Pentoxifylline inhibits interleukin-2-induced toxicity in C57BL/6 mice but preserves antitumor efficacy.
Interleukin 2 (IL-2) mediates the regression of metastatic cancer but clinical use has been limited due to associated toxicities. Tumor necrosis factor (TNF) is an important mediator of IL-2 toxicity and may have a limited role in IL-2 antitumor efficacy. Because pentoxifylline (PTXF) inhibits TNF production, we hypothesized that PTXF would ameliorate IL-2 toxicity without compromising antitumor efficacy. Four groups of female C57BL/6 mice with pulmonary metastases from a 3-methylcholanthrene-induced fibrosarcoma (MCA-105) and four groups of nontumored mice were treated every 6 h for 4 d by intraperitoneal injections of either IL-2 alone, IL-2 and PTXF, PTXF alone, or equal volumes of saline. Upon completion of therapy, we found that PTXF suppressed many of the IL-2-induced effects including TNF production, lymphocytic infiltration of multiple organs, multiple organ edema, hepatic dysfunction, leukopenia, and thrombocytopenia. Tumor response was determined 21 d after cessation of therapy by quantitating the number and surface area of pulmonary metastases. PTXF preserved antitumor efficacy while reducing the morbidity and mortality caused by IL-2 treatment. These data strongly support the use of PTXF in extending the therapeutic index of IL-2 in the treatment of cancer.
Edwards
M J
MJ
Department of Surgery, J. Graham Brown Cancer Center, University of Louisville, School of Medicine, Kentucky 40292.
Heniford
B T
BT
Klar
E A
EA
Doak
K W
KW
Miller
F N
FN
D000818:Animals; D000970:Antineoplastic Agents; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D010431:Pentoxifylline / Q000494:pharmacology*; D012513:Sarcoma, Experimental / Q000188:drug therapy; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000970:Antineoplastic Agents; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D010431:Pentoxifylline