Dasatinib targets earlier progenitors than imatinib in primary chronic myeloid leukemia

08-11-2006

Dasatinib targets earlier progenitors than imatinib in primary chronic myeloid leukemia, but does not eliminate quiescent fraction.

According to recent research published in the journal Blood, "Dasatinib (BMS-354825), a novel dual SRC/BCR-ABL kinase inhibitor, exhibits greater potency than imatinib mesylate (IM) and inhibits the majority of kinase mutations in IM-resistant chronic myeloid leukemia (CIVIL). We have previously demonstrated that IM reversibly blocks proliferation but does not induce apoptosis of primitive CML cells."

"Here, we have attempted to overcome this resistance with dasatinib. Primitive IM-resistant CML cells showed only single-copy BCR-ABL but expressed significantly higher BCR-ABL transcript levels and BCR-ABL protein compared with more mature CML cells (p=0.031).

"In addition," wrote M. Copland and colleagues at the Royal Infirmary in Glasgow, "CrKL phosphorylation was higher in the primitive CD34+CD38- than in the total CD34+ population (p=0.002)."

"In total, CD34+ CIVIL cells, IM inhibited phosphorylation of CrKL at 16 but not 72 hours, consistent with enrichment of an IM-resistant primitive population.

"CD34+CD38- CML cells proved resistant to IM-induced inhibition of CrKL phosphorylation and apoptosis, whereas dasatinib led to significant inhibition of CrKL phosphorylation. Kinase domain mutations were not detectable in either IM or dasatinib-resistant primitive CML cells," researchers said.

"These data confirm that dasatinib is more effective than IM within the CML stem cell compartment; however," scientists concluded, "the most primitive quiescent CML cells appear to be inherently resistant to both drugs."

Copland and colleagues published their study in Blood (Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood, 2006;107(11):4532-4539).

For additional information, contact T.L. Holyoake, Royal Infirmary, Dept. of Hematology, Sect Experimental Hematology, Academy Transfusion Med Unit, 10 Alexandra Parade, Glasgow G31 2ER, Lanark, Scotland.

The publisher's contact information for the journal Blood is: American Society Hematology, 1900 M Street. NW Suite 200, Washington, DC 20036, USA.

Keywords: Lanark, Scotland, Apoptosis, Chronic Myeloid Leukemia, Quiescent Cells Dasatinib, Imatinib.

This article was prepared by Clinical Oncology Week editors from staff and other reports. Copyright 2006, Clinical Oncology Week via NewsRx.com.