In vitro augmentation of cytotoxic activity of peripheral blood lymphocytes and spleen cells of cancer patients by ubenimex.
Ubenimex is used for the immunotherapy of malignant diseases as a biological response modifier (BRM) and shows beneficial effects as an adjuvant treatment. In the present study, the in vitro effects of ubenimex on the cytotoxic activity of peripheral blood lymphocytes (PBL) and spleen cells of cancer patients and the mechanism of killer cell activation were investigated. Cytotoxic activity against K562, KATO-III and autologous tumor cells was augmented by in vitro sensitization with ubenimex (p < 0.05). The optimal concentration of ubenimex for induction of cytotoxic activity was 1 micrograms/ml, similar to serum levels after clinical oral administration. The major population of killer cells activated by ubenimex recognizing K562 was CD16+, and those recognizing KATO-III were mainly CDA+ or CD8(5) cels and CD16+ NK cells, while CDA5 or CD8+T cells comprised the majority of killer cells which showed autologous tumor-killing activity. Augmentation of the cytotoxic activity of mononuclear cells by ubenimex was blocked by both anti-IL-1 beta Ab and anti-IL-2 AB. However, the expression of IL-2 receptor (p55, p75) on effector cells was not altered. Ubenimex augmented not only NK activity but also autologous tumor killing activity of PBL and spleen cells via macrophage activation. These activities of ubenimex may be clinically beneficial as an adjuvant treatment.
Department of Gastroenterological Surgery, Wakayama Medical College, Japan.
M
M
Iwahashi
H
H
Tanimura
H
H
Yamaue
T
T
Tsunoda
M
M
Tani
K
K
Noguchi
S
S
Mizobata
M
M
Tamai
T
T
Hotta
K
K
Arii
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007375:Interleukin-1 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D004915:Leukemia, Erythroblastic, Acute; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013154:Spleen / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000903:Antibiotics, Antineoplastic; D000906:Antibodies; D015703:Antigens, CD; D007375:Interleukin-1; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D003165:Complement System Proteins; D007930:Leucine; C012211:ubenimex