Regression mechanisms of mouse fibrosarcoma cells after in vitro exposure to quercetin: diminution of tumorigenicity with a corresponding decrease in the production of prostaglandin E2.
We have previously reported that both regressor (QR) and progressor (metastatic, QP) clones were obtained after the in vitro exposure of a mouse fibrosarcoma BMT-11 cl-9 to quercetin. In this study, we investigated possible mechanisms of spontaneous regression of QR clones as compared with tumorigenic QP and BMT-11 cl-9 tumor clones. We observed that BMT-11 cl-9 cells produced relatively high amounts of prostaglandin E2 (PGE2) during in vitro culture. The average production by 11 subclones of BMT-11 cl-9 cells was 9236 +/- 2829 pg/ml whereas that by 9 QR clones was 3411 +/- 2213 pg/ml (P less than 0.02). Indomethacin not only inhibited in vitro PGE2 synthesis by QP clones (high-PGE2 producers) but also the s.c. growth of QP clones in mice. Chronological changes in host immune responses to tumor-associated antigen were measured by cytotoxic T lymphocyte (CTL) activity examined after mixed lymphocyte/tumor cell culture of spleen cells obtained from tumor-bearing mice. The CTL activity disappeared abruptly in the spleen of QP-clone-bearing mice 21 days after the inoculation of tumors, whereas the spleen cells of QR-clone-inoculated mice retained their CTL activity. We determined that the mechanism responsible for the regression of these regressor clones is not due to any qualitative or quantitative increase in pre-existing membrane antigens, nor the emergence of new antigen(s) on the cell surface of the QR clones: nor was it due to enhanced susceptibility of QR clones to natural killer cells, lymphokine-activated killer cells and macrophages. These finding suggest that the regression mechanism of QR clones may be the diminished inhibition of host response to tumor-associated antigen caused by the reduced production of PGE2 by QR clones.
Okada
F
F
Cancer Institute, Hokkaido University School of Medicine, Sapporo, Japan.
Hosokawa
M
M
Hasegawa
J
J
Ishikawa
M
M
Chiba
I
I
Nakamura
Y
Y
Kobayashi
H
H
D000818:Animals; D003429:Cross Reactions; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D005354:Fibrosarcoma / Q000473:pathology*; D005419:Flavonoids / Q000494:pharmacology*; D006183:H-2 Antigens / Q000032:analysis; D006412:Hematopoietic Stem Cells / Q000276:immunology; D007213:Indomethacin / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011794:Quercetin / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured
D005419:Flavonoids; D006183:H-2 Antigens; D011794:Quercetin; D015232:Dinoprostone; D007213:Indomethacin