A C-14 labeled Py–Im polyamide localizes to a subcutaneous prostate cancer tumor

Raskatov, Jevgenij A.; Puckett, James W.; Dervan, Peter B.

doi:10.1016/j.bmc.2014.04.010

Cited by 14 publications

(23 citation statements)

References 29 publications

(34 reference statements)

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“…Labeled HIF-PA localization in the nuclei was confirmed by fluorescent confocal microscopy of excised tumor sections, costained with DAPI (Supplemental Figure 1B). This is consistent with the recent studies on the uptake C 14 labeled Py-Im polyamides into tumors (34)…”

Section: Resultssupporting

confidence: 93%

A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity

Veena

Szablowski

Dervan

et al. 2016

Molecular Cancer Research

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Multiple myeloma (MM) is incurable and invariably becomes resistant to chemotherapy. Although the mechanisms remain unclear, hypoxic conditions in the bone marrow have been implicated in contributing to MM progression, angiogenesis, and resistance to chemotherapy. These effects occur via adaptive cellular responses mediated by hypoxia-inducible transcription factors (HIFs), and targeting HIFs can have anti-cancer effects in both solid and hematological malignancies. Here, it was found that in most myeloma cell lines tested, HIF1α, but not HIF2α expression was oxygen dependent and this could be explained by the differential expression of the regulatory prolyl-hydroxylase isoforms. The anti-MM effects of a sequence-specific DNA-binding pyrrole-imidazole polyamide (HIF-PA), that disrupts the HIF heterodimer from binding to its cognate DNA sequences, were also investigated. HIF-PA is cell permeable, localizes to the nuclei, and binds specific regions of DNA with an affinity comparable to that of HIF transcription factors. Most of the MM cells were resistant to hypoxia-mediated apoptosis, and HIF-PA treatment could overcome this resistance in vitro. Using xenograft models, it was determined that HIF-PA significantly decreased tumor volume and increased hypoxic and apoptotic regions within solid tumor nodules and the growth of myeloma cells engrafted in the bone marrow. This provides a rationale for targeting the adaptive cellular hypoxic response of the O2-dependent activation of HIFα using polyamides.

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Section: Resultssupporting

confidence: 93%

A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity

Veena

Szablowski

Dervan

et al. 2016

Molecular Cancer Research

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“…This contrasted with the outcome of our in vivo investigations, with LNCaP xenografts exhibiting tumor burden reduction in response to treatment with 1 in the xenograft setting, 16b while related studies with the A549 cell line were unsuccessful. 18a The present investigation demonstrates this unanticipated result to be rooted, at least in part, in the pronounced difference in polyamide uptake between the two xenograft types, LNCaP tumors accumulating the compound at 5- to 7-fold higher levels than their A549 counterparts (Figure 1 ) in both the dual and the single xenograft experiments conducted with A549 and LNCaP, 19 respectively. Additional discrepancy may stem from the difference in the time frame employed for in vitro cytotoxicity measurement (3 days) and in vivo antitumor evaluation (at least 7 days) and the fact that the polyamide concentration is kept constant over the course of the experiment in vitro but not in vivo.…”

Section: Discussionmentioning

confidence: 66%

“… 16 Our recent C-14 based quantitation study established significant enrichment of a Py-Im polyamide in the LNCaP tumor xenograft tissue over lung and kidney. 19 The present investigation evaluates the biodistribution of the C-14 radioactively labeled Py-Im polyamide 1 (Figure 1 A) in a range of tumor xenografts, addresses the influence of xenografted cell line on systemic polyamide elimination, and provides an extended biodistribution profile of the molecule.…”

Section: Introductionmentioning

confidence: 99%

Tumor Xenograft Uptake of a Pyrrole–Imidazole (Py-Im) Polyamide Varies as a Function of Cell Line Grafted

2014

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Subcutaneous xenografts represent a popular approach to evaluate efficacy of prospective molecular therapeutics in vivo. In the present study, the C-14 labeled radioactive pyrrole–imidazole (Py-Im) polyamide 1, targeted to the 5′-WGWWCW-3′ DNA sequence, was evaluated with regard to its uptake properties in subcutaneous xenografts, derived from the human tumor cell lines LNCaP (prostate), A549 (lung), and U251 (brain), respectively. Significant variation in compound tumor concentrations was seen in xenografts derived from these three cell lines. Influence of cell line grafted on systemic polyamide elimination was established. With A549, a marked variation in localization of 1 was determined between Matrigel-negative and -positive xenografts. An extensive tissue distribution analysis of 1 in wild-type animals was conducted, enabling the comparison between the xenografts and the corresponding host organs of origin.

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“…Serum for analysis of toxicity markers (IDEXX) was obtained by RO collection and centrifugation (2000g, 15 min) in Serum Separator Tubes (BD Biosciences). The radioquantitation of 2 was performed as described elsewhere (33). …”

Section: Methodsmentioning

confidence: 99%

An HRE-Binding Py-Im Polyamide Impairs Hypoxic Signaling in Tumors

Szablowski

Raskatov

Dervan

2016

Molecular Cancer Therapeutics

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Hypoxic gene expression contributes to the pathogenesis of many diseases, including organ fibrosis, age-related macular degeneration and cancer. HIF-1, a transcription factor central to the hypoxic gene expression, mediates multiple processes including neovascularization, cancer metastasis and cell survival. Py-Im polyamide 1 has been shown to inhibit HIF-1-mediated gene expression in cell culture but its activity in vivo was unknown. This study reports activity of polyamide 1 in subcutaneous tumors capable of mounting a hypoxic response and showing neovascularization. We show that 1 distributes into subcutaneous tumor xenografts and normal tissues, reduces the expression of proangiogenic and prometastatic factors, inhibits the formation of new tumor blood vessels and suppresses tumor growth. Tumors treated with 1 show no increase in HIF-1a and have reduced ability to adapt to the hypoxic conditions, as evidenced by increased apoptosis in HIF-1a positive regions and the increased proximity of necrotic regions to vasculature. Overall, these results show that a molecule designed to block the transcriptional activity of HIF-1 has potent anti-tumor activity in vivo, consistent with partial inhibition of the tumor hypoxic response.

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A C-14 labeled Py–Im polyamide localizes to a subcutaneous prostate cancer tumor

Cited by 14 publications

References 29 publications

A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity

A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity

Tumor Xenograft Uptake of a Pyrrole–Imidazole (Py-Im) Polyamide Varies as a Function of Cell Line Grafted

An HRE-Binding Py-Im Polyamide Impairs Hypoxic Signaling in Tumors

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