Effect of stem cell factor on leukemic progenitor cell growth and sensitivity to cytosine-arabinoside.
Recruitment of quiescent, clonogenic blasts from patients with acute myeloid leukemia (AML) by hematopoietic growth factors (HGFs) may improve the cytotoxic effects of cell-cycle-specific drugs like cytosine-arabinoside (Ara-C). Using the culture methods described by Nara and McCulloch and making a distinction between self-renewing and post-deterministic mitoses, we analyzed the effects of stem cell factor (SCF), a growth factor acting on early hematopoietic progenitor and stem cells. First, we demonstrated that SCF, used in combination with other HGFs included in fetal calf serum (FCS) and/or in 5637 cell line supernatant (5637-CM), stimulated both colony formation and self-renewal of blast progenitors from 10 patients, unlike SCF alone. We tested the effects of SCF on the recruitment of cells in the S-phase by using a bromodeoxyuridine/DNA (BrdUrd/DNA) staining method in flow cytometry (FCM). We showed that SCF stimulated proliferation of AML cells significantly in 9/18 patients with AML. Second, we tested the influence of SCF on the sensitivity to Ara-C of self-renewing leukemic cells from 18 patients with AML. We showed that SCF was efficient in increasing the toxicity of Ara-C on the self-renewing blast progenitors, especially with high concentrations of Ara-C. However, a large patient-to-patient heterogeneity was found and the activity of SCF was not correlated with its effect on the cell cycle. These data indicate that SCF can enhance sensitivity to Ara-C of some leukemic cells with self-renewing capacity.
Viallard
J F
JF
Laboratoire de Greffe de Moëlle, URA CNRS 1456, Université de Bordeaux II, France.
Grosset
C
C
Lacombe
F
F
David
S
S
Mahon
F X
FX
Barbot
C
C
Vianes
I
I
Dupouy
M
M
Reiffers
J
J
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D003470:Culture Media / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D005434:Flow Cytometry; D016298:Hematopoietic Cell Growth Factors / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008747:Methylcellulose; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology*; D013535:Suspensions; D014410:Tumor Stem Cell Assay
D000964:Antimetabolites, Antineoplastic; D003470:Culture Media; D016895:Culture Media, Serum-Free; D016298:Hematopoietic Cell Growth Factors; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D013535:Suspensions; D003561:Cytarabine; D008747:Methylcellulose