Chemoprotective effects of recombinant human IL-1 alpha in cyclophosphamide-treated normal and tumor-bearing mice. Protection from acute toxicity, hematologic effects, development of late mortality, and enhanced therapeutic efficacy
Futami, H.; Jansen, R.; MacPhee, M.J.; Keller, J.; McCormick, K.; Longo, D.L.; Oppenheim, J.J.; Ruscetti, F.W.; Wiltrout, R.H.
Journal of Immunology 145(12): 4121-4130
1990
ISSN/ISBN: 0022-1767 PMID: 2258610 Accession: 007107978
In this study, recombinant human IL-1.alpha. (rhIL-1.alpha.) was used to protect normal and tumor-bearing BALB/c mice from the acute toxicity caused by lethal doses of cyclophosphamide (Cy) and 5-fluorouracil. Pretreatment of mice for 7 days with 10,000 U/day of rhIL-1.alpha. protected 70 to 100% of mice from the acute death induced by lethal doses of both Cy (380 mg/kg) and 5-fluorouracil (250 mg/kg). In contrast, post-treatment of mice with single or multiple doses of rhIL-1.alpha. was not chemoprotective. Pretreatment of mice with rhIL-1.alpha. increased the acute LD90 of Cy from 380 mg/kg to >500 mg/kg in normal mice, and LD90 dose-modifying effect of at least 1.25, was accompanied by a more rapid recovery from neutropenia and a less severe reduction in the number of bone marrow single lineage monocyte, myeloid, or myelomonocytic colonies. Some of the mice (10 to 50%) that were successfully protected by pretreatment with rhIL-1.alpha. died after day 50. These mice consistently presented with extensive pulmonary inflammation and fibrosis at death. Mice bearing murine renal cancer (Renca) were also protected from the acute toxic effects of Cy (450 mg/kg) by pretreatment with rhIL-1.alpha. Renca-bearing mice pretreated with rhIL-1.alpha. and either sublethal (300 mg/kg) or lethal (450 mg/kg) doses of Cy exhibited enhanced survival times over those of untreated Renca-bearing mice. Interestingly, the cause of death in Renca-bearing mice that ultimately failed treatment with rhIL-1.alpha. plus 300 mg/kg Cy was recurrent tumor, whereas mice treated with rhIL-1.alpha. plus 450 mg/kg Cy had no detectable tumor, although several died from late pulmonary inflammation and fibrosis. Thus, the dose escalation of Cy in rhIL-1.alpha. pretreated mice, results in greater antitumor effects of Cy. However, the dose escalation of some cytotoxic agents allowed by the use of myelostimulatory agents can result in late fatal complications not detected in acute toxicity testing.