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Featured researches published by Xueqin Song.


Molecular Cancer Therapeutics | 2005

Targeted delivery to PEPT1-overexpressing cells: Acidic, basic, and secondary floxuridine amino acid ester prodrugs

Christopher P. Landowski; Balvinder S. Vig; Xueqin Song; Gordon L. Amidon

Floxuridine is a clinically proven anticancer agent in the treatment of metastatic colon carcinomas and hepatic metastases. However, prodrug strategies may be necessary to improve its physiochemical properties and selectivity and to reduce undesirable toxicity effects. Previous studies with amino acid ester prodrugs of nucleoside drugs targeted to the PEPT1 transporter coupled with recent findings of the functional expression of the PEPT1 oligopeptide transporter in pancreatic adenocarcinoma cell lines suggest the potential of PEPT1 as therapeutic targets for cancer treatment. In this report, we show the feasibility of achieving enhanced transport and selective antiproliferative action of amino acid ester prodrugs of floxuridine in cell systems overexpressing PEPT1. All prodrugs exhibited affinity for PEPT1 (IC50, 1.1–2.3 mmol/L). However, only the prolyl and lysyl prodrugs exhibited enhanced uptake (2- to 8-fold) with HeLa/PEPT1 cells compared with HeLa cells, suggesting that the aspartyl prodrugs are PEPT1 inhibitors. The selective growth inhibition of Madine-Darby canine kidney (MDCK)/PEPT1 cells over MDCK cells by the prodrugs was consistent with the extent of their PEPT1-mediated transport. All ester prodrugs hydrolyzed to floxuridine fastest in Caco-2 cell and MDCK homogenates and slower in human plasma and were most chemically stable in pH 6.0 buffer. Prolyl and lysyl prodrugs were relatively less stable compared with aspartyl prodrugs in buffers and in cell homogenates. The results suggest that optimal design for targeted delivery would be possible by combining both stability and transport characteristics afforded by the promoiety.


Pharmaceutical Research | 2005

Floxuridine Amino Acid Ester Prodrugs: Enhancing Caco-2 Permeability and Resistance to Glycosidic Bond Metabolism

Christopher P. Landowski; Xueqin Song; Philip L. Lorenzi; John M. Hilfinger; Gordon L. Amidon

PurposeThe aim of this study was to synthesize amino acid ester prodrugs of 5-fluoro-2′-deoxyuridine (floxuridine) to enhance intestinal absorption and resistance to glycosidic bond metabolism.MethodsAmino acid ester prodrugs were synthesized and examined for their hydrolytic stability in human plasma, in Caco-2 cell homogenates, and in the presence of thymidine phosphorylase. Glycyl-l-sarcosine uptake inhibition and direct uptake studies with HeLa/PEPT1 cells [HeLa cells overexpressing oligopeptide transporter (PEPT1)] were conducted to determine PEPT1-mediated transport and compared with permeability of the prodrugs across Caco-2 monolayers.ResultsIsoleucyl prodrugs exhibited the highest chemical and enzymatic stability. The prodrugs enhanced the stability of the glycosidic bond of floxuridine. Thymidine phosphorylase rapidly cleaved floxuridine to 5-fluorouracil, whereas with the prodrugs no detectable glycosidic bond cleavage was observed. The 5′-l-isoleucyl and 5′-l-valyl monoester prodrugs exhibited 8- and 19-fold PEPT1-mediated uptake enhancement in HeLa/PEPT1 cells, respectively. Uptake enhancement in HeLa/PEPT1 cells correlated highly with Caco-2 permeability for all prodrugs tested. Caco-2 permeability of 5′-l-isoleucyl and 5′-l-valyl prodrugs was 8- to 11-fold greater compared with floxuridine.ConclusionsAmino acid ester prodrugs such as isoleucyl floxuridine that exhibit enhanced Caco-2 transport and slower rate of enzymatic activation to parent, and that are highly resistant to metabolism by thymidine phosphorylase may improve oral delivery and therapeutic index of floxuridine.


Pharmaceutical Research | 2007

Proline Prodrug of Melphalan Targeted to Prolidase, a Prodrug Activating Enzyme Overexpressed in Melanoma

