A diphtheria toxin-interleukin 3 fusion protein is cytotoxic to primitive acute myeloid leukemia progenitors but spares normal progenitors.
The relative cytotoxicity of a diphtheria toxin (DT) human interleukin 3(IL3) fusion protein (DT(388)IL3) was tested against primitive normal (n = 3)and acute myeloid leukemia (AML) progenitors (n = 7). After 24-h culture with 50 ng/ml DT(388)IL3, the mean percentages of kill of AML colony-forming cells (CFCs), long-term culture-initiating cells (LTC-ICs), and suspension culture-ICs (SC-ICs) were 82% (range, 47-100), 56% (range, 28-91), and 74% (range, 43-87), respectively, with most surviving progenitors being cytogenetically normal. Engraftment of DT(388)IL-3-treated AML cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice followed for 16 weeks was eradicated for two of these samples. In contrast, with normal bone marrow, mean percentages of CFC kill of 49 and 64% were seen with 50 or 250 ng/ml DT(388)IL3, respectively, whereas no significant kills were observed in the LTC-IC and SC-IC assays. The NOD/SCID mouse repopulating cell (RC) frequency in normal BM cells was also not reduced by DT(388)IL3 treatment. In subsequent experiments, NOD/SCID mice that received AML blasts i.v. followed in 24 h by 0.045 microg/g DT(388)IL3 daily i.p. x 5 showed mean percentages of reduction in AML engraftment of 83% (range, 14-100) and 57% (range, 0-98) after 4 and 12 weeks, respectively (n = 6). No evidence of leukemia was detected with two of six AML samples 12 weeks after one 5-day course of DT(388)IL3. Repeating the DT(388)IL3 treatment every 4 weeks enhanced its effectiveness against two additional samples. Thus, DT(388)IL3 kills primitive leukemic progenitors from a proportion of AML patients but shows no significant toxicity against equivalent normal cells.
Feuring-Buske
Michaela
M
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 1L3 Canada.
Frankel
Arthur E
AE
Alexander
Richard L
RL
Gerhard
Brigitte
B
Hogge
Donna E
DE
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D004167:Diphtheria Toxin / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007377:Interleukin-3 / Q000494:pharmacology* / Q000633:toxicity; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy / Q000473:pathology; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D023461:Myeloid Progenitor Cells / Q000187:drug effects*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; D007377:Interleukin-3; D011993:Recombinant Fusion Proteins; C407154:diphtheria toxin-interleukin-3 fusion protein, recombinant