|
|
 Previous Article | Table of Contents | Next Article 
Correlation of drug-perturbed marrow cell growth kinetics and intracellular
1-B-D-arabinofuranosylcytosine metabolism with clinical response in adult
acute myelogenous leukemia
JE Karp, RC Donehower, GB Dole and PJ Burke
To define the relationship between leukemic cell growth, intracellular
metabolism of 1-B-D-arabinofuranosylcytosine (ara-C), and the clinical
response to timed sequential induction therapy with ara-C in adult acute
myelogenous leukemia (AML), growth kinetic and biochemical pharmacologic
determinants were examined in AML bone marrow populations. Leukemic blasts
from 45 previously untreated patients obtained prior to therapy were
cultured in vitro in autologous pretreatment serum (APS) and in serum
containing drug-induced humoral stimulatory activity (HSA). Cell
populations cultured in HSA demonstrated both increased proliferation, as
measured by both [3H]dThd incorporation into DNA and [3H]dThd leukemic
blast labeling index, and greater [3H] ara-C leukemic blast labeling index
relative to cells maintained in APS. HSA-cultured marrow cells from the 31
patients who achieved complete remission with ara-C-containing therapy
demonstrated enhanced intracellular formation of ara-C 5'-triphosphate over
three hours and retention of this active form during one subsequent hour in
drug-free medium relative to cells maintained in APS. In contrast, cells
from the 14 nonresponsive patients demonstrated no such HSA- induced
increases in intracellular ara-C metabolism. These studies of human AML
marrow cells identify behavior patterns of ara-C activation and net
metabolism in the kinetically perturbed, proliferative state that may
discriminate clinical sensitivity from clinical resistance to ara-C-based
timed sequential therapy. Sensitive AML populations behave similarly to
normal hematopoietic cohorts, with direct linkage of HSA- perturbed growth
and pharmacologic parameters, while refractory cells demonstrate uncoupling
of these determinants in the growth-stimulated state. These in vitro
measurements may further serve as a template for prediction of clinical
outcome to timed sequential therapy with ara-C, where both pharmacologic
and cytokinetic determinants of response are intrinsic to the success of
the designed drug scheduling.
Volume 69,
Issue 4,
pp. 1134-1140,
04/01/1987
Copyright © 1987 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
R. A. Mesa, D. Loegering, H. L. Powell, K. Flatten, S. J. H. Arlander, N. T. Dai, M. P. Heldebrant, B. T. Vroman, B. D. Smith, J. E. Karp, et al.
Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine
Blood,
July 1, 2005;
106(1):
318 - 327.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Byrd, A. S. Ruppert, K. Mrozek, A. J. Carroll, C. G. Edwards, D. C. Arthur, M. J. Pettenati, J. Stamberg, P. R.K. Koduru, J. O. Moore, et al.
Repetitive Cycles of High-Dose Cytarabine Benefit Patients With Acute Myeloid Leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): Results from CALGB 8461
J. Clin. Oncol.,
March 15, 2004;
22(6):
1087 - 1094.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. Karp, D. D. Ross, W. Yang, M. L. Tidwell, Y. Wei, J. Greer, D. L. Mann, T. Nakanishi, J. J. Wright, and A. D. Colevas
Timed Sequential Therapy of Acute Leukemia with Flavopiridol: In Vitro Model for a Phase I Clinical Trial
Clin. Cancer Res.,
January 1, 2003;
9(1):
307 - 315.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Rowe and M. S. Tallman
Intensifying Induction Therapy in Acute Myeloid Leukemia: Has a New Standard of Care Emerged?
Blood,
September 15, 1997;
90(6):
2121 - 2126.
[Full Text]
[PDF]
|
|
|
|
|
