Timed Sequential Therapy of Acute Leukemia with Flavopiridol
Purpose: The survival of adults with acute leukemias remains unsatisfactory and requires new treatment approaches. Flavopiridol modulates cell cycle progression, inhibits transcription, and induces apoptosis. We designed an in vitro model of timed sequential therapy for acute leukemia to determine w...
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Published in | Clinical cancer research Vol. 9; no. 1; p. 307 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
American Association for Cancer Research
01.01.2003
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Online Access | Get full text |
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Summary: | Purpose: The survival of adults with acute leukemias remains unsatisfactory and requires new treatment approaches. Flavopiridol modulates
cell cycle progression, inhibits transcription, and induces apoptosis. We designed an in vitro model of timed sequential therapy for acute leukemia to determine whether flavopiridol can: ( a ) trigger apoptosis in fresh acute leukemia; and ( b ) recruit surviving leukemic cells to a proliferative state, thereby priming such cells for the S-phase-related cytotoxicity
of 1-β- d -arabinofuranosylcytosine (ara-C).
Experimental Design: Bone marrow cells from 20 adults with relapsed and refractory acute leukemias were enriched for blasts by Ficoll Hypaque
sedimentation. Blasts were cultured on day 0 in flavopiridol 250 n m for 24 h, removed from flavopiridol for 24 h, and then cultured in ara-C 1 μ m for an additional 72 h (F 250 A 1 ). Apoptosis and cell cycle phase distribution were estimated from cells stained with propidium iodide. Cell survival was
determined after the 72 h ara-C exposure by double cytofluorescence assay with fluorescein diacetate and propidium iodide.
Results: Flavopiridol induced a 4.3-fold increase in apoptosis in human leukemia samples within the first 24 h of culture. Subsequent
removal of flavopiridol led to a 1.7-fold increase in the proportion of cells in S phase by day 2. Mean survival in F 250 A 1 cultures after 72 h exposure to ara-C was 35.6% compared with flavopiridol alone (F 250 A 0 , 56.1%; P = 0.0003) and ara-C alone (F 0 A 1 , 65.2%; P < 0.00001).
Conclusions: Flavopiridol induces apoptosis in marrow blasts from patients with refractory acute leukemias. Furthermore, flavopiridol
pretreatment increases the proapoptotic and cytotoxic effects of ara-C. The advantage of sequential FP 250 A 1 over either agent alone is seen for both acute myelogenous leukemia and acute lymphoblastic leukemia. These findings support
a clinical trial of timed sequential therapy where flavopiridol is given for cytoreduction and subsequent priming of remaining
leukemic cells for enhanced cycle-dependent drug cytotoxicity. |
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ISSN: | 1078-0432 1557-3265 |