Effect of cytokines on the toxicity of cytostatic drugs on leukemic cells in vitro and in vivo.
Most cytostatic drugs exert their effect on cells in active cell cycle. To improve the effect of cytostatic drugs we have tried, prior to treatment in vitro, to recruit tumor cells from G0 with growth factors. Leukemic cells from the bone marrows of 26 patients with AML and CML in blast crisis were incubated with G-CSF, GM-CSF and IL-3 for 24 h prior to incubation with cytostatic drugs. The cells were incubated with mitoxantrone, etoposide or daunorubicin for 1 h, or with Ara-C continuously. Prior to treatment, 4 patients with AML received GM-CSF for 24 h, after which blast cells from bone marrow were incubated with cytostatic drugs. After incubation with the cytostatic drugs, cells were cultured in a suspension culture for 4 d. The drug effect was determined with a bioluminescence ATP method. Leukemic cells were significantly stimulated by all three cytokines compared to an untreated control. GM-CSF and IL-3 increased the amount of cells 3- to 4-fold and G-CSF increased the amount 3 times compared to untreated cells. G-CSF significantly enhanced the cytotoxic effect of daunorubicin, mitoxantrone, etoposide and Ara-C by 20-40%, which GM-CSF and IL-3 showed a significantly increased toxicity for Ara-C only. Although the cytokines induced a higher percentage of cells killed with the cytostatic drugs, proliferation of the remaining cells resulted in an increased total number of cells from 1.5 to 3 times compared to the unstimulated incubations. We conclude that cytokines induce a higher level of toxicity of cytostatic drugs on leukemic cells, but the increased proliferation of the remaining cells may offset the clinical benefit.
Sundman-Engberg
B
B
Department of Medicine, Karolinska Insitutet, Huddinge Hospital, Sweden.
Tidefelt
U
U
Paul
C
C
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity*; D001752:Blast Crisis; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003561:Cytarabine / Q000633:toxicity; D016207:Cytokines / Q000494:pharmacology*; D003630:Daunorubicin / Q000633:toxicity; D004347:Drug Interactions; D005047:Etoposide / Q000633:toxicity; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology*; D008942:Mitoxantrone / Q000633:toxicity
D000970:Antineoplastic Agents; D016207:Cytokines; D006133:Growth Substances; D007377:Interleukin-3; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D000255:Adenosine Triphosphate; D008942:Mitoxantrone; D003630:Daunorubicin