• Início
  • Resultados da busca
  • Dipeptidyl peptidase IV as a potential target for selective prodrug activation and chemotherapeutic action in cancers.

Dipeptidyl peptidase IV as a potential target for selective prodrug activation and chemotherapeutic action in cancers.

Molecular pharmaceutics (2014-11-05)
Arik Dahan, Omri Wolk, Peihua Yang, Sachin Mittal, Zhiqian Wu, Christopher P Landowski, Gordon L Amidon
RESUMO

The efficacy of chemotherapeutic drugs is often offset by severe side effects attributable to poor selectivity and toxicity to normal cells. Recently, the enzyme dipeptidyl peptidase IV (DPPIV) was considered as a potential target for the delivery of chemotherapeutic drugs. The purpose of this study was to investigate the feasibility of targeting chemotherapeutic drugs to DPPIV as a strategy to enhance their specificity. The expression profile of DPPIV was obtained for seven cancer cell lines using DNA microarray data from the DTP database, and was validated by RT-PCR. A prodrug was then synthesized by linking the cytotoxic drug melphalan to a proline-glycine dipeptide moiety, followed by hydrolysis studies in the seven cell lines with a standard substrate, as well as the glycyl-prolyl-melphalan (GP-Mel). Lastly, cell proliferation studies were carried out to demonstrate enzyme-dependent activation of the candidate prodrug. The relative RT-PCR expression levels of DPPIV in the cancer cell lines exhibited linear correlation with U95Av2 Affymetrix data (r(2) = 0.94), and with specific activity of a standard substrate, glycine-proline-p-nitroanilide (r(2) = 0.96). The significantly higher antiproliferative activity of GP-Mel in Caco-2 cells (GI₅₀ = 261 μM) compared to that in SK-MEL-5 cells (GI₅₀ = 807 μM) was consistent with the 9-fold higher specific activity of the prodrug in Caco-2 cells (5.14 pmol/min/μg protein) compared to SK-MEL-5 cells (0.68 pmol/min/μg protein) and with DPPIV expression levels in these cells. Our results demonstrate the great potential to exploit DPPIV as a prodrug activating enzyme for efficient chemotherapeutic drug targeting.

MATERIAIS
Número do produto
Marca
Descrição do produto

Sigma-Aldrich
N,N-Dimethylformamide, anhydrous, 99.8%
Sigma-Aldrich
Triethylamine, ≥99.5%
Sigma-Aldrich
Trifluoroacetic acid, suitable for HPLC, ≥99.0%
Sigma-Aldrich
Trifluoroacetic acid, ReagentPlus®, 99%
Sigma-Aldrich
Triethylamine, ≥99%
Sigma-Aldrich
N,N-Dimethylformamide, suitable for HPLC, ≥99.9%
Sigma-Aldrich
N,N-Dimethylformamide, ACS reagent, ≥99.8%
Sigma-Aldrich
Triethylamine, puriss. p.a., ≥99.5% (GC)
Sigma-Aldrich
N,N-Dimethylformamide, for molecular biology, ≥99%
Sigma-Aldrich
Trifluoroacetic acid, puriss. p.a., suitable for HPLC, ≥99.0% (GC)
Sigma-Aldrich
Triisopropylsilane, 98%
Sigma-Aldrich
Triethylamine, BioUltra, ≥99.5% (GC)
Sigma-Aldrich
Triethanolamine, reagent grade, 98%
Sigma-Aldrich
Phenazine methosulfate, ≥90% (UV)
Sigma-Aldrich
HBTU, ≥98.0% (T)
Sigma-Aldrich
4-Nitroaniline, ≥99%
Sigma-Aldrich
N,N-Dimethylformamide, ReagentPlus®, ≥99%
Supelco
Dimethylformamide, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
N,N-Dimethylformamide, puriss. p.a., ACS reagent, reag. Ph. Eur., ≥99.8% (GC)
Sigma-Aldrich
Trifluoroacetic acid, ≥99%, for protein sequencing
Sigma-Aldrich
Triethanolamine, puriss. p.a., ≥99% (GC)
Supelco
N,N-Dimethylformamide, analytical standard
Sigma-Aldrich
Fmoc N-hydroxysuccinimide ester, ≥98.0% (HPLC)
Supelco
Trifluoroacetic acid, analytical standard
Supelco
Triethylamine, analytical standard
Sigma-Aldrich
Triethylamine, for amino acid analysis, ≥99.5% (GC)
Sigma-Aldrich
N,N-Dimethylformamide, biotech. grade, ≥99.9%
Sigma-Aldrich
Melphalan, powder
Sigma-Aldrich
Ile-Pro-Ile, ≥97% (HPLC)
Sigma-Aldrich
Triethylamine, for protein sequence analysis, ampule, ≥99.5% (GC)