Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors

Rami G Azrak; Jinsheng Yu; Lakshmi Pendyala; Patrick F Smith; Shousong Cao; Xia Li; William D Shannon; Farukh A Durrani; Howard L McLeod; Youcef M Rustum

doi:10.1158/1535-7163.MCT-04-0315

Back

Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors

Journal article

Peer reviewed

Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors

Rami G Azrak, Jinsheng Yu, Lakshmi Pendyala, Patrick F Smith, Shousong Cao, Xia Li, William D Shannon, Farukh A Durrani, Howard L McLeod and Youcef M Rustum

Molecular cancer therapeutics, Vol.4(5), pp.843-854

05/2005

DOI: 10.1158/1535-7163.MCT-04-0315

PMID: 15897249

View Online

Abstract

The combination of methylselenocysteine and irinotecan (CPT-11) is synergistic against FaDu and A253 xenografts. Methylselenocysteine/CPT-11 increased tumor cure rate to 100% in FaDu and to 60% in A253. In this study, the effect of methylselenocysteine on pharmacokinetic and pharmacogenetic profiles of genes relevant to CPT-11 metabolic pathway was evaluated to identify possible mechanisms associated with the observed combinational synergy. Nude mice bearing tumors (FaDu and A253) were treated with methylselenocysteine, CPT-11, and a combination of methylselenocysteine/CPT-11. Samples were collected and analyzed for plasma and intratumor concentration of CPT-11 and 7-ethyl-10-hydroxyl-camptothecin (SN-38) by high-performance liquid chromatography. The intratumor relative expression of genes related to the CPT-11 metabolic pathway was measured by real-time PCR. After methylselenocysteine treatment, the intratumor area under the concentration-time curve of SN-38 increased to a significantly higher level in A253 than in FaDu and was associated with increased expression of CES1 in both tumors. Methylselenocysteine/CPT-11 treatment, compared with CPT-11 alone, resulted in a significant decrease in levels of ABCC1 and DRG1 in FaDu tumors and an increase in levels of CYP3A5 and TNFSF6 in A253 tumors. No statistically significant changes induced by methylselenocysteine/CPT-11 were observed in the levels of other investigated variables. In conclusion, the significant increase in the cure rate after methylselenocysteine/CPT-11 could be related to increased drug delivery into both tumors (CES1), reduced resistance to SN-38 (ABCC1 and DRG1) in FaDu, and induced Fas ligand apoptosis (TNFSF6) in A253. No correlation was observed between cure rate and other investigated variables (transporters, degradation enzymes, DNA repair, and cell survival/death genes) in either tumor.

Animals

Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics

Antineoplastic Combined Chemotherapy Protocols - pharmacology

Biomarkers, Tumor - metabolism

Camptothecin - administration & dosage

Camptothecin - analogs & derivatives

Carcinoma, Squamous Cell - blood

Carcinoma, Squamous Cell - drug therapy

Carcinoma, Squamous Cell - genetics

Cysteine - administration & dosage

Cysteine - analogs & derivatives

Female

Head and Neck Neoplasms - blood

Head and Neck Neoplasms - drug therapy

Head and Neck Neoplasms - genetics

Humans

Mice

Mice, Nude

Organoselenium Compounds - administration & dosage

Pharmacogenetics

Reverse Transcriptase Polymerase Chain Reaction

RNA, Messenger - genetics

RNA, Messenger - metabolism

RNA, Neoplasm - genetics

RNA, Neoplasm - metabolism

Selenocysteine - analogs & derivatives

Transplantation, Heterologous

Tumor Cells, Cultured

Details

Title: Subtitle: Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors
Creators: Rami G Azrak - Roswell Park Cancer Institute
Jinsheng Yu
Lakshmi Pendyala
Patrick F Smith
Shousong Cao
Xia Li
William D Shannon
Farukh A Durrani
Howard L McLeod
Youcef M Rustum
Resource Type: Journal article
Publication Details: Molecular cancer therapeutics, Vol.4(5), pp.843-854
DOI: 10.1158/1535-7163.MCT-04-0315
PMID: 15897249
ISSN: 1535-7163
eISSN: 1538-8514
Grant note: CA 16056 / NCI NIH HHS CA76561 / NCI NIH HHS GM63340 / NIGMS NIH HHS
Language: English
Date published: 05/2005
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984359845802771

Metrics

8 Record Views

11 Times Cited - Web of Science