Submitted to: Biochemical Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/21/2006
Publication Date: 5/1/2007
Citation: Azrak, R.G., Cao, S., Pendyala, L., Durrani, F.A., Fakih, M., Combs, G.F., Prey, J., Smith, P.F., Rustum, Y.M. 2007. Efficacy of increasing the therapeutic index of irinotecan, plasma and tissue selenium concentrations is methylselenocysteine dose dependent. Biochemical Pharmacology. 73(9):1280-1287. Interpretive Summary: The manuscript reports the results of studies to determine whether a form of selenium, methylselenocysteine, which had been shown to reduce cancer risk, could improve the therapeutic value of an anti-cancer drug, irinotecan. The study was conducted using an animal model of cancer: the mice into which cancerous tissues of two types were introduced as tissue grafts. The results showed that one tumor type took up selenium from methylselenocysteine very small amounts of which were effective in improving the anti-cancer efficacy of irinotecan. This suggests that selenium compounds may be useful in cancer therapy, at least for some types of cancers.
Technical Abstract: This study was designed to understand the basis for the efficacy of methylselenocysteine (MSC) in increasing the therapeutic index of irinotecan against human tumore xenografts. Nude mice bearing human FaDu and A253 tumors were treated orally with different doses of MSC and irinotecan. Plasma, tumor and normal tissue samples were collected at different times after MSC treatments and were analyzed for selenium (Se) concentration using electrothermal atomic absorption spectrophotometry. MSC is highly effective in modulating the therapeutic index of irinotecan in the treatment of human squamous cells carcinoma of the head and neck xenografts (FaDu and A253). Enhanced irinotecan efficacy was greater in FaDu tumors (100% CR) than in A253 tumors (60% CR), and depended on MSC dose with a minimum effective dose of 0.01 mg/d x 28. The highest plasma Se concentration was achieved 1 h after a single dose and 28 d after daily treatments of MSC. The ability of FaDu tumors to retain Se was significantly better than A253 tumors, and the highest Se concentration in normal tissue was achieved in the liver. Peak plasma and tissue Se concentrations were functions of the dose and duration of MSC treatment. The MSC-dependent increase in Se level in normal tissues may contribute to the protective effect against irinotecan toxicity observed in those tissues. Instratumoral total Se concentration was not found to be predictive of the combination therapy response rates. There is a critical need to develop a method to measure the active metabolite of MSC, rather than total Se.