Effects of rhGM-CSF on intracellular ara-C pharmacology in vitro in acute myelocytic leukemia: comparability with drug-induced humoral stimulatory activity.
Human acute myelocytic leukemia (AML) marrow cells respond to stimulation with increased proliferation and enhanced intracellular metabolism of the cytotoxic antimetabolite 1-B-D arabinofuranosylcytosine (ara-C). Our previous studies have focused on the drug-induced humoral stimulatory activity (HSA) present in serum following initial cytoreduction which augments in vitro growth and biochemical pharmacology. The activity of HSA likely relates to the presence of multiple stimulators. The effect of 18-hr culture in purified recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) (1 ng/ml) on in vitro AML marrow cell [3H]dThd incorporation into DNA, intracellular ara-C activation to the triphosphate form (ara-CTP), and subsequent ara-CTP retention were determined in leukemic cells of 11 patients and compared with cells similarly cultured in HSA-containing sera. The stimulatory effects of rhGM-CSF and HSA on both growth and pharmacologic parameters were comparable for each AML population, with maximal response to both regulators detected for FAB M2. These data demonstrate that GM-CSF acts similarly to HSA as an active stimulator of leukemic cell proliferation and net intracellular ara-C metabolism in vitro, and support clinical trials designed to examine the role of rhGM-CSF in enhancing ara-C cytotoxicity by increasing the growth fraction of drug-responsive target cells in vivo.
Adult Leukemia Program, Johns Hopkins Oncology Center, Baltimore, Maryland 21205.
J E
JE
Karp
P J
PJ
Burke
R C
RC
Donehower
D000328:Adult; D000368:Aged; D001711:Biotransformation; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D003561:Cytarabine / Q000378:metabolism / Q000493:pharmacokinetics*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D011994:Recombinant Proteins; D003561:Cytarabine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor