Effect of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on hematopoietic regeneration as demonstrated in a nonhuman primate chemotherapy model.
Using a recently developed hepsulfam-induced pancytopenia model in rhesus macaques, we have studied the effects of recombinant human interleukin-6 (rhIL-6) and rhIL-3 on marrow regeneration. Control animals were given hepsulfam (1.5 g/m2 by a single 30-minute intravenous [i.v.] injection, n = 4), while study animals received hepsulfam followed by rhIL-6, rhIL-3, or a combination of rhIL-6 and rhIL-3 (n = 3 per study group). Each cytokine was administered by once-daily subcutaneous (SC) injection (15 micrograms/kg/d) for 3 weeks beginning the day after chemotherapy (days 2 through 22). Mean platelet counts in control animals were < 100,000/microL on days 15 through 24, with 50% of the counts < 50,000/microL and two of four animals requiring platelet transfusion. In the rhIL-6- and rhIL-6/rhIL-3-treated groups, the nadir mean platelet counts were 164,000 +/- 58,700/microL and 162,300 +/- 23,800/microL, respectively, and occurred on day 15. Platelet counts in the rhIL-3-treated group were similar to those in controls. Mean absolute neutrophil counts (ANCs) < 1,000/microL occurred on days 10 through 29 in control animals, days 8 through 15 in rhIL-6-treated animals, and days 6 through 8 and 13 in rhIL-6/rhIL-3-treated animals. The frequency of ANCs < 500/microL was significantly less in the rhIL-6- and rhIL-6/rhIL-3-treated groups versus control groups (2.7 +/- 0.6 and 2.0 +/- 1.0 vs 7.0 +/- 1.4 occurrences, respectively; P < .05). rhIL-3-treated animals had ANCs similar to those in controls; one animal died with septicemia on day 21. Monkeys receiving rhIL-6 were significantly more anemic during the cytokine administration period; however, the anemia resolved by day 24. Coadministration of rhIL-3 and rhIL-6 partially corrected the anemia. The data indicate that rhIL-6 prevents significant thrombocytopenia and shortens the neutropenic period in this chemotherapy model.
Winton
E F
EF
Emory University School of Medicine, Atlanta, GA.
Srinivasiah
J
J
Kim
B K
BK
Hillyer
C D
CD
Strobert
E A
EA
Orkin
J L
JL
Swenson
R B
RB
McClure
H M
HM
Myers
L A
LA
Saral
R
R
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006454:Hemoglobins / Q000032:analysis; D007377:Interleukin-3 / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000627:therapeutic use*; D008253:Macaca mulatta; D008297:Male; D009503:Neutropenia / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012156:Reticulocytes / Q000187:drug effects; D013451:Sulfonic Acids / Q000633:toxicity; D013921:Thrombocytopenia / Q000517:prevention & control*
D006454:Hemoglobins; D007377:Interleukin-3; D015850:Interleukin-6; D011994:Recombinant Proteins; D013451:Sulfonic Acids; C052475:hepsulfam