Efficacy of increasing the therapeutic index of irinotecan, plasma and tissue selenium concentrations is methylselenocysteine dose dependent

Rami G. Azrak; Shousong Cao; Lakshmi Pendyala; Farukh A. Durrani; Marwan Fakih; Gerald F. Combs; Joshua Prey; Patrick F. Smith; Youcef M. Rustum

doi:10.1016/j.bcp.2006.12.020

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Efficacy of increasing the therapeutic index of irinotecan, plasma and tissue selenium concentrations is methylselenocysteine dose dependent

Journal article

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Efficacy of increasing the therapeutic index of irinotecan, plasma and tissue selenium concentrations is methylselenocysteine dose dependent

Rami G. Azrak, Shousong Cao, Lakshmi Pendyala, Farukh A. Durrani, Marwan Fakih, Gerald F. Combs, Joshua Prey, Patrick F. Smith and Youcef M. Rustum

Biochemical pharmacology, Vol.73(9), pp.1280-1287

05/01/2007

DOI: 10.1016/j.bcp.2006.12.020

PMCID: PMC2062575

PMID: 17239826

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https://www.ncbi.nlm.nih.gov/pmc/articles/2062575View

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Abstract

This study was designed to understand the basis for the efficacy of methylselenocysteine (MSC) in increasing the therapeutic index of irinotecan against human tumor xenografts. Nude mice bearing human head and neck squamous cells carcinoma xenografts (FaDu and A253) 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. 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 0.01mg/d×28. The highest plasma Se concentration was achieved 1h 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. Intratumoral 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.

A253

FaDu

Irinotecan

Methylselenocysteine

Selenium

Details

Title: Subtitle: Efficacy of increasing the therapeutic index of irinotecan, plasma and tissue selenium concentrations is methylselenocysteine dose dependent
Creators: Rami G. Azrak - Roswell Park Cancer Institute
Shousong Cao - Roswell Park Cancer Institute
Lakshmi Pendyala - Roswell Park Cancer Institute
Farukh A. Durrani - Roswell Park Cancer Institute
Marwan Fakih - Roswell Park Cancer Institute
Gerald F. Combs - Grand Forks Human Nutrition Research Center
Joshua Prey - Roswell Park Cancer Institute
Patrick F. Smith - Roswell Park Cancer Institute
Youcef M. Rustum - Roswell Park Cancer Institute
Resource Type: Journal article
Publication Details: Biochemical pharmacology, Vol.73(9), pp.1280-1287
DOI: 10.1016/j.bcp.2006.12.020
PMID: 17239826
PMCID: PMC2062575
NLM abbreviation: Biochem Pharmacol
ISSN: 0006-2952
eISSN: 1873-2968
Publisher: Elsevier Inc
Language: English
Date published: 05/01/2007
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984359837202771

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