Pentoxifylline inhibits interleukin-2-induced leukocyte-endothelial adherence and reduces systemic toxicity.
Interleukin-2 (IL-2) mediates the regression of metastatic cancer, but clinical application has been limited by the induction of dose-dependent toxicities in normal tissues. The most clinically significant toxicities occur secondary to a vascular leak syndrome and include acute respiratory failure and hemodynamic instability. Because previous studies suggested a role for pentoxifylline in attenuating the toxic effects of IL-2, we hypothesized that pentoxifylline would inhibit alterations in the microvasculature induced by IL-2 and would ultimately reduce IL-2-induced toxicity. To determine the validity of this hypothesis, we prepared four groups of rats for in vivo microvascular observation. In the first group, a bolus intravenous injection of IL-2 (1 x 10(6) units/kg) acutely induced hypotension, tachypnea, hypoxia, increased lung water, decreased microvascular blood flow, and increased leukocyte-endothelial adherence. No significant changes occurred in animals treated by pentoxifylline alone or the control IL-2 vehicle-alone group. However, pentoxifylline inhibited many of the IL-2-induced systemic and microvascular effects, such as hypotension, tachypnea, increased lung water, hypoxia, and increased leukocyte-endothelial adherence, but not tachycardia or increased microvascular protein leakage. These data support our hypothesis that systemic toxicities induced by IL-2 are associated with alterations in the microcirculation, which may be ameliorated by pentoxifylline.
Edwards
M J
MJ
Department of Surgery, University of Louisville School of Medicine, Ky 40292.
Abney
D L
DL
Miller
F N
FN
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects*; D006985:Hyperventilation / Q000139:chemically induced / Q000517:prevention & control; D007022:Hypotension / Q000139:chemically induced / Q000517:prevention & control; D000860:Hypoxia / Q000139:chemically induced / Q000517:prevention & control; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007962:Leukocytes / Q000187:drug effects*; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D010431:Pentoxifylline / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D007376:Interleukin-2; D010431:Pentoxifylline