Unique dual targeting of thymidylate synthase and topoisomerase1 by FdUMP[10] results in high efficacy against AML and low toxicity

Pardee, Timothy S.; Gomes, Evan; Jennings-Gee, Jamie; Caudell, David L.; Gmeiner, William H.

doi:10.1182/blood-2011-06-362442

Cited by 40 publications

(73 citation statements)

References 35 publications

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“…F10 is cytotoxic, 1–4 demonstrably more efficacious as a therapeutic, and better tolerated in vivo 5–8 than the widely used 5-fluorouracil (5-FU). 9,10 Zinc is itself cytotoxic and shows promise as a selective treatment for prostatic adenocarcinoma.…”

Section: Introductionmentioning

confidence: 99%

All-Atom Molecular Dynamics Reveals Mechanism of Zinc Complexation with Therapeutic F10

2016

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Advancing the use of therapeutic nucleic acids requires understanding the chemical and structural properties that allow these polymers to promote the death of malignant cells. Here we explore Zn2+ complexation by the fluoropyrimidine polymer F10, which has strong activities in multiple preclinical models of cancer. Delivery of fluoropyrimidine FdUMP in the 10-residue polymer F10 rather than the nucleobase (5-fluorouracil) allows consideration of metal ion binding effects on drug delivery. The differences in metal ion interactions with fluoropyrimidine compared to normal DNA results in conformation changes that affect protein binding, cell uptake, and codelivery of metals such as zinc, and the cytoxicity thereof. Microsecond-time-scale, all-atom simulations of F10 predict that zinc selectively stabilizes the polymer via interactions with backbone phosphate groups and suggest a mechanism of complexation for the zinc-base interactions shown in previous experimental work. The positive zinc ions are attracted to the negatively charged phosphate groups. Once the Zn2+ ions are near F10, they cause the base’s N3 nitrogen to deprotonate. Subsequently, magnesium atoms displace zinc from their interactions with phosphate, freeing the zinc ions to interact with the FdU bases by forming weak interactions with the O4 oxygen and the fluorine attached to C5. These interactions of magnesium with phosphate groups and zinc with nucleobases agree with previous experimental results and are seen in MD simulations only when magnesium is introduced after N3 deprotonation, indicating a specific order of metal binding events. Additionally, we predict interactions between zinc and F10’s O2 atoms, which were not previously observed. By comparison to 10mers of polyU and polydT, we also predict that the presence of fluorine increases the binding affinity of zinc to F10 relative to analogous strands of RNA and DNA consisting of only native nucleotides.

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Section: Introductionmentioning

confidence: 99%

All-Atom Molecular Dynamics Reveals Mechanism of Zinc Complexation with Therapeutic F10

2016

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“…To determine to what extent ZnPy treatment affected the cytotoxic effects of chemotherapy drugs we investigated co-treatment of ZnPy with F10, a novel polymer of 5-fluoro-2′-deoxyuridine-5′-O-monophosphate, the active metabolite of fluoropyrimidine chemotherapy that displays strong anti-cancer activity and minimal systemic toxicity in pre-clinical models of AML [13, 14], GBM [15], and advanced prostate cancer [16]. F10 reduced the viability of both PC3 and C4-2 cells with IC 50 values in the nanomolar range (Figure 3 – see data at 0 ZnPy).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, there remains a clear and imminent need for drugs that produce more effective and prolonged response in this incurable disease state. Pre-clinical studies with the fluoropyrimidine polymer F10 have demonstrated this novel drug-candidate displays excellent anti-cancer activity in pre-clinical animal models of acute myeloid leukemia (AML) [13, 14], glioblastoma [15], and advanced prostate cancer [16], highly lethal malignancies for which new treatment options are urgently needed. Data from the NCI 60 cell line screen as well as from our laboratory have demonstrated that F10 is highly cytotoxic to prostate cancer cells [17] with the present studies demonstrating F10 is cytotoxic to C4-2 and PC3 cells at nanomolar levels.…”

