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Prevention of Acute Chemotherapy-induced Death in Mice by Recombinant Human Interleukin 1: Protection from Hematological and Nonhematological Toxicities¹

Laboratory of Experimental Immunology [G. D., H. F., M. E. G., R. H. W.], Biological Carcinogenesis and Development Program, PRI/DynCorp. [K. L. K., T. B., J. R. K.], Laboratory of Molecular Immunoregulation [F. W. R.], and Biological Response Modifiers Program [D. L. L.], National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201

Previous studies have demonstrated that interleukin 1 (IL-1) can protect most mice from the acute lethal toxicity mediated by high doses of radiation and/or some chemotherapeutic drugs. The results presented herein demonstrate that the pretreatment of mice with recombinant human interleukin 1 (rhIL-1) protects mice from the lethal effects of several myelotoxic chemotherapeutic drugs, including 5-fluorouracil (5FUra), cyclophosphamide, cis-diammine(1,1-cyclobutanedicarboxyl-ato)platinum(II), and 1,3-bis-(2-chloroethyl)-1-nitrosourea. However, pretreatment with rhIL-1 was not effective against the acute lethal toxicity generated by doxorubicin and cisplatin. The chemoprotective effects appear to be at least partially due to myeloprotection/restoration, since the recovery of myeloid colony-forming units and the total cellularity in the bone marrow and spleen were accelerated in the rhIL-1-pretreated mice. However, the chemoprotective effects of rhIL-1 are apparently not limited to myeloprotection, since pretreatment with rhIL-1 protects mice against the lethal toxicity of both 5FUra and cyclophosphamide, yet bone marrow transplants rescue mice treated with 5FUra but not those treated with cyclophosphamide. The chemoprotective effects of rhIL-1 may be at least partially indirect, since the efficacy of chemoprotection by rhIL-1 is reduced in athymic mice, and interleukin 6, but not tumor necrosis factor , can substitute for rhIL-1 in chemoprotection from 5FUra.

¹ Funded in part with Federal funds from the Department of Health and Human Services, under Contract N01-CO-74102 with Program Resources, Inc./DynCorp. The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

² Present address: Istituto di Ricerche Farmacologiche, Mario Negri, Via Eritrea, 20157 Milan, Italy.

³ H. F. was supported during these studies by a Japanese Overseas Cancer Fellowship from the Foundation for the Promotion of Cancer Research. Present address: Growth Factor Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104, Japan.

⁴ To whom requests for reprints should be addressed, at National Cancer Institute-Frederick Cancer Research and Development Center, Building 560, Room 31-93, Frederick, MD 21702-1201.

Received 8/13/91. Accepted 5/13/92.

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