Sachin Mittal; Xueqin Song; Balvinder S. Vig; Gordon L. Amidon

PurposeTo determine the bioactivation and uptake of prolidase-targeted proline prodrugs of melphalan in six cancer cell lines with variable prolidase expression and to evaluate prolidase-dependence of prodrug cytotoxicity in the cell lines compared to that of the parent drug, melphalan.Materials and MethodsHydrolysis, cell uptake, and cell proliferation studies of melphalan and the L- and D-proline prodrugs of melphalan, prophalan-L and prophalan-D, respectively, were conducted in the cancer cell lines using established procedures.ResultsThe bioactivation of prophalan-L in the cancer cell lines exhibited high correlation with their prolidase expression levels (r2 = 0.86). There were no significant differences in uptake of melphalan and its prodrugs. The cytotoxicity of prophalan-L (GI50) in cancer cells also showed high correlation with prolidase expression (r2 = 0.88), while prophalan-D was ineffective at comparable concentrations. A prolidase targeting index (ratio of melphalan to prophalan-L cytotoxicity normalized to their uptake) was computed and showed high correlation with prolidase expression (r2 = 0.82).ConclusionsThe data corroborates the specificity of prophalan-L activation by prolidase as well as prolidase-targeted cytotoxicity of prophalan-L in cancer cell lines. Hence, prophalan-L, a stable prodrug of melphalan, exhibits potential for efficiently targeting melanoma with reduced systemic toxicity.


Drug Metabolism and Disposition | 2006

N-methylpurine DNA glycosylase and 8-oxoguanine DNA glycosylase metabolize the antiviral nucleoside 2-bromo-5,6-dichloro-1-(β-D-ribofuranosyl)benzimidazole

Philip L. Lorenzi; Christopher P. Landowski; Andrea Brancale; Xueqin Song; Leroy B. Townsend; John C. Drach; Gordon L. Amidon

The rapid in vivo degradation of the potent human cytomegalovirus inhibitor 2-bromo-5,6-dichloro-1-(β-d-ribofuranosyl)benzimidazole (BDCRB) compared with a structural l-analog, maribavir (5,6-dichloro-2-(isopropylamino)-1-β-l-ribofuranosyl-1H-benzimidazole), has been attributed to selective glycosidic bond cleavage. An enzyme responsible for this selective BDCRB degradation, however, has not been identified. Here, we report the identification of two enzymes, 8-oxoguanine DNA glycosylase (OGG1) and N-methylpurine DNA glycosylase (MPG), that catalyze N-glycosidic bond cleavage of BDCRB and its 2-chloro homolog, 2,5,6-trichloro-1-(β-d-ribofuranosyl)benzimidazole, but not maribavir. To our knowledge, this is the first demonstration that free nucleosides are substrates of OGG1 and MPG. To understand how these enzymes might process BDCRB, docking and molecular dynamics simulations were performed with the native human OGG1 crystal coordinates. These studies showed that OGG1 was not able to bind a negative control, guanosine, yet BDCRB and maribavir were stabilized through interactions with various binding site residues, including Phe319, His270, Ser320, and Asn149. Only BDCRB, however, achieved orientations whereby its anomeric carbon, C1′, could undergo nucleophilic attack by the putative catalytic residue, Lys249. Thus, in silico observations were in perfect agreement with experimental observations. These findings implicate DNA glycosylases in drug metabolism.


Molecular Pharmaceutics | 2005

Amino acid ester prodrugs of the anticancer agent gemcitabine: synthesis, bioconversion, metabolic bioevasion, and hPEPT1-mediated transport.

Xueqin Song; Philip L. Lorenzi; Christopher P. Landowski; Balvinder S. Vig; John M. Hilfinger; Gordon L. Amidon


Journal of Medicinal Chemistry | 2005

Amino Acid Ester Prodrugs of the Antiviral Agent 2-Bromo-5,6-dichloro-1-(β-d-ribofuranosyl)benzimidazole as Potential Substrates of hPEPT1 Transporter

Xueqin Song; Balvinder S. Vig; Philip L. Lorenzi; John C. Drach; Leroy B. Townsend; Gordon L. Amidon


Molecular Pharmaceutics | 2004

A novel nucleoside prodrug-activating enzyme: substrate specificity of biphenyl hydrolase-like protein.

Insook Kim; Xueqin Song; Balvinder S. Vig; Sachin Mittal; Ho-Chul Shin; Philip J. Lorenzi; Gordon L. Amidon


Journal of Pharmacology and Experimental Therapeutics | 2005

Nucleoside ester prodrug substrate specificity of liver carboxylesterase

Christopher P. Landowski; Philip L. Lorenzi; Xueqin Song; Gordon L. Amidon


Journal of Pharmacology and Experimental Therapeutics | 2005

Amino Acid Ester Prodrugs of 2-Bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole Enhance Metabolic Stability in Vitro and in Vivo

Philip L. Lorenzi; Christopher P. Landowski; Xueqin Song; Katherine Z. Borysko; Julie M. Breitenbach; Jae Seung Kim; John M. Hilfinger; Leroy B. Townsend; John C. Drach; Gordon L. Amidon


Molecular Pharmaceutics | 2005

Prolidase, a Potential Enzyme Target for Melanoma: Design of Proline-Containing Dipeptide-like Prodrugs

Sachin Mittal; Xueqin Song; Balvinder S. Vig; Christopher P. Landowski; Insook Kim; John M. Hilfinger; Gordon L. Amidon

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Insook Kim

National Institutes of Health

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