Free radical generating organic
peroxides and hydroperoxides are known to promote
tumors in mouse skin and
iron has been shown to participate in
free radical generating reactions. In the present study, we have used various
peroxides and hydroperoxides as stage-I and -II
tumor promoters and have studied the effect of
iron-overload on the two stages of
tumor promotion. Swiss albino mice were
iron-overloaded by injecting
iron-
dextran (1.0 mg Fe/mouse per day for 15 days). Twenty-four hours after the last injection of
iron-
dextran, the animals were initiated with 40 microg 7,12 dimethylbenz[a]
anthracene. One week following initiation stage-I
tumor promotion was accomplished by applying 12-O-tetradecanoyl phorbol-13-acetate (TPA),
benzoyl peroxide (BPO),
cumene hydroperoxide (COOH) or H(2)O(2) to mice twice weekly for 2 weeks. Stage-II
tumor promotion was accomplished by applying
mezerein, BPO, COOH or H(2)O(2) to these mice twice weekly for 40 weeks. The appearance of the first
papilloma and the number of
tumors/mouse were recorded weekly. When compared to non-
iron-overloaded mice, the
iron-overloaded mice showed a higher
tumor incidence and number of
tumors/mouse. The order in which
iron-overload was effective in increasing
tumor promotion by stage-I
tumor promoters was H(2)O(2)>COOH>BPO>TPA and the order in which
iron-overload was effective in increasing
tumor promotion by stage-II
tumor promoters was COOH>
mezerein>BPO. Induction in
ornithine decarboxylase (ODC) activity, [(3)H]
thymidine incorporation in cutaneous
DNA and cutaneous lipid peroxidation were also higher in the
iron-overloaded mice. TPA was the most effective in inducing epidermal ODC activity and [(3)H]
thymidine incorporation followed by
mezerein, COOH and BPO. In addition, the level of epidermal
reduced glutathione and the activities of
antioxidant enzymes were lower in
iron-overloaded mice. Besides this, cutaneous
iron levels were higher in
iron-overloaded mice. Thus, we conclude from this study that
iron-overload augments stage-I and stage-II of
tumor promotion in murine skin.