Timing of chemically induced neoplasia in mice revealed by the antineoplastic action of caffeine
Nomura, T.
Cancer Research 40(4): 1332-1340
1980
ISSN/ISBN: 0008-5472 PMID: 6766806 Document Number: 166570
When young adult ICR/Jcl mice or mouse fetuses were treated with 4-nitroquinoline 1-oxide (4NQO) or urethan, the final yields of lung tumors were markedly reduced by caffeine posttreatment. The lungs of day 15 mouse fetuses treated with 4NQO or urethan were sensitive to the antineoplastic action of caffeine for only 1.5 days. The lungs of young adult mice treated with 4NQO or urethan remained sensitive to the antineoplastic action of caffeine for 21 days after 4NQO treatment, and for at least 10 days after urethan treatment. The difference in the caffeine-sensitive period is compatible with the difference in the generation time of the stem cells in the lung between young adults (20-25 days) and day 15 fetuses (1.5 days). The caffeine-sensitive period for suppression of neoplasia apparently is limited to the time between carcinogen treatment and the 1st postcarcinogen DNA replication, indicating the possibility that the replication-dependent process, e.g., inducible error-prone postreplication repair, of fixing the 4NQO- or urethan-induced preneoplastic damage to DNA is inhibited by caffeine or that damage-bearing cells are selectively killed by caffeine when they begin DNA replication after carcinogen treatment. Caffeine did not reduce the tumor yields induced by the alkylating