Tumour necrosis factor mediates the survival benefit of interleukin 2 in a murine pulmonary metastases model.
Antibody to tumour necrosis factor (TNF Ab) markedly decreases the toxicity of systemic interleukin-2 (IL-2) in mice but does not completely abrogate the anti-tumour response in terms of number of pulmonary metastases. Experiments were performed with a murine model of pulmonary metastases treated with high-dose IL-2 and concomitant TNF Ab or control antibody (CON Ab) to determine the effects of TNF Ab on survival. Mice were given either equal doses of IL-2 and TNF Ab or CON Ab or equitoxic doses of IL-2. In four consecutive experiments mice given TNF Ab tolerated 5 to 6 additional IL-2 doses (a 40-60% increase in total doses) in the equitoxic IL-2 dose group compared to the maximally tolerated dose with CON Ab. In all four experiments TNF Ab-treated mice had decreased survival compared to the CON Ab group given equal doses of IL-2 and in two of four experiments this difference was statistically significant (P2 < 0.01). Mice given 40-60% additional doses of IL-2 with TNF Ab had no improvement in survival compared with equitoxic doses of IL-2 with CON Ab in three of four experiments (P2 = 0.32, P2 = 0.67, P2 = 0.69). The TNF Ab preparation had no direct inhibition of IL-2 activity in an in vitro IL-2 proliferation bioassay. TNF Ab consistently blocks IL-2 toxicity and it also abrogates IL-2 therapeutic efficacy such that survival parallels treatment toxicity in this experimental model.
Fraker
D L
DL
Surgical Metabolism Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Thom
A K
AK
Doherty
G M
GM
Langstein
H N
HN
Buresh
C M
CM
Norton
J A
JA
D000818:Animals; D000906:Antibodies / Q000302:isolation & purification / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D005260:Female; D007376:Interleukin-2 / Q000627:therapeutic use* / Q000633:toxicity; D008175:Lung Neoplasms / Q000401:mortality / Q000556:secondary* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000627:therapeutic use / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D000906:Antibodies; D007376:Interleukin-2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha