Oxidative stress may enhance prostatic
carcinogenesis. A polymorphism [
valine (V) -->
alanine (A)] of
manganese superoxide dismutase (MnSOD), the primary
antioxidant enzyme in mitochondria, has been recently associated with
prostate cancer. We examined the relationship between
prostate cancer and the MnSOD polymorphism and its interactions with baseline plasma
antioxidant levels (
selenium,
lycopene, and
alpha-tocopherol) and
beta-carotene treatment among 567 cases and 764 controls nested in the prospective Physicians' Health Study. We found little overall association between MnSOD polymorphism and
prostate cancer risk; however, this polymorphism significantly modified risk of
prostate cancer associated with prediagnostic plasma
antioxidants (P(interaction) > or = 0.05). Among men with the AA genotype, high
selenium level (4th versus 1st quartile) was associated with a relative risk (RR) of 0.3 [95% confidence interval (CI), 0.2-0.7] for total
prostate cancer; for clinically aggressive
prostate cancer, the RR was 0.2 (95% CI, 0.1-0.5). In contrast, among men with the VV/VA genotype, the RRs were 0.6 (0.4-1.0) and 0.7 (0.4-1.2) for total and clinically aggressive
prostate cancer. These patterns were similar for
lycopene and
alpha-tocopherol and were particularly strong when these
antioxidants and
selenium were combined; men with the AA genotype had a 10-fold gradient in risk for aggressive
prostate cancer across quartiles of
antioxidant status. Men with AA genotype who were randomly assigned to
beta-carotene treatment (versus placebo) had a RR of 0.6 (95% CI, 0.2-0.9; P(interaction) = 0.03) for fatal
prostate cancer, but no significant association was observed in men with the VV/VA genotype. Both endogenous and exogenous
antioxidants play an important and interdependent role in preventing clinically significant
prostate cancer.