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

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. [Mol Cancer Ther 2005;4(5):843 -54]

Differentiation-Related Gene-1 Decreases Bim Stability by Proteasome-Mediated Degradation

“…The results from serial biopsies indicated that clinical benefit to therapy was only observed in patients who exhibited a decrease or no induction in Drg1 protein expression. These findings are consistent with emerging data that Drg1 plays an essential role in the resistance to CPT-11 (31), and suppressing its expression both by pharmacologic or molecular means could increase sensitization to this agent both in vitro and in vivo across a spectrum of tumor types. Nevertheless, the function of this protein relative to chemotherapy resistance has remained essentially unknown.…”

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

“…Azrak et al [23] previously evaluated and compared the expression of multiple molecular markers in untreated controls of A253 and FaDu xenografts that were known to be associated with the irinotecan metabolic pathway. Briefly, no significant difference (p<0.05) in expression levels of those investigated markers was associated with the enhanced therapeutic efficacy of irinotecan except decreased expressions of ATP binding cassette transporters (ABCC1 and ABCG2, efflux pumps of SN-38 the active metabolite of irinotecan) and SN-38 resistant gene developmentally regulated GTP binding protein 1 (DRG1).…”

Ugt1a is required for the protective effect of selenium against irinotecan-induced toxicity

“…Thus, the protective effect of selenium against irinotecan-induced host toxicities could be due to enhanced activities of carboxylesterases/UDPGT encoded by Ugt1a and/or Cyp3a4/Cyp3a5 by selenium. Although it has been reported that selenium could significantly increase expression of Cyp3a5 [25], it is presently unknown if the expression of Cyp3a4 is elevated. Promoting expression of Ugt1a by selenium has also been reported [26, 27].…”