Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Expression of manganese superoxide disumutase influences of chemo-sensitivity in esophageal and gastric cancers

R Izutani MD, M Kato MD, S Asano MD, M Imano MD, H Ohyanagi MD

Dept Surgery II, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan,

AIM: Our previous studies demonstrated that manganese superoxide disumutase (MnSOD) was expressed more extensively in the tissue of esophageal and gastric cancers than in non-cancerous tissue. We subsequently examined the effect of cytokines of TGFβ and TNFα on the expression of MnSOD in cultured cell lines of human esophageal cancer (T.T.) and gastric cancers (MKN28 and MKN 45). The purpose of this study was to examined whether the sensitivity of cancer cells to adriamycin (ADR), which is known to kill cancer cells through producing superoxide radicals, would increase in the presence of TGFβ by suppressing MnSOD expression. METHODS: T.T., MKN28, and MKN45 cells were treated with TGFβ or TNFα before exposure to ADR. Synergistic effects were assessed by MTT assay. Athymic female mice inoculated with the MKN 28 cells were treated with TGFβ, ADR, or TGFβ+ADR. Antitumor effects were evaluated by quantitation of tumor growth and survival time. RESULTS: TNFα induced MnSOD expression in these cell lines, however, TGFβ suppressed the expression of MnSOD in a time- and dose-dependent manner. In MKN28 cells, TGFβ reduced MnSOD mRNA level to about half of the control level at 1ng /ml. Pretreatment of T.T., MKN28, and MKN45 cell lines with TGFβ increased their sensitivity to ADR. In contrast, simultaneous exposure to TNFα decreased sensitivity to ADR. In vivo studies demonstrated that the combined administration of TGFβ and ADR postpone tumor growth compared to the treatment of either agent alone. CONCLUSIONS: Our result suggests that the synergistic antitumor effects of TGFβ and ADR could be induced through decreased MnSOD expression in cancer cells. Thus, the combination of TGFβ and ADR might prove useful for treatment of cancer cells, which express large amount of MnSOD.

KEY WORDS: WARDS MnSOD, Gastric Cancer, Esophageal Cancer.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on synergistic therapies.