Goshi Nishimura

An experimental model of tumor dormancy therapy for advanced head and neck carcinoma was developed. After transplantation of KB cells into nude mice, the mice were given tiracoxib, a selective cyclooxygenase (COX)‐2 inhibitor, probucol, an antioxidant, and S‐1, an oral pro‐drug of 5‐fluorouracil (5‐FU), or combinations of two of them. The combined administration of tiracoxib with probucol significantly inhibited the tumor growth. The angiogenesis in this group was markedly reduced. Tiracoxib and probucol did not affect the intratumoral concentration of 5‐FU when coadministered with S‐1. The combined use of tiracoxib and probucol is thus a candidate for use in maintenance therapy after the primary therapy for patients with advanced head and neck carcinoma.

Probucol is a very strong synthetic antioxidant that was been safely used for the treatment of hyperlipidemia in Japan since 1985. It has been reported that lipid oxidation products can alter growth factor production, which could influence smooth muscle cell proliferation. Oxidized low density lipoprotein can influence smooth muscle cell proliferation by enhancing the expression of platelet‐derived growth factor (PDGF)‐AA gene and PDGF receptor in vascular smooth muscle cell. Further, free radical reactions can cause irreversible alterations of genomic constituents during the initiation phase of carcinogenesis. Antioxidant is considered to protect lipids and low density lipoprotein (LDL) from oxidation, which potentially inhibits angiogenesis, and rapid removal of free radicals by antioxidants could have an anti‐carcinogenic effect. In the present study, we investigated whether antioxidant treatment with probucol had an antitumor effect on KB cells, a human head and neck squamous carcinoma cell line. Probucol did not have any effect on KB cells in vitro, but probucol treatment of KB cells xenografts in mice had a significant antitumor effect through anti‐angiogenic and apoptosis‐inducing actions. These results support the idea that probucol is useful for preventing and/or treating cancer.

The anti‐tumor effect of a selective cyclooxygenase (COX)‐2 inhibitor, JTE‐522, was examined with the human head and neck squamous cell carcinoma cell line KB. KB cells do not produce prostaglandin (PG)‐E2. In vitro, JTE‐522 induced an increase of G1 phase‐arrested cells, suppression of platelet‐derived growth factor (PDGF) production and inhibition of telomerase activity. No cytotoxic effect was detected. In vivo, the growth of the tumor xenografted into nude mice was significantly suppressed by JTE‐522. Suppression of angiogenesis at the periphery of the tumor, increase of G1‐arrested cells and suppression of telomerase activity were observed, together with an increase of apoptotic cell death in the tumor. Immunological enhancement did not play a role. We concluded that the anti‐tumor effect of JTE‐522 was caused by anti‐angiogenesis action, cell cycle arrest and inhibition of telomerase activity of the tumor cells. These combined effects might induce apoptosis.