<b>
                     <i>In Vitro</i>
                  </b> Studies with Methylproamine

Martin, Roger F.; Broadhurst, Sam; Reum, Monica E.; Squire, C.J.; Clark, George R.; Lobachevsky, Pavel; White, Jonathan M.; Clark, Christopher I.; Sy, D.; Spotheim-Maurizot, M.; Kelly, David P.

doi:10.1158/0008-5472.can-03-2423

Cited by 45 publications

(26 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The saturation level has been estimated to be 0.173 fmole per nucleus and corresponds to approximately 1 ligand per 58 bp. This value is similar to the size of the binding site calculated from in vitro DNA binding studies with methylproamine and analogues (Loontiens et al, 1990;Martin et al, 2004). The fraction of DNA bound methylproamine is not less than 98% as estimated assuming nucleus radius of 5 m (DNA concentration 26 mM bp), binding dissociation constant K d = 100 nM and methylproamine concentration 450 M (total nuclear uptake 0.234 fmole at 10 M in medium).…”

Section: Dna Bound Methylproamine Is Responsible For Radioprotection supporting

confidence: 83%

DNA-Binding Radioprotectors

Lobachevsky¹,

Ivashkevich²,

Martin³

et al. 2011

Selected Topics in DNA Repair

View full text Add to dashboard Cite

Section: Dna Bound Methylproamine Is Responsible For Radioprotection supporting

confidence: 83%

DNA-Binding Radioprotectors

Lobachevsky¹,

Ivashkevich²,

Martin³

et al. 2011

Selected Topics in DNA Repair

View full text Add to dashboard Cite

“…Hence, investigations related to development of potential radiation protectors and sensitizers are focused on molecules that act within the nucleus. For example, certain DNA minor groove binding bisbenzimidazoles, such as Hoechst 33342 40 and methylproamine, 41 possess radioprotective properties, and various halogenated DNA binding ligands such as bromodeoxyuridine, 42 have been shown to sensitize cells to the effects of ionizing radiation. Since HDAC inhibitors alter chromatin structure it was conceivable that these compounds may modulate the effects of ionizing radiation.…”

Section: Discussionmentioning

confidence: 99%

The histone deacetylase inhibitor, trichostatin A, enhances radiation sensitivity and accumulation of gammaH2A.X

Karagiannis¹,

Harikrishnan²,

El‐Osta³

2005

Cancer Biology & Therapy

View full text Add to dashboard Cite

Histone deacetylase inhibitors have been shown to induce numerous biologic effects including, altering cell cycle distribution, cytostasis and in certain cases apoptosis. Given their ability to disrupt critical biological processes in cancer cells, these agents are emerging as potential therapeutics for cancer. Recently, it has been identified that histone deacetylase inhibitors can also efficiently enhance the radiation sensitivity of cells, both in vitro and in vivo. In this study, we investigated whether the potent histone deacetylase inhibitor, Trichostatin A, modulates the radiation sensitivity of human erythroleukemic K562 cells.The endpoints we used were clonogenic survival, apoptosis and γH2AX immunoprecipitations of soluble chromatin. The findings from clonogenic survival assays indicated that incubation with Trichostatin A 24 hours prior to irradiation enhances the radiation sensitivity of K562 cells. The dose modification factors ranged from 1.1 when cells were incubated with 0.1 µM Trichostatin A to 2.3 at 1 µM Trichostatin A. Similarly, caspase-3 and caspase-7 assays indicated that Trichostatin A potentiates radiation-induced apoptosis in K562 cells, in a concentration dependent manner. Our results suggest the modulation of radiation effects observed at the lower Trichostatin A concentrations was associated with histone hyperacetylation and changes in phosphorylated γH2A.X formation on euchromatin. In contrast, at the higher Trichostatin A concentrations mechanisms such as drug-mediated cytotoxicity and G 1 cell cycle arrest, contributed to the sensitization effect. More generally, our findings are consistent with those from recent studies and support the development of histone deacetylase inhibitors for use as radiation sensitizers, particularly for targeting radioresistant cancers.

show abstract

“…119,120 Although the lead compound methylproamine has been shown to be a much more potent radioprotector than amifostine in cell cultures, further development is required. 120 The interest in HDAC inhibitors as potential radiation protectors came about from the knowledge that these compounds can downregulate transcription of oncogenes including Myc and Bcl-2 and repress inflammatory cytokines such as interleukin (IL)-1, IL-8, tumour necrosis factor (TNF)-α and fibrogenic growth factors such as transforming growth factor (TGF)-β. 111,[121][122][123] It was recognized that the release of cytokines and growth factors is involved in augmenting the inflammatory response to radiation.…”

Section: Radioprotective Properties Of Hdac Inhibitorsmentioning

confidence: 99%

The Paradox of Histone Deacetylase Inhibitor-Mediated Modulation of Cellular Responses to Radiation

Karagiannis

El‐Osta

2006

Cell Cycle

View full text Add to dashboard Cite

Given the widespread use of radiotherapy in cancer, there has been a longstanding interest in the development of chemical compounds that can modify cellular responses to ionizing radiation. Additionally, recent terrorism threats suggesting attacks with 'dirty bombs' containing combinations of radioactive isotopes with conventional explosives, has increased the interest in compounds that can protect from radiation injury. Histone deacetylase inhibitors represent a new class of compounds that can modulate the effects of radiation. Research with histone deacetylase inhibitors has largely focussed on the consequences of their ability to alter gene transcription via histone acetylation and on their properties as anti-cancer agents. They have been shown to cause cell cycle and growth arrest, differentiation and in certain cases apoptosis in cell cultures and in vivo. In addition to their intrinsic anti-cancer properties, numerous studies have demonstrated that histone deacetylase inhibitors can modulate cellular responses to other toxicity-inducing modalities including ionizing radiation. The consensus is that histone deacetylase inhibitors markedly enhance the sensitivity of cells to radiation by altering numerous molecular pathways. Intriguingly, a report has also shown that histone deacetylase inhibitors can reduce radiation induced acute and late skin damage using a well-established animal model of cutaneous radiation syndrome. Hence, there is an emerging interest in potential use of histone deacetylase inhibitors as radiation sensitizers or protectors. This review focuses on the different mechanisms by which histone deacetylase inhibitors modify cellular responses to ionizing radiation.

show abstract

In Vitro Studies with Methylproamine

Cited by 45 publications

References 24 publications

DNA-Binding Radioprotectors

DNA-Binding Radioprotectors

The histone deacetylase inhibitor, trichostatin A, enhances radiation sensitivity and accumulation of gammaH2A.X

The Paradox of Histone Deacetylase Inhibitor-Mediated Modulation of Cellular Responses to Radiation

Contact Info

Product

Resources

About