Methylproamine

Description: IC50 Value: N/A Methylproamine is a DNA-binding radioprotector which, on the basis of published pulse radiolysis studies, acts by repair of transient radiation-induced oxidative species on DNA. in vitro: The extent of radioprotection at the clonogenic survival endpoint increased with methylproamine concentration up to a maximum dose modification factor (DMF) of 2.0 at 10 μM. At least 0.1 fmole/nucleus of methylproamine is required to achieve a substantial level of radioprotection (DMF of 1.3) with maximum protection (DMF of 2.0) achieved at 0.23 fmole/nucleus. The γH2AX focus yield per cell nucleus 45 min after irradiation decreased with drug concentration with a DMF of 2.5 at 10 μM [1]. Methylproamine-treated cells had fewer γH2AX foci after IR compared to untreated cells. Also, the presence ofmethylproamine decreased the amount of lower molecular weight DNA entering the gel as shown by the pulsed field gel electrophoresis assay [2]. Experiments with V79 cells have shown that methylproamine is approximately 100-fold more potent than the classical aminothiol radioprotector WR1065. The crystal structures of methylproamine and proamine complexes with the dodecamer d(CGCGAATTCGCG)(2) confirm that the new analogues also are minor groove binders [3]. in vivo: N/A Clinical trial: N/A

Protection by methylproamine of irradiated human keratinocytes correlates with reduction of DNA damage.[Pubmed:21087168]

Int J Radiat Biol. 2011 Mar;87(3):274-83.

PURPOSE: The therapeutic ratio for ionising radiation treatment of tumour is a trade-off between normal tissue side-effects and tumour control. Application of a radioprotector to normal tissue can reduce side-effects. Here we study the effects of a new radioprotector on the cellular response to radiation. Methylproamine is a DNA-binding radioprotector which, on the basis of published pulse radiolysis studies, acts by repair of transient radiation-induced oxidative species on DNA. To substantiate this hypothesis, we studied protection by Methylproamine at both clonogenic survival and radiation-induced DNA damage, assessed by gammaH2AX (histone 2AX phosphorylation at serine 139) focus formation endpoints. MATERIALS AND METHODS: The human keratinocyte cell line FEP1811 was used to study clonogenic survival and yield of gammaH2AX foci following irradiation ((1)(3)(7)Cs gamma-rays) of cells exposed to various concentrations of Methylproamine. Uptake of Methylproamine into cell nuclei was measured in parallel. RESULTS: The extent of radioprotection at the clonogenic survival endpoint increased with Methylproamine concentration up to a maximum dose modification factor (DMF) of 2.0 at 10 muM. At least 0.1 fmole/nucleus of Methylproamine is required to achieve a substantial level of radioprotection (DMF of 1.3) with maximum protection (DMF of 2.0) achieved at 0.23 fmole/nucleus. The gammaH2AX focus yield per cell nucleus 45 min after irradiation decreased with drug concentration with a DMF of 2.5 at 10 muM. CONCLUSIONS: These results are consistent with the hypothesis that radioprotection by Methylproamine is mediated by attenuation of the extent of initial DNA damage.

Methylproamine protects against ionizing radiation by preventing DNA double-strand breaks.[Pubmed:20732333]

Mutat Res. 2010 Oct 13;692(1-2):49-52.

PURPOSE: The majority of cancer patients will receive radiotherapy (RT), therefore, investigations into advances of this modality are important. Conventional RT dose intensities are limited by adverse responses in normal tissues and a primary goal is to ameliorate adverse normal tissue effects. The aim of these experiments is to further our understanding regarding the mechanism of radioprotection by the DNA minor groove binder, Methylproamine, in a cellular context at the DNA level. MATERIALS AND METHODS: We used immunocytochemical methods to measure the accumulation of phosphorylated H2AX (gammaH2AX) foci following ionizing radiation (IR) in patient-derived lymphoblastoid cells exposed to Methylproamine. Furthermore, we performed pulsed field gel electrophoresis DNA damage and repair assays to directly interrogate the action of Methylproamine on DNA in irradiated cells. RESULTS: We found that Methylproamine-treated cells had fewer gammaH2AX foci after IR compared to untreated cells. Also, the presence of Methylproamine decreased the amount of lower molecular weight DNA entering the gel as shown by the pulsed field gel electrophoresis assay. CONCLUSIONS: These results suggest that Methylproamine acts by preventing the formation of DNA double-strand breaks (dsbs) and support the hypothesis that radioprotection by Methylproamine is mediated, at least in part, by decreasing initial DNA damage.

In vitro studies with methylproamine: a potent new radioprotector.[Pubmed:14871839]

Cancer Res. 2004 Feb 1;64(3):1067-70.

New analogues of the minor groove binding ligand Hoechst 33342 have been investigated in an attempt to improve radioprotective activity. The synthesis, DNA binding, and in vitro radioprotective properties of Methylproamine, the most potent derivative, are reported. Experiments with V79 cells have shown that Methylproamine is approximately 100-fold more potent than the classical aminothiol radioprotector WR1065. The crystal structures of Methylproamine and proamine complexes with the dodecamer d(CGCGAATTCGCG)(2) confirm that the new analogues also are minor groove binders. It is proposed that the DNA-bound Methylproamine ligand acts as a reducing agent by an electron transfer mechanism, repairing transient radiation-induced oxidizing species on DNA.

Radioprotection of targeted and bystander cells by methylproamine.[Pubmed:25245467]

Strahlenther Onkol. 2015 Mar;191(3):248-55.

INTRODUCTION: Radioprotective agents are of interest for application in radiotherapy for cancer and in public health medicine in the context of accidental radiation exposure. Methylproamine is the lead compound of a class of radioprotectors which act as DNA binding anti-oxidants, enabling the repair of transient radiation-induced oxidative DNA lesions. This study tested Methylproamine for the radioprotection of both directly targeted and bystander cells. METHODS: T98G glioma cells were treated with 15 muM Methylproamine and exposed to (137)Cs gamma-ray/X-ray irradiation and He(2+) microbeam irradiation. Radioprotection of directly targeted cells and bystander cells was measured by clonogenic survival or gammaH2AX assay. RESULTS: Radioprotection of directly targeted T98G cells by Methylproamine was observed for (137)Cs gamma-rays and X-rays but not for He(2+) charged particle irradiation. The effect of Methylproamine on the bystander cell population was tested for both X-ray irradiation and He(2+) ion microbeam irradiation. The X-ray bystander experiments were carried out by medium transfer from irradiated to non-irradiated cultures and three experimental designs were tested. Radioprotection was only observed when recipient cells were pretreated with the drug prior to exposure to the conditioned medium. In microbeam bystander experiments targeted and nontargeted cells were co-cultured with continuous Methylproamine treatment during irradiation and postradiation incubation; radioprotection of bystander cells was observed. DISCUSSION AND CONCLUSION: Methylproamine protected targeted cells from DNA damage caused by gamma-ray or X-ray radiation but not He(2+) ion radiation. Protection of bystander cells was independent of the type of radiation which the donor population received.