The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable  Nucleoside Analogs

Tsume, Yasuhiro; Borras-Bermejo, Blanca; Amidon, Gordon L.

doi:10.3390/ph7020169

Cited by 11 publications

(13 citation statements)

References 87 publications

(121 reference statements)

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“…Therefore, the effects of SQ2-drug conjugates could not be studied on this cell line. Panc-1 insensitivity toward 5FdU and other prodrugs like gemcitabine has been reported by other groups as well [40,41].…”

Section: Alppl2-mediated Clathrin-independent Pathways Are Involved Isupporting

confidence: 54%

ALPPL2 Aptamer-Mediated Targeted Delivery of 5-Fluoro-2′-Deoxyuridine to Pancreatic Cancer

Dua

Sajeesh

Kim

et al. 2015

Nucleic Acid Therapeutics

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Nucleoside analogues are the most promising drugs for the treatment of pancreatic cancer to date. However, their use is often limited due to toxic side effects. Aptamer-mediated targeted delivery of these drugs to cancer cells could maximize their effectiveness and concomitantly minimize the toxic side effects by reducing uptake into normal cells. Previously, we identified a pancreatic cancer-specific, nuclease-resistant RNA aptamer, SQ2, which binds to alkaline phosphatase placental-like 2 (ALPPL2), a putative biomarker for pancreatic cancer. In this study, we demonstrate that the aptamer can be internalized into pancreatic cancer cells and can thus be used for the targeted delivery of therapeutics. Using the aptamer as a ligand, we established that glycophosphatidylinositol-anchored ALPPL2 is internalized by the cells through clathrin-independent and caveolae-dependent or dynamin-mediated cell-type-dependent pathways. Finally, we show that SQ2 can deliver nucleoside drug 5-fluoro-2'-deoxyuridine specifically to ALPPL2-expressing pancreatic cancer cells, inhibiting cell proliferation.

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Section: Alppl2-mediated Clathrin-independent Pathways Are Involved Isupporting

confidence: 54%

ALPPL2 Aptamer-Mediated Targeted Delivery of 5-Fluoro-2′-Deoxyuridine to Pancreatic Cancer

Dua

Sajeesh

Kim

et al. 2015

Nucleic Acid Therapeutics

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“…Both prodrugs were more potent than parent gemcitabine in AsPC-1 pancreatic cancer cells [ 121 ]. Likewise, in another report, the dipeptide prodrugs of gemcitabine showed significantly higher uptake and superior anti-proliferative ability compared to the parent drug in the pancreatic cancer cell lines AsPC-1 and PANC-1 [ 122 ].…”

Section: Potential Ways To Improve Gemcitabine Delivery and Efficamentioning

confidence: 99%

Pancreatic Cancer Chemoresistance to Gemcitabine

Amrutkar

2017

Cancers

359

304

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Pancreatic ductal adenocarcinoma (PDAC), commonly referred to as pancreatic cancer, ranks among the leading causes of cancer-related deaths in the Western world due to disease presentation at an advanced stage, early metastasis and generally a very limited response to chemotherapy or radiotherapy. Gemcitabine remains a cornerstone of PDAC treatment in all stages of the disease despite suboptimal clinical effects primarily caused by molecular mechanisms limiting its cellular uptake and activation and overall efficacy, as well as the development of chemoresistance within weeks of treatment initiation. To circumvent gemcitabine resistance in PDAC, several novel therapeutic approaches, including chemical modifications of the gemcitabine molecule generating numerous new prodrugs, as well as new entrapment designs of gemcitabine in colloidal systems such as nanoparticles and liposomes, are currently being investigated. Many of these approaches are reported to be more efficient than the parent gemcitabine molecule when tested in cellular systems and in vivo in murine tumor model systems; however, although promising, their translation to clinical use is still in a very early phase. This review discusses gemcitabine metabolism, activation and chemoresistance entities in the gemcitabine cytotoxicity pathway and provides an overview of approaches to override chemoresistance in pancreatic cancer.

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“…Prodrug strategies have been employed to overcome unfavorable physicochemical properties of the drug for the improvement of oral bioavailability and/or the minimization of toxic side effects. Amino acid and dipeptide monoester prodrugs of poorly permeable anticancer and antiviral drugs have been developed and investigated for their improved oral bioavailability and metabolic disposition [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine

et al. 2017

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One of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug approach for gemcitabine was adopted. Amino acid and dipeptide monoester prodrugs of gemcitabine were synthesized and their chemical stability in buffers, resistance to thymidine phosphorylase and cytidine deaminase, antiproliferative activity, and uptake/permeability in HFF cells as a surrogate to stroma cells were determined and compared to their parent drug, gemcitabine. The activation of all gemcitabine prodrugs was faster in pancreatic cell homogenates than their hydrolysis in buffer, suggesting enzymatic action. All prodrugs exhibited great stability in HFF cell homogenate, enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase, and deamination by cytidine deaminase compared to their parent drug. All gemcitabine prodrugs exhibited higher uptake in HFF cells and better permeability across HFF monolayers than gemcitabine, suggesting a better delivery to tumor sites. Cell antiproliferative assays in Panc-1 and Capan-2 pancreatic ductal cell lines indicated that the gemcitabine prodrugs were more potent than their parent drug gemcitabine. The transport and enzymatic profiles of gemcitabine prodrugs suggest their potential for delayed enzymatic bioconversion and enhanced resistance to metabolic enzymes, as well as for enhanced drug delivery to tumor sites, and cytotoxic activity in cancer cells. These attributes would facilitate the prolonged systemic circulation and improved therapeutic efficacy of gemcitabine prodrugs.

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The Dipeptide Monoester Prodrugs of Floxuridine and Gemcitabine—Feasibility of Orally Administrable Nucleoside Analogs

Cited by 11 publications

References 87 publications

ALPPL2 Aptamer-Mediated Targeted Delivery of 5-Fluoro-2′-Deoxyuridine to Pancreatic Cancer

ALPPL2 Aptamer-Mediated Targeted Delivery of 5-Fluoro-2′-Deoxyuridine to Pancreatic Cancer

Pancreatic Cancer Chemoresistance to Gemcitabine

Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine

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