Induced proteins in human peripheral mononuclear cells over a range of clinically tolerable doses of interferon-gamma.
This study assessed biologic response modification at three different dose levels (0.15, 1.5, and 15 mg/m2) of interferon-gamma (IFN-gamma) administered by intravenous bolus three times weekly. A final total of 24 patients were evaluable. Dose-limiting toxicity occurred at the highest dose level (15 mg/m2) and included fatigue, leukopenia, and hepatotoxicity. Evaluation of biologic response modification included assessment of 2',5'-oligoadenylate (2-5A) synthetase activity in peripheral mononuclear cells, measurement of serum beta 2-microglobulin and expression of beta 2-microglobulin on monocytes, measurement of monocyte HLA Class II expression (HLA-DR, HLA-DQ), and measurement of hydrogen peroxide generation by monocytes 24 h after the first and fourth IFN-gamma treatments. Significant increases (p less than 0.05) from baseline were seen at 24 h with all parameters except H2O2 generation. Except for enhancement of HLA-DR, even the lowest dose (0.15 mg/m2) augmented synthesis of 2-5A synthetase and HLA proteins. A dose-response effect was noted for changes in serum and monocyte beta 2-microglobulin levels but not for 2-5A synthetase levels or HLA Class II antigen expression on monocytes. After 4 doses administered over 9 days, most parameters remained increased when compared to pretreatment, but were not further enhanced when compared with levels attained after the first dose. The results of this study document the efficacy of IFN-gamma for biological activation over a wide dose range and are consistent with the postulate that immunoregulatory effects of biological therapeutics can be obtained in man at doses substantially less than those that are maximally tolerated. Further documentation of biologic response parameters by IFN-gamma at low doses will be necessary to determine the importance of biologic activation in relation to antitumor activity.
Paulnock
D M
DM
Department of Human Oncology, University of Wisconsin Medical School, Madison 53792.
Havlin
K A
KA
Storer
B M
BM
Spear
G T
GT
Sielaff
K M
KM
Borden
E C
EC
D015088:2',5'-Oligoadenylate Synthetase / Q000097:blood; D000917:Antibody Formation; D006683:HLA-DQ Antigens / Q000096:biosynthesis; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D006861:Hydrogen Peroxide / Q000097:blood; D007371:Interferon-gamma / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin / Q000378:metabolism
D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D015088:2',5'-Oligoadenylate Synthetase