title: Recombinant human interleukin-1 receptor antagonist reduces acute lethal toxicity and protects hematopoiesis from chemotoxicity in vivo.
abstract: Cyclophosphamide (CY), targeting to fast dividing cells, results in bone marrow (BM) suppression, which is the most common side effect of cancer chemotherapy. Interleukin-1 receptor antagonist (IL-1Ra), activated by variety of chemotherapeutic drugs, is a natural inhibitor of interleukin-1 (IL-1) and blocks the functional IL-1 receptor signaling. Our previous studies showed the protective effect of recombinant murine IL-1Ra on hematopoiesis in mice after treatment with chemotherapeutic agent 5-fluorouracil. In this report, we demonstrate that the pretreatment use of recombinant human IL-1Ra (rhIL-1Ra) significantly alleviated chemotherapy-induced peripheral blood injury in mice, and reduced the incidence and severity of neutropenia in beagle dogs. Moreover, acute lethal toxicity in single and repeated CY treatment was markedly reduced by rhIL-1Ra administration. The chemoprotective role of rhIL-1Ra is attributed to the attenuated BM damage, accelerated recovery of BM cells, and enhanced survival of hematopoietic progenitor cells which expressed high level of aldehyde dehydrogenase and IL-1 receptor type I. Thus, our data strongly suggest that the prophylactic use of exogenous rhIL-1Ra renders BM primitive hematopoietic cells resistant to chemotherapy, which provides novel strategies to prevent BM suppression in clinical settings.
authors: Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors: Lan
authors: L
authors: Qian
authors: Di
authors: D
authors: Xiang
authors: Jing
authors: J
authors: Zhang
authors: Shunying
authors: S
authors: Zhu
authors: Jin
authors: J
authors: Gao
authors: Xia
authors: X
authors: Wang
authors: Jing
authors: J
authors: Gao
authors: Yang
authors: Y
authors: Zhang
authors: Jiaqing
authors: J
authors: Shen
authors: Yan
authors: Y
authors: Yu
authors: Wei
authors: W
authors: Han
authors: Mingyuan
authors: M
authors: Wu
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D003520:Cyclophosphamide / Q000009:adverse effects / Q000494:pharmacology; D004285:Dogs; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009503:Neutropenia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D003520:Cyclophosphamide; D000444:Aldehyde Dehydrogenase