STI571 (CGP 57148B) inhibits c-abl, bcr-abl, PDGFR and c-kit tyrosine kinaies in vitro with high degree of specificity. Inhibition of bcr-abl was documented in cell syptems and proven to be the basis for successful therapeutic exploration of STI571 in bèr-abl positive diseases. However, the significance of c-kit inhibition is unclear. Recently, inhibition of SCF-induced c-kit phosphorylation was reported in a growth factor-dependent ce[l line M07 and was associated with growth inhibition. This suggested a possibility of therapeutic exploration of STI571 in c-kit positive malignancies. Because about 70% of AML leases are c-kit positive, we were interested in evaluating in vitro effects of STI571 on c-kit positive cell lines and primary c-kit-positive AML-derived blast cells. At concentrations 5-10 micromolar, the drug moderately inhibited proliferation of AML cell line and mbst of patient blasts. The inhibition, however, was not related to the percentage of c-kit expression as detected by flow cytometry. Western blot analysis with c-kit antibody showed a distinct band of 145 KD in all cases. Interestingly, there was no correlation between the intensity of the c-kit band on Western blots and percentage of c-kit positive blast calls as detected by flow cytometry. AML cells were also cultured for 30 minutes in me[dium supplemented with 15% PCS and 5% of PHA-LCM, in presence or absence of S1JI571, before being processed for Western blotting and evaluation of c-kit phosphorylation. Exposure to STI571 did not influence the level of expression of c-kit as determined by densitometry of Western blots. In primary AML cells as well as AML cell (ines, phosphorylation of c-kit was barely detectable even in presence of PHA-LCN-4. No significant changes in phosphorylation were detected after exposure to STI571. Studies of interaction between Ara-C and STI571 in the growth inhibition of AML cells showed no impact of STI571 on Ara-C toxicity. In conclusion, STI571 was mildly effective in reducing cell growth only at high concentrations, without a definite inhibition of SCF independent c-kit phosphorylation. STI571 neither inhibited nor potentiated the antiproliferative activity of Ara-C.

Effects of STI571 on acute myelogenous leukemia (AML) cells in vitro / B. Scappini, F. Onida, H. Kantarjian, L. Dong, M.J. Keating, B. Beran. - In: BLOOD. - ISSN 0006-4971. - 96:11: Supplement 1(2000 Dec), pp. 114A-115A. ((Intervento presentato al 42. convegno Annual Meeting of the American Society of Hematology tenutosi a S. Francisco, California, USA nel 2000.

Effects of STI571 on acute myelogenous leukemia (AML) cells in vitro

F. Onida
Secondo
;
2000

Abstract

STI571 (CGP 57148B) inhibits c-abl, bcr-abl, PDGFR and c-kit tyrosine kinaies in vitro with high degree of specificity. Inhibition of bcr-abl was documented in cell syptems and proven to be the basis for successful therapeutic exploration of STI571 in bèr-abl positive diseases. However, the significance of c-kit inhibition is unclear. Recently, inhibition of SCF-induced c-kit phosphorylation was reported in a growth factor-dependent ce[l line M07 and was associated with growth inhibition. This suggested a possibility of therapeutic exploration of STI571 in c-kit positive malignancies. Because about 70% of AML leases are c-kit positive, we were interested in evaluating in vitro effects of STI571 on c-kit positive cell lines and primary c-kit-positive AML-derived blast cells. At concentrations 5-10 micromolar, the drug moderately inhibited proliferation of AML cell line and mbst of patient blasts. The inhibition, however, was not related to the percentage of c-kit expression as detected by flow cytometry. Western blot analysis with c-kit antibody showed a distinct band of 145 KD in all cases. Interestingly, there was no correlation between the intensity of the c-kit band on Western blots and percentage of c-kit positive blast calls as detected by flow cytometry. AML cells were also cultured for 30 minutes in me[dium supplemented with 15% PCS and 5% of PHA-LCM, in presence or absence of S1JI571, before being processed for Western blotting and evaluation of c-kit phosphorylation. Exposure to STI571 did not influence the level of expression of c-kit as determined by densitometry of Western blots. In primary AML cells as well as AML cell (ines, phosphorylation of c-kit was barely detectable even in presence of PHA-LCN-4. No significant changes in phosphorylation were detected after exposure to STI571. Studies of interaction between Ara-C and STI571 in the growth inhibition of AML cells showed no impact of STI571 on Ara-C toxicity. In conclusion, STI571 was mildly effective in reducing cell growth only at high concentrations, without a definite inhibition of SCF independent c-kit phosphorylation. STI571 neither inhibited nor potentiated the antiproliferative activity of Ara-C.
dic-2000
Article (author)
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/66567
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 2
  • ???jsp.display-item.citation.isi??? ND
social impact