Methylproamine protects against ionizing radiation by preventing DNA double-strand breaks.
OBJECTIVE
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.


METHODS
We used immunocytochemical methods to measure the accumulation of phosphorylated H2AX (γH2AX) 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 γH2AX 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.
Sprung
Carl N
CN
Division of Research, Peter MacCallum Cancer Centre, St. Andrews Pl. Melbourne, 8006 Victoria, Australia. carl.sprung@med.monash.edu.au
Vasireddy
Raja S
RS
Karagiannis
Tom C
TC
Loveridge
Shanon J
SJ
Martin
Roger F
RF
McKay
Michael J
MJ
D016587:Antimutagenic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D006801:Humans; D011839:Radiation, Ionizing; D011837:Radiation-Protective Agents / Q000494:pharmacology*
D016587:Antimutagenic Agents; D001562:Benzimidazoles; D011837:Radiation-Protective Agents; C483319:methylproamine