Dynamics of interaction between DNA-specific antitumor agents and serum-contained cytokines in the initiation of ML-1 human myeloblastic leukemia cell differentiation.
When added to RPMI-1640 medium containing fetal bovine serum, DNA-directed antineoplastic agents such as cytosine arabinoside (araC), daunorubicin, and actinomycin D induce the monocytic differentiation of ML-1 human myeloblastic leukemia cell populations to an extent that depends upon both drug and serum concentration. Differentiation is not induced in the absence of serum or when antibodies to tumor necrosis factor-alpha and transforming growth factor-beta are added to the cultures, indicating that these serum-contained cytokines participate in initiating the differentiation process. The drug- and cytokine-dependent cell maturation, which results in the inhibition of leukemic cell growth, is achieved at much lower concentrations of drug than is required for growth-inhibition through drug-mediated cell kill. RNA- and protein-targeted agents cannot replace DNA-specific agents in the process of differentiation-induction. The DNA-specific agents render the leukemic cells responsive to the low concentrations of differentiation-inducing cytokines that are present in serum, causing them to mature, and subsequently, to cease growth. This sensitization may be a component of the clinically selective action of DNA-specific antitumor agents.
Bloch
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Department of Experimental Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D016207:Cytokines / Q000097:blood / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000187:drug effects*; D003609:Dactinomycin / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D009000:Monocytes / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000970:Antineoplastic Agents; D016207:Cytokines; D004273:DNA, Neoplasm; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D003561:Cytarabine; D003609:Dactinomycin; D003630:Daunorubicin