Immunopharmacology and cytokine production of a low-dose schedule of intraperitoneally administered human recombinant interleukin-2 in patients with advanced epithelial ovarian carcinoma.
We determined in the peritoneal cavity (p.c.) of epithelial ovarian carcinoma patients during a 4-day treatment cycle of low-dose recombinant human interleukin-2 (rIL-2): (a) pharmacokinetics of IL-2, (b) endogenous cytokine production, and (c) numbers and percentages of peritoneal exudate lymphocytes. We administered 6 x 10(5) IU/m2 of rIL-2 (0.03 mg/m2 Proleukin rIL-2) intraperitoneally (i.p.) over 30 min on each of 4 days. One and one-half liters of D5 0.25 NS was injected i.p. before each rIL-2 infusion. Multiple peritoneal fluid samples were obtained from each of four patients on day 1 and day 4 for detection of IL-2, endogenous cytokines, and soluble IL-2 receptor (IL-2R-alpha). IL-2 concentrations in the peritoneal fluid were determined by bioassay and interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-10, transforming growth factor (TGF)-beta 2, and sIL-2R-alpha by enzyme-linked immunosorbent assay. Numbers of cells per microliter and lymphocyte subpopulation percentages after staining with a panel of monoclonal antibodies were determined on day 1, day 4, and subsequent off-treatment days. IL-2 disappearance in the p.c. was well described by a pharmacokinetic model having constant-rate infusion and biexponential disposition. About 90% of the IL-2 disappearance occurred during the beta-phase, during which IL-2 concentrations were sustained at approximately 10-30 ng/ml (day 1 and day 4) and the median t1/2 beta was 21.5 and 9.2 h on days 1 and 4, respectively. In four of four patients, p.c. production of IL-10 was observed on day 1 and day 4 (maximum 387 pg/ml). Maximum levels of IFN-gamma and sIL-2R-alpha were observed on day 4. (IFN-gamma 217 pg/ml; sIL2-R-alpha: 3486 U/ml). No increases in TNF-alpha or TGF-beta 2 were observed. Large increases in p.c. CD3+, CD4+, CD8+, CD16+, and CD56+ cells were observed. We conclude that biologically active levels of IL-2 are generated in p.c. fluids after i.p. administration of rIL-2 at 0.03 mg/m2.
Freedman
R S
RS
Department of Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Gibbons
J A
JA
Giedlin
M
M
Kudelka
A P
AP
Kavanagh
J J
JJ
Edwards
C L
CL
Carrasco
C H
CH
Nash
M A
MA
Platsoucas
C D
CD
D000328:Adult; D001772:Blood Cell Count / Q000187:drug effects; D002277:Carcinoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D016207:Cytokines / Q000096:biosynthesis*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D016131:Lymphocyte Subsets / Q000145:classification; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*
D016207:Cytokines; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins