\%} of such patients. FTIs prevent the attachment of a lipid farnesyl moiety to dependent proteins prior to their insertion into the plasma membrane and thereby prevent activity of these prenylation-dependent proteins, but their mechanism of tumor suppression remains unknown. Many patients receiving FTIs do experience myelosuppression. In this work, the in vitro effects of the FTI, R115777 on normal and leukemic hematopoiesis have been examined as have its effects on apoptosis induction and cell cycle profile in both leukemic blasts and normal CD34+ cells. R115777 was inhibitory to normal CD34+ cell proliferation and to leukemic blast cells, but did not affect long-term culture initiating cell frequency nor NOD-SCID reconstituting capacity. No induction of apoptosis or cell cycle changes were noted in AML blasts. These data suggest that myelosuppression with R115777 occurs largely at the intermediate to late progenitor stage of hematopoiesis and that cyclic use might avoid long-term marrow suppression.",
keywords = "Farnesyl transferase inhibitors, Hematopoiesis, Myelodysplasia",
author = "Liesveld, {J. L.} and Lancet, {J. E.} and Rosell, {K. E.} and A. Menon and C. Lu and C. McNair and Abboud, {C. N.} and Rosenblatt, {Joseph D}",
year = "2003",
month = "9",
day = "1",
doi = "10.1038/sj.leu.2403063",
language = "English",
volume = "17",
pages = "1806--1812",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis

AU - Liesveld, J. L.

AU - Lancet, J. E.

AU - Rosell, K. E.

AU - Menon, A.

AU - Lu, C.

AU - McNair, C.

AU - Abboud, C. N.

AU - Rosenblatt, Joseph D

PY - 2003/9/1

Y1 - 2003/9/1

N2 - Patients with acute myelogenous leukemia or myelodysplastic syndrome may respond to farnesyl transferase inhibitors (FTIs) with partial or complete response rates noted in about 30% of such patients. FTIs prevent the attachment of a lipid farnesyl moiety to dependent proteins prior to their insertion into the plasma membrane and thereby prevent activity of these prenylation-dependent proteins, but their mechanism of tumor suppression remains unknown. Many patients receiving FTIs do experience myelosuppression. In this work, the in vitro effects of the FTI, R115777 on normal and leukemic hematopoiesis have been examined as have its effects on apoptosis induction and cell cycle profile in both leukemic blasts and normal CD34+ cells. R115777 was inhibitory to normal CD34+ cell proliferation and to leukemic blast cells, but did not affect long-term culture initiating cell frequency nor NOD-SCID reconstituting capacity. No induction of apoptosis or cell cycle changes were noted in AML blasts. These data suggest that myelosuppression with R115777 occurs largely at the intermediate to late progenitor stage of hematopoiesis and that cyclic use might avoid long-term marrow suppression.

AB - Patients with acute myelogenous leukemia or myelodysplastic syndrome may respond to farnesyl transferase inhibitors (FTIs) with partial or complete response rates noted in about 30% of such patients. FTIs prevent the attachment of a lipid farnesyl moiety to dependent proteins prior to their insertion into the plasma membrane and thereby prevent activity of these prenylation-dependent proteins, but their mechanism of tumor suppression remains unknown. Many patients receiving FTIs do experience myelosuppression. In this work, the in vitro effects of the FTI, R115777 on normal and leukemic hematopoiesis have been examined as have its effects on apoptosis induction and cell cycle profile in both leukemic blasts and normal CD34+ cells. R115777 was inhibitory to normal CD34+ cell proliferation and to leukemic blast cells, but did not affect long-term culture initiating cell frequency nor NOD-SCID reconstituting capacity. No induction of apoptosis or cell cycle changes were noted in AML blasts. These data suggest that myelosuppression with R115777 occurs largely at the intermediate to late progenitor stage of hematopoiesis and that cyclic use might avoid long-term marrow suppression.

KW - Farnesyl transferase inhibitors

KW - Hematopoiesis

KW - Myelodysplasia

UR - http://www.scopus.com/inward/record.url?scp=0141502201&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0141502201&partnerID=8YFLogxK

U2 - 10.1038/sj.leu.2403063

DO - 10.1038/sj.leu.2403063

M3 - Article

VL - 17

SP - 1806

EP - 1812

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 9

ER -