Receptor and nonreceptor protein tyrosine kinases (PTKs) play a key rote in the control of normal and neoplastic cell growth. It was ihe aim of the present study to evaluate the effects of genistein, a natural inhibitor of PTKs, on the in vitro colony formation by normal multilineage colony-form ing units (CPU-Mix), erythroid bursts (BFU-E), granulocyte-macrophage CPU (CFU-GM), long-term culture-initiating cells (LTC-IC), and acute myelogenous leukemia CPU (CFUAML). Continuous exposure of normal marrow and blood mononuclear cells, blood CD34'CD45RA cells, and leukemic blasts to increasing doses of genistein (1-100 p,M) resulted in a statistically significant (P <.()5) dose-de pendent suppression of CPU-Mix, BFU-E, CFU-GM and CFU-AML growth. Regression analysis showed that growth inhibition was linearly related to genistein concentration. Genistein dose causing 50% inhibition (IDW) of CFU-AML was significantly lower as compared to CFU-GM 1DM| for marrow (19 vs 32 |iM, P <.OI7), unseparated blood (19 vs 44 u.M. P S.02X) or CD34 CD45RA' blood 119 vs 36, P <.04). Preincubation of leukemic blasts with genistein (200 u.M) for 1-2 hours confirmed thai CFU-AML were significantly more sensitive than normal marrow and blood CFU-GM to genisiein. Preincubation conditions (200 (iM, 18 hours) maximally suppressing leukemic and normal colony growth spared a substantial percentage of marrow (29 ±4(£) and blood (40 ±3%) LTCIC. In conclusion, our data demonstrate that: (a) genistein stronuly inhibits the growth of normal and leukemic progenitors in dose- and tinif Jcpcndent manner; (b) leukemic progenitors are more sensitive than normal pm-icnitors to genistein-induced growth inhibition; (c) genistein exens a direct toxic effect on hematopoietic cells while sparing a substantial proportion of LTC-IC. These data strongly supports the use of yenistein t'or hematopodtic cell purging.
Leukemic cfu-aml are more sensittve than normal progenitors to genistejn-induced growth inhibition
Carlo Stella C.;
1996-01-01
Abstract
Receptor and nonreceptor protein tyrosine kinases (PTKs) play a key rote in the control of normal and neoplastic cell growth. It was ihe aim of the present study to evaluate the effects of genistein, a natural inhibitor of PTKs, on the in vitro colony formation by normal multilineage colony-form ing units (CPU-Mix), erythroid bursts (BFU-E), granulocyte-macrophage CPU (CFU-GM), long-term culture-initiating cells (LTC-IC), and acute myelogenous leukemia CPU (CFUAML). Continuous exposure of normal marrow and blood mononuclear cells, blood CD34'CD45RA cells, and leukemic blasts to increasing doses of genistein (1-100 p,M) resulted in a statistically significant (P <.()5) dose-de pendent suppression of CPU-Mix, BFU-E, CFU-GM and CFU-AML growth. Regression analysis showed that growth inhibition was linearly related to genistein concentration. Genistein dose causing 50% inhibition (IDW) of CFU-AML was significantly lower as compared to CFU-GM 1DM| for marrow (19 vs 32 |iM, P <.OI7), unseparated blood (19 vs 44 u.M. P S.02X) or CD34 CD45RA' blood 119 vs 36, P <.04). Preincubation of leukemic blasts with genistein (200 u.M) for 1-2 hours confirmed thai CFU-AML were significantly more sensitive than normal marrow and blood CFU-GM to genisiein. Preincubation conditions (200 (iM, 18 hours) maximally suppressing leukemic and normal colony growth spared a substantial percentage of marrow (29 ±4(£) and blood (40 ±3%) LTCIC. In conclusion, our data demonstrate that: (a) genistein stronuly inhibits the growth of normal and leukemic progenitors in dose- and tinif Jcpcndent manner; (b) leukemic progenitors are more sensitive than normal pm-icnitors to genistein-induced growth inhibition; (c) genistein exens a direct toxic effect on hematopoietic cells while sparing a substantial proportion of LTC-IC. These data strongly supports the use of yenistein t'or hematopodtic cell purging.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
