TY - JOUR
T1 - Role of reactive intermediates in tumor promotion and progression.
AU - Kensler, T.
AU - Guyton, K.
AU - Egner, P.
AU - McCarthy, T.
AU - Lesko, S.
AU - Akman, S.
PY - 1995
Y1 - 1995
N2 - Many tumor promoters, including the phorbol esters, do not require biotransformation to stimulate cell growth. By contrast, some promoters, notably organic peroxides and hydroperoxides, must be metabolized to reactive intermediates to trigger signal transduction pathways for mitogenesis. These intermediates can be both free radicals and electrophiles. For example, skin tumor promoters such as tert-butyl hydroperoxide, cumene hydroperoxide, dicumyl peroxide and benzoyl peroxide undergo metal-dependent activation in keratinocytes to form alkoxyl, alkyl and aryl radicals as determined by spin trapping and electron paramagnetic resonance spectroscopy. These radicals can participate in substitution, addition or hydrogen-abstraction reactions leading to protein oxidation or alkylation, lipid peroxidation and/or DNA damage. Scavenger studies indicate that these macromolecular interactions mediate the cytotoxic and mitogenic effects of these peroxides. In some instances radicals can undergo further oxidation to electrophiles. The promoting activity of butylated hydroxytoluene hydroperoxide is mediated by a quinone methide, an electrophile formed through a phenoxyl radical intermediate. In this instance, covalent interaction of the quinone methide with sulfhydryl groups or other nucleophiles in the target cell appears to transmit the molecular signal for cell division and replication. Like the phorbol esters, peroxides and hydroperoxides lead to a genetic reprogramming manifest by the induction of immediate early response genes such as c-jun and late response genes such as ornithine decarboxylase, suggesting convergence in the molecular signalling processes among different classes of promoters.
AB - Many tumor promoters, including the phorbol esters, do not require biotransformation to stimulate cell growth. By contrast, some promoters, notably organic peroxides and hydroperoxides, must be metabolized to reactive intermediates to trigger signal transduction pathways for mitogenesis. These intermediates can be both free radicals and electrophiles. For example, skin tumor promoters such as tert-butyl hydroperoxide, cumene hydroperoxide, dicumyl peroxide and benzoyl peroxide undergo metal-dependent activation in keratinocytes to form alkoxyl, alkyl and aryl radicals as determined by spin trapping and electron paramagnetic resonance spectroscopy. These radicals can participate in substitution, addition or hydrogen-abstraction reactions leading to protein oxidation or alkylation, lipid peroxidation and/or DNA damage. Scavenger studies indicate that these macromolecular interactions mediate the cytotoxic and mitogenic effects of these peroxides. In some instances radicals can undergo further oxidation to electrophiles. The promoting activity of butylated hydroxytoluene hydroperoxide is mediated by a quinone methide, an electrophile formed through a phenoxyl radical intermediate. In this instance, covalent interaction of the quinone methide with sulfhydryl groups or other nucleophiles in the target cell appears to transmit the molecular signal for cell division and replication. Like the phorbol esters, peroxides and hydroperoxides lead to a genetic reprogramming manifest by the induction of immediate early response genes such as c-jun and late response genes such as ornithine decarboxylase, suggesting convergence in the molecular signalling processes among different classes of promoters.
UR - http://www.scopus.com/inward/record.url?scp=0029456127&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029456127&partnerID=8YFLogxK
M3 - Review article
C2 - 8532709
AN - SCOPUS:0029456127
VL - 391
SP - 103
EP - 116
JO - Progress in Clinical and Biological Research
JF - Progress in Clinical and Biological Research
SN - 0361-7742
ER -