Favorable therapeutic index of a p210(BCR-ABL)-specific tyrosine kinase inhibitor; activity on lineage-committed and primitive chronic myelogenous leukemia progenitors
B. Kasper et al., Favorable therapeutic index of a p210(BCR-ABL)-specific tyrosine kinase inhibitor; activity on lineage-committed and primitive chronic myelogenous leukemia progenitors, CANC CHEMOT, 44(5), 1999, pp. 433-438
Purpose: In order to assess the effect of the tyrosine kinase inhibitor CGP
57148B on lineage-committed and primitive chronic myelogenous leukemia (CML
) progenitor cells, peripheral blood progenitor cells (PBPC) mobilized in c
hronic phase CML were exposed to this compound in vitro. Methods: Both shor
tterm (II week) and long-term exposure (greater than or equal to 2 weeks) t
o CGP57148B were investigated using suspension culture, semisolid (methylce
llulose) assay or stroma-dependent long-term culture (LTC). The proportion
of bcr/abl-positive progenitors was determined after direct plating [2 week
s in colony-forming cell (CFC) assay] as well as after 2 or 6 weeks LTC (LT
C always followed by CFC replates). Results: Incubation of CML PBPC over 48
h in suspension culture with 100 mu M CGP57148B reduced the proportion of
bcr/abl-positive colonies to 4.4 +/- 4.3% (n=5) after direct plating, 6.6 /- 4.2% (n = 5) after 2 weeks LTC and 5 =/- 5.6% (n = 2) after 6 weeks LTC.
At this dose, survival of drug-exposed normal PBPC was 53 +/- 4.2%, 51 +/-
2.8% and 54.5 +/- 4.9% (n = 2), respectively. Incubation with CGP57148B at
a concentration of 10 mu M over 1 week under LTC conditions reduced the nu
mber of bcr/abl-positive colonies to 11.8 +/- 6.1% (n= 5) after direct plat
ing, 12 +/- 6.4% (n=4) after 2 weeks LTC and 14.3 +/- 11.4% (n=3) after 6 w
eeks LTC; survival of normal PBPC was 84.5 +/- 2.1%, 93 +/- 4.2% and 86 +/-
1.4% (n=2), respectively. Following long-term exposure to CGP57148B at a c
oncentration of 1 mu M, the proportion of remaining bcr/abl-positive coloni
es was 35%, 9% and 25% of untreated CML samples after direct plating as wel
l as after 2 and 6 weeks LTC, respectively. The respective values for 10 mu
M CGP57148B were 10%, 11% and 19%. Long-term exposure of normal progenitor
s to CGP57148B yielded a survival of 98%, 100% and 93% (1 I-IM) or 77%, 86%
and 80% (10 mu M), respectively. Conclusion: The results support the use o
f CGP57148B either for short-term exposure in vitro (e.g. purging) or for c
ontinuous treatment of CML in vivo.