Modulation of ras p21 oncoprotein levels and DNA strand breakage in human cells with chemotherapeutic agents and/or deferoxamine.
Oncogenes are involved with the regulation of cellular proliferation. Ras oncogenes can be activated by chemical treatment and any increased activity could be modulated by further chemical treatment. In the present study, therefore, ras p21 protein expression was examined in in vitro cultures of human lymphocytes treated with mitomycin C and in the human colon adenocarcinoma Caco-2 cell line treated with doxorubicin with and without deferoxamine. Both chemotherapeutic agents act partially through oxygen radical mechanisms. Increases in p21 protein levels were seen with mitomycin C but no clear response was seen with doxorubicin. However, deferoxamine, with and without doxorubicin, altered p21 expression. Deferoxamine is an iron chelator so these results support the hypothesis that oxygen radicals were responsible for the altered p21 protein levels. Modulating responses were confirmed by measuring DNA strand-breakage in the Comet assay after treatment with doxorubicin and deferoxamine. Alterations of ras p21 protein expression in vitro might prove a suitable system for examining modulating effects on chemical carcinogens.
Anderson
D
D
BIBRA International, Carshalton, Surrey, United Kingdom.
Yardley-Jones
A
A
Yu
T W
TW
Hughes
J A
JA
Brinkworth
M H
MH
D000970:Antineoplastic Agents / Q000633:toxicity*; D018938:Caco-2 Cells; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D003676:Deferoxamine / Q000494:pharmacology*; D004317:Doxorubicin / Q000633:toxicity*; D005609:Free Radicals; D006801:Humans; D016685:Mitomycin / Q000633:toxicity*; D016283:Proto-Oncogene Proteins p21(ras) / Q000032:analysis*
D000970:Antineoplastic Agents; D005609:Free Radicals; D016685:Mitomycin; D004317:Doxorubicin; D004247:DNA; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D003676:Deferoxamine