Cytosine arabinoside (ara-C) and cis-dichlorodiammineplatinum II (cisplatin) alone and in combination: effects on acute myeloblastic leukemia blast cells in culture and in vivo.
Cytosine arabinoside (ara-C) and cis-dichlorodiammineplatinum II (cisplatin) are lethal to mammalian cells by very different mechanisms; however, they share interactions with the biology of blast cells in acute myelogeneous leukemia (AML). Both agents are more toxic to AML blasts in suspension than when a clonogenic assay in methyl cellulose is used; both agents are more toxic in suspension in the presence of rG-CSF than with rGM-CSF. Accordingly, preclinical tests were undertaken of cisplatin and ara-C in combination. At the same time, a phase I/II clinical trial of the combination was conducted, using AML patients refractory to treatment or in relapse. In the laboratory, blasts from eight AML patients were tested against each agent singly and in combination. The observed survival values for the mixture were compared with those predicted by assuming either an additive effect or a more general effect that allows synergism or antagonism. Blasts from two patients were tested with this design in the presence of rG-CSF or rGM-CSF. In most instances the toxic effects of ara-C and cisplatin were additive. Evidence of synergism was seen in blasts from three patients.
Wang
Y F
YF
Ontario Cancer Institute, University of Toronto, Ontario, Canada.
Curtis
J E
JE
Lipton
J
J
Minkin
S
S
McCulloch
E A
EA
Lipton
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology*; D004341:Drug Evaluation; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D011994:Recombinant Proteins; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002945:Cisplatin