Amifostine pretreatment allows the use of higher doses' of the bcr-abl-specific tyrosine kinase innibitor agh12

D. Cilloni, A. Levitzki, E. Regazzi, D. Garau, B. Savoldo, G. Sammarelli, C. Almici, V. Rizzoli, C. Carlo-Stella

Research output: Contribution to journalArticlepeer-review

Abstract

Several evidences demonstrate the existence of residual normal stem/progenitor cells in chronic myelogenous leukemia (CML). The increased protein tyrosine kinase (PTK) activity of the chimeric BCRABL gene product (p210B(tm)'ABL) can be blocked by a number of compounds specifically inhibiting p210BCR'ABL activity, including the tyrphostin AGI 112. At high dose, AGI 112 might be toxic for residual normal progenitors. Amifostine, a phosphorylated aminothiol, increases die selectivity of specific anticancer drugs for neoplastic cells by protecting normal hematopoietic cells. One potential application of this protector is during stem cell purging to allow the use of higher doses of a given antileukemic compound without damaging residual normal progenitors. We evaluated the effects of Amifostine pretreatment on CML-derived marrow and blood progenitors cells exposed to AGI 112. Amifostine pretreatment (3 mg/ml, 15 min, 37C) was followed by AGI 112 incubation (50-200 jiM, 18 hours, 37 C). The effect of AGI 112 and Amifostine was studied on committed (CPUMix, BFU-E, CFU-GM) and primitive (LTC-IC) progenitors. Preincubation of CML cells with AGI 112 induced a dose-dependent suppression of hematopoietic progenitors. AGI 112 doses causing 50% inhibition of colony formation (ID50) were 203 \iM and 121 pM for CFU-Mix+BFU-E and CFU-GM, respectively. Amifostine pretreatment prior to AGI 112 exposure resulted in ID50 values which were significantly higher as compared to those detected for AGI 112 alone (>300 nM for CFU-Mix+BFU-E, 188 uM for CFU-GM). Analysis of LTC-IC demonstrated 64% and 75% surviving colonies after AGI 112 (200nM) and Amifostine plus AGI 112, respectively. In conclusion, our data demonstrate that Amifostine pretreatment results in a protective effect on primitive and committed progenitors exposed to AGI 112. This could allow to explore the use of higher AGI 112 doses for CML purging in order to improve its antileukemic effects without damaging residual normal stem/progenitor cells.

Original languageEnglish
Pages (from-to)837
Number of pages1
JournalExperimental Hematology
Volume25
Issue number8
Publication statusPublished - 1997

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

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