Synthesis, Crystallization, and Biological Evaluation of an Orally Active Prodrug of Gemcitabine

Bender, David M.; Bao, Jennifer; Dantzig, Anne H.; Diseroad, William D.; Law, Kenneth S.; Magnus, Nicholas A.; Peterson, Jeffery A.; Perkins, E.J.; Pu, Yangwei John; Reutzel‐Edens, Susan M.; Remick, David M.; Starling, James J.; Stephenson, Gregory A.; Vaid, Radhe K.; Zhang, Deyi; McCarthy, James R.

doi:10.1021/jm901181h

Cited by 95 publications

(105 citation statements)

References 16 publications

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“…Notably, this approach is potentially advantageous, because the simple smallmolecule masking group could be readily applied to many other cytotoxic agents, including chemotherapeutic drugs currently used in the clinic. For example, amide coupling-based prodrugs of gemcitabine and cytarabine were developed by masking their amino group 37,38 . Thus, introduction of the Boc-Lys(Ac) group to their amino group should be technically feasible for evaluation of their improved efficacy.…”

Section: Discussionmentioning

confidence: 99%

Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

et al. 2013

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Eradication of cancer cells while minimizing damage to healthy cells is a primary goal of cancer therapy. Highly selective drugs are urgently needed. Here we demonstrate a new prodrug strategy for selective cancer therapy that utilizes increased histone deacetylase (HDAC) and tumour-associated protease activities produced in malignant cancer cells. By coupling an acetylated lysine group to puromycin, a masked cytotoxic agent is created, which is serially activated by HDAC and an endogenous protease cathepsin L (CTSL) that remove the acetyl group first and then the unacetylated lysine group liberating puromycin. The agent selectively kills human cancer cell lines with high HDAC and CTSL activities. In vivo studies confirm tumour growth inhibition in prodrug-treated mice bearing human cancer xenografts. This cancer-selective cleavage of the masking group is a promising strategy for the next generation of anticancer drug development that could be applied to many other cytotoxic agents.

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Section: Discussionmentioning

confidence: 99%

Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

et al. 2013

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“…When dosed orally, LY2334737 is rapidly absorbed intact and shows rate-limited formation of gemcitabine and prolonged gemcitabine exposure (9). Therefore, different treatment regimens were used to evaluate the efficacy of the prodrug as a single agent.…”

Section: Ly2334737 Dose-response Studies In the Hct-116 Xenograft Modelmentioning

confidence: 99%

“…In contrast to intravenous delivery of maximally tolerated doses of chemotherapeutic agents, advantages include: (i) direct, continual tumor growth inhibition and (ii) an indirect effect through inhibition of angiogenesis and vasculogenesis (13)(14)(15) or, as shown for LY2334737, increased tumor blood flow thereby potentially enhancing drug delivery (16). When metronomically dosed orally once a day for 14 days in the human colon HCT-116 xenograft model, LY2334737 showed excellent antitumor activity that is equivalent to standard high doses of gemcitabine.HCl typically administered intraperitoneally (9). Orthotopic models of human metastatic breast LM2-and ovarian SK-OV-3 cancers also responded well to LY2334737 treatment (16).…”

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

“…1) was designed to reduce intestinal activation and first-pass deamination with a stable amide linkage of valproate to gemcitabine (9). Oral LY2334737 is absorbed intact and cleaved slowly resulting in high plasma levels of circulating prodrug and prolonged, lower levels of circulating gemcitabine emulating a slow gemcitabine infusion (9,10). Recently, carboxylesterase 2 (CES2), expressed at high levels in the liver, kidney, and intestine, was identified as the hydrolase responsible for LY2334737 cleavage (11,12).…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Pratt

Durland-Busbice

Shepard

et al. 2013

Molecular Cancer Therapeutics

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LY2334737, an oral prodrug of gemcitabine, is cleaved in vivo, releasing gemcitabine and valproic acid. Oral dosing of mice results in absorption of intact prodrug with slow systemic hydrolysis yielding higher plasma levels of LY2334737 than gemcitabine and prolonged gemcitabine exposure. Antitumor activity was evaluated in human colon and lung tumor xenograft models. The dose response for efficacy was examined using 3 metronomic schedules, once-a-day dosing for 14 doses, every other day for 7 doses, and once a day for 7 doses, 7 days rest, followed by an additional 7 days of once-a-day dosing. These schedules gave significant antitumor activity and were well tolerated. Oral gavage of 6 mg/kg LY2334737 daily for 21 days gave equivalent activity to i.v. 240 mg/kg gemcitabine. HCl administered once a week for 3 weeks to mice bearing a patient mesothelioma tumor PXF 1118 or a non-small cell lung cancer tumor LXFE 937. The LXFE 397 tumor possessed elevated expression of the equilibrative nucleoside transporter-1 (ENT1) important for gemcitabine uptake but not prodrug uptake and responded significantly better to treatment with LY2334737 than gemcitabine (P 0.001). In 3 colon xenografts, antitumor activity of LY2334737 plus a maximally tolerated dose of capecitabine, an oral prodrug of 5-fluorouracil, was significantly greater than either monotherapy. During treatment, the expression of carboxylesterase 2 (CES2) and concentrative nucleoside transporter-3 was induced in HCT-116 tumors; both are needed for the activity of the prodrugs. Thus, metronomic oral low-dose LY2334737 is efficacious, well tolerated, and easily combined with capecitabine for improved efficacy. Elevated CES2 or ENT1 expression may enhance LY2334737 tumor response.

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Alkoxyalkyl Ester Prodrugs of Antiviral Nucleoside Phosphates and Phosphonates

Beadle

Hostetler

2011

Antiviral Drug Strategies

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Synthesis, Crystallization, and Biological Evaluation of an Orally Active Prodrug of Gemcitabine

Cited by 95 publications

References 16 publications

Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Alkoxyalkyl Ester Prodrugs of Antiviral Nucleoside Phosphates and Phosphonates

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