Suppression and transient induction of lymphokines in cancer patients after administration of polyethylene glycolated interleukin-2.
Polyethylene glycolated (pegylated) interleukin-2 (PEG IL-2) was administered as a weekly i.v. bolus to patients with metastatic cancer in a phase-I trial. Efficacy, toxicity and pharmacokinetics have been described previously. To explore mechanism of IL-2 action and discover predictors of efficacy, the levels of several lymphokines were measured in pharmacokinetic serum samples. IL-1 beta and IL-6 were elevated in many patients before PEG IL-2 administration, forming a continuous, log-normal distribution among patients. The levels of the two lymphokines were strongly correlated. However, no significant correlation could be found between these levels, clinical chemistry, or tumor regression seen after PEG IL-2 administration. Three hours after PEG IL-2 administration, IL-1 beta and IL-6 levels, if elevated, fell to normal. In all patients, independent of initial levels, IL-6 and IFN-gamma, but not IL-1 beta, increased 4 to 6 h after the injection and then fell rapidly, even though PEG IL-2 levels were high and often changed only slightly during this period. This suggests an active shut down of lymphokine synthesis, or an increase in elimination rate. After the fourth administration of PEG IL-2, the peak level of IFN-gamma was 2 to 20 times higher than after the first, while the peak level of IL-6 did not change in a consistent direction. Responding patients had typical peak levels of IL-6 and IFN-gamma. Low levels of TNF and IL-4 were occasionally seen before and after PEG IL-2 administration, but no consistent pattern was evident.
Shih
Y
Y
Cetus Corporation, Emeryville.
Konrad
M W
MW
Warren
M K
MK
Childs
A
A
Paradise
C
C
Meyers
F J
FJ
Groves
E S
ES
D002097:C-Reactive Protein / Q000032:analysis; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D007375:Interleukin-1 / Q000097:blood; D007376:Interleukin-2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D008222:Lymphokines / Q000097:blood*; D009369:Neoplasms / Q000097:blood*; D011092:Polyethylene Glycols; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D008222:Lymphokines; D014409:Tumor Necrosis Factor-alpha; C067245:interleukin-2, polyethylene glycol-modified; D011092:Polyethylene Glycols; D007371:Interferon-gamma; D002097:C-Reactive Protein