Section: Discussionmentioning

confidence: 99%

The cytotoxic and pro-apoptotic activities of the novel fluoropyrimidine F10 towards prostate cancer cells are enhanced by Zn²⁺ -chelation and inhibiting the serine protease Omi/HtrA2

et al. 2014

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BACKGROUND Intracellular Zn2+ levels decrease during prostate cancer progression and agents that modulate intracellular Zn2+ are cytotoxic to prostate cancer cells by an incompletely described mechanism. F10 is a new polymeric fluoropyrimidine drug-candidate that displays strong activity with minimal systemic toxicity in pre-clinical models of prostate cancer and other malignancies. The effects of exogenous Zn2+ or Zn2+ chelation for enhancing F10 cytotoxicity are investigated as is the role of Omi/HtrA2, a serine protease that promotes apoptosis in response to cellular stress. METHODS To test the hypothesis that the pro-apoptotic effects of F10 could be enhanced by modulating intracellular Zn2+ we investigated cell-permeable and cell-impermeable Zn2+ chelators and exogenous Zn2+ and evaluated cell viability and apoptosis in cellular models of castration-resistant prostate cancer (CRPC; PC3, C4-2). The role of Omi/HtrA2 for modulating apoptosis was evaluated by pharmacological inhibition and Western blotting. RESULTS Exogenous Zn2+ initially reduced prostate cancer cell viability but these effects were transitory and were ineffective at enhancing F10 cytotoxicity. The cell-permeable Zn2+-chelator tetrakis-(2-pyridylmethl)ethylenediamine (TPEN) induced apoptosis in prostate cancer cells and enhanced the pro-apoptotic effects of F10. The pro-apoptotic effects of Zn2+-chelation in combination with F10 treatment were enhanced by inhibiting Omi/HtrA2 implicating this serine protease as a novel target for prostate cancer treatment. CONCLUSIONS Zn2+-chelation enhances the pro-apoptotic effects of F10 and may be useful for enhancing the effectiveness of F10 for treatment of advanced prostate cancer. The serine protease Omi/HtrA2 modulates Zn2+-dependent apoptosis in prostate cancer cells and represents a new target for treatment of CRPC.

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“…A number of recent studies have also proposed novel approaches for improved drug-delivery using NPs. Our laboratory has shown that creating a nano-sized DNA polymer results in enhanced antileukemic activity relative to low MW drugs [82]. …”

Section: Np-mediated Cancer Treatmentmentioning

confidence: 99%

Nanotechnology for cancer treatment

Gmeiner¹,

Ghosh²

2014

Nanotechnology Reviews

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Nanotechnology has the potential to increase the selectivity and potency of chemical, physical, and biological approaches for eliciting cancer cell death while minimizing collateral toxicity to nonmalignant cells. Materials on the nanoscale are increasingly being targeted to cancer cells with great specificity through both active and passive targeting. In this review, we summarize recent literature that has broken new ground in the use of nanotechnology for cancer treatment with an emphasis on targeted drug delivery.

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Unique dual targeting of thymidylate synthase and topoisomerase1 by FdUMP[10] results in high efficacy against AML and low toxicity

Cited by 40 publications

References 35 publications

All-Atom Molecular Dynamics Reveals Mechanism of Zinc Complexation with Therapeutic F10

All-Atom Molecular Dynamics Reveals Mechanism of Zinc Complexation with Therapeutic F10

The cytotoxic and pro-apoptotic activities of the novel fluoropyrimidine F10 towards prostate cancer cells are enhanced by Zn²⁺ -chelation and inhibiting the serine protease Omi/HtrA2

Nanotechnology for cancer treatment

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Unique dual targeting of thymidylate synthase and topoisomerase1 by FdUMP[10] results in high efficacy against AML and low toxicity

Cited by 40 publications

References 35 publications

All-Atom Molecular Dynamics Reveals Mechanism of Zinc Complexation with Therapeutic F10

All-Atom Molecular Dynamics Reveals Mechanism of Zinc Complexation with Therapeutic F10

The cytotoxic and pro-apoptotic activities of the novel fluoropyrimidine F10 towards prostate cancer cells are enhanced by Zn2+ -chelation and inhibiting the serine protease Omi/HtrA2

Nanotechnology for cancer treatment

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About

The cytotoxic and pro-apoptotic activities of the novel fluoropyrimidine F10 towards prostate cancer cells are enhanced by Zn²⁺ -chelation and inhibiting the serine protease Omi/HtrA2