In vivo radiosensitizing effects of recombinant interleukin 6 on radiation resistant BCL-1 B-lineage leukemia cells in a murine syngeneic bone marrow transplant model system.
The ability of total body irradiation (TBI) to eradicate clonogenic leukemia cells from B-lineage acute lymphoblastic leukemia patients prior to bone marrow transplantation (BMT) is greatly hampered by their inherent or acquired radiation resistance. The radiorefractory nature of these cells is believed to contribute to the high relapse rate subsequent to TBI and BMT in patients with B-lineage acute lymphoblastic leukemia (ALL). A method by which clonogenic leukemia cells could be radiosensitized in vivo could be clinically beneficial. In the present study, we used a highly radiation resistant subclone of the murine B-lineage leukemia cell line BCL-1 in a syngeneic BMT model to investigate if any of the B-cell stimulatory cytokines interleukin 2, interleukin 4, interleukin 5, or interleukin 6 could have radiosensitizing effects. All untreated BALB/c mice (N = 33) inoculated with 1 x 10(6) BCL-1 cells died of disseminated leukemia within 24 days with a median survival of 13.3 days. TBI (700 cGy = LD100/30 for BALB/c mice) followed by syngeneic BMT (N = 70) extended the median survival to 23.6 days (P < 0.001 by log-rank test). A single intraperitoneal bolus injection of 100 ng, 500 ng, or 2500 ng recombinant murine interleukin 6(rmIL-6) 2-4 hours before TBI extended the median survival to 32.5 days, 31.0 days, and 30.5 days, respectively (P < 0.01 by log-rank test for all dose groups). The improved survival was not due to any direct anti-leukemic activity of rmIL-6 and all control BALB/c mice (N = 15) that received the same doses of rmIL-6 but did not undergo TBI and BMT died of BCL-1 leukemia within 28 days with a median survival of 13.6 days. In contrast to rmIL-6, recombinant murine interleukin 5 (rmIL-5) had minimal radiosensitizing effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Waddick
K G
KG
Department of Therapeutic Radiology, University of Minnesota Health Sciences Center, Minneapolis.
Finnegan
D M
DM
Chelstrom
L M
LM
Uckun
F M
FM
D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D015448:Leukemia, B-Cell / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D007942:Leukemia, Experimental / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D014185:Transplantation, Isogeneic; D014916:Whole-Body Irradiation
D015850:Interleukin-6; D011838:Radiation-Sensitizing Agents; D011994:Recombinant Proteins