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Open Access 01-03-2015 | Original article

Radioprotection of targeted and bystander cells by methylproamine

Authors: Dr. med. Susanne Burdak-Rothkamm, Dr. Andrea Smith, Dr. Pavel Lobachevsky, Prof. Roger Martin, Prof. Kevin M. Prise

Published in: Strahlentherapie und Onkologie | Issue 3/2015

Abstract

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 μM methylproamine and exposed to ¹³⁷Cs γ-ray/X-ray irradiation and He²⁺ microbeam irradiation. Radioprotection of directly targeted cells and bystander cells was measured by clonogenic survival or γH2AX assay.

Results

Radioprotection of directly targeted T98G cells by methylproamine was observed for ¹³⁷Cs γ-rays and X-rays but not for He²⁺ charged particle irradiation. The effect of methylproamine on the bystander cell population was tested for both X-ray irradiation and He²⁺ 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 γ-ray or X-ray radiation but not He²⁺ ion radiation. Protection of bystander cells was independent of the type of radiation which the donor population received.

Schneider RA, Vitolo V, Albertini F et al (2013) Small bowel toxicity after high dose spot scanning-based proton beam therapy for paraspinal/retroperitoneal neoplasms. Strahlenther Onkol 189:1020–1025CrossRefPubMed

Maier P, Wenz F, Herskind C (2014) Radioprotection of normal tissue cells. Strahlenther Onkol 190:745–752CrossRefPubMed

Wygoda A, Rutkowski T, Hutnik M et al (2013) Acute mucosal reactions in patients with head and neck cancer. Three patterns of mucositis observed during radiotherapy. Strahlenther Onkol 189:547–551CrossRefPubMed

Citrin D, Cotrim AP, Hyodo F et al (2010) Radioprotectors and mitigators of radiation-induced normal tissue injury. Oncologist 15:360–371CrossRefPubMedCentralPubMed

Bourgier C, Levy A, Vozenin MC et al (2012) Pharmacological strategies to spare normal tissues from radiation damage: useless or overlooked therapeutics? Cancer Metastasis Rev 31:699–712CrossRefPubMed

Smith PJ, Anderson CO (1984) Modification of the radiation sensitivity of human tumour cells by a bis-benzimidazole derivative. Int J Radiat Biol Relat Stud Phys Chem Med 46:331–344CrossRefPubMed

Young SD, Hill RP (1989) Radiation sensitivity of tumour cells stained in vitro or in vivo with the bisbenzimide fluorochrome Hoechst 33342. Br J Cancer 60:715–721CrossRefPubMedCentralPubMed

Denison L, Haigh A, D’Cunha G et al (1992) DNA ligands as radioprotectors: molecular studies with Hoechst 33342 and Hoechst 33258. Int J Radiat Biol 61:69–81CrossRefPubMed

Martin RF, Broadhurst S, Reum ME et al. (2004) In vitro studies with methylproamine: a potent new radioprotector. Cancer Res 64:1067–1070CrossRefPubMed

10.

Rogakou EP, Pilch DR, Orr AH et al (1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273:5858–5868CrossRefPubMed

11.

Lobachevsky PN, Vasireddy RS, Broadhurst S et al (2011) Protection by methylproamine of irradiated human keratinocytes correlates with reduction of DNA damage. Int J Radiat Biol 87:274–283CrossRefPubMed

12.

Azzam EI, De Toledo SM, Spitz DR et al. (2002) Oxidative metabolism modulates signal transduction and micronucleus formation in bystander cells from alpha-particle-irradiated normal human fibroblast cultures. Cancer Res 62:5436–5442PubMed

13.

Chaudhry MA (2006). Bystander effect: Biological endpoints and microarray analysis. Mutat Res 597:98–112CrossRefPubMed

14.

Burdak-Rothkamm S, Rothkamm K, Prise KM (2008) ATM acts downstream of ATR in the DNA damage response signaling of bystander cells. Cancer Res 68:7059–7065CrossRefPubMedCentralPubMed

15.

Burdak-Rothkamm S, Short SC, Folkard M et al (2007) ATR-dependent radiation-induced gammaH2AX foci in bystander primary human astrocytes and glioma cells. Oncogene 26:993–1002CrossRefPubMed

16.

Sokolov MV, Smilenov LB, Hall EJ et al (2005) Ionizing radiation induces DNA double-strand breaks in bystander primary human fibroblasts. Oncogene 24:7257–7265CrossRefPubMed

17.

Shao C, Stewart V, Folkard M et al (2003) Nitric oxide-mediated signaling in the bystander response of individually targeted glioma cells. Cancer Res 63:8437–8442PubMed

18.

Shao C, Folkard M, Prise KM (2008) Role of TGF-beta1 and nitric oxide in the bystander response of irradiated glioma cells. Oncogene 27:434–440CrossRefPubMedCentralPubMed

19.

Han W, Chen S, Yu KN et al (2010) Nitric oxide mediated DNA double strand breaks induced in proliferating bystander cells after alpha-particle irradiation. Mutat Res 684:81–89CrossRefPubMed

20.

Hei TK (2006) Cyclooxygenase-2 as a signaling molecule in radiation-induced bystander effect. Mol Carcinog 45:455–460CrossRefPubMed

21.

Tartier L, Gilchrist S, Burdak-Rothkamm S et al (2007) Cytoplasmic irradiation induces mitochondrial-dependent 53BP1 protein relocalization in irradiated and bystander cells. Cancer Res 67:5872–5879CrossRefPubMedCentralPubMed

22.

Zhou H, Ivanov VN, Lien YC et al (2008) Mitochondrial function and nuclear factor-kappaB-mediated signaling in radiation-induced bystander effects. Cancer Res 68:2233–2240CrossRefPubMedCentralPubMed

23.

Lyng FM, Howe OL, McClean B Reactive oxygen species-induced release of signalling factors in irradiated cells triggers membrane signalling and calcium influx in bystander cells. Int J Radiat Biol 87:683–695

24.

Mothersill C, Seymour C (2003) Radiation-induced bystander effects, carcinogenesis and models. Oncogene 22:7028–7033CrossRefPubMed

25.

Prise KM, O’Sullivan JM (2009) R0adiation-induced bystander signalling in cancer therapy. Nat Rev Cancer 9:351–360CrossRefPubMedCentralPubMed

26.

Burdak-Rothkamm S, Prise K (2009) New molecular targets in radiotherapy: DNA damage signalling and repair in targeted and non-targeted cells. Eur J Pharmacol 625:151–155CrossRefPubMedCentralPubMed

27.

Folkard M, Vojnovic B, Prise KM et al (1997) A charged-particle microbeam: I. Development of an experimental system for targeting cells individually with counted particles. Int J Radiat Biol 72:375–385CrossRefPubMed

28.

Folkard M, Vojnovic B, Hollis KJ et al (1997) A charged-particle microbeam: II. A single-particle micro-collimation and detection system. Int J Radiat Biol 72:387–395CrossRefPubMed

29.

Sedelnikova OA, Nakamura A, Kovalchuk O et al (2007) DNA double-strand breaks form in bystander cells after microbeam irradiation of three-dimensional human tissue models. Cancer Res 67:4295–4302CrossRefPubMed

30.

Han W, Wu L, Chen S et al (2007) Constitutive nitric oxide acting as a possible intercellular signaling molecule in the initiation of radiation-induced DNA double strand breaks in non-irradiated bystander cells. Oncogene 26:2330–2339CrossRefPubMed

31.

Goodhead DT (1994) Initial events in the cellular effects of ionizing radiations: clustered damage in DNA. Int J Radiat Biol 65:7–17CrossRefPubMed

32.

Martin RF, Anderson RF (1998) Pulse radiolysis studies indicate that electron transfer is involved in radioprotection by Hoechst 33342 and methylproamine. Int J Radiat Oncol Biol Phys 42:827–831CrossRefPubMed

33.

Shinde S, Maroz A, Hay M et al (2009) One-electron reduction potential of the neutral guanyl radical in the GC base pair of duplex DNA. J Am Chem Soc 131:5203–5207CrossRefPubMedCentralPubMed

34.

Giese B (2002) Long-distance electron transfer through DNA. Annu Rev Biochem 71:51–70CrossRefPubMed

35.

Martin R, Hendley J, Carolan M (1997) DNA-binding radioprotectors: Active with low but not high-LET radiation. Advances in Neutron Capture Therapy Volume 2. Chemistry and Biology :604–608

36.

Sedelnikova OA, Redon CE, Dickey JS et al (2010) Role of oxidatively induced DNA lesions in human pathogenesis. Mutat Res 704:152–159CrossRefPubMedCentralPubMed

37.

Dickey JS, Baird BJ, Redon CE et al (2009) Intercellular communication of cellular stress monitored by gamma-H2AX induction. Carcinogenesis 30:1686–1695CrossRefPubMedCentralPubMed

38.

Martin OA, Redon CE, Nakamura AJ et al (2011) Systemic DNA damage related to cancer. Cancer Res 71:3437–3441CrossRefPubMedCentralPubMed

39.

Redon CE, Dickey JS, Nakamura AJ et al (2010) Tumors induce complex DNA damage in distant proliferative tissues in vivo. Proc Natl Acad Sci U S A 107:17992–17997CrossRefPubMedCentralPubMed

40.

Redon CE, Nakamura AJ, Martin OA et al (2011) Recent developments in the use of gamma-H2AX as a quantitative DNA double-strand break biomarker. Aging (Albany NY) 3:168–174

Title: Radioprotection of targeted and bystander cells by methylproamine
Authors: Dr. med. Susanne Burdak-Rothkamm
Dr. Andrea Smith
Dr. Pavel Lobachevsky
Prof. Roger Martin
Prof. Kevin M. Prise
Publication date: 01-03-2015
Publisher: Springer Berlin Heidelberg
Published in: Strahlentherapie und Onkologie / Issue 3/2015
Print ISSN: 0179-7158
Electronic ISSN: 1439-099X
DOI: https://doi.org/10.1007/s00066-014-0751-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Radioprotection of targeted and bystander cells by methylproamine

Abstract

Introduction

Methods

Results

Discussion and conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Methods

Results

Discussion and conclusion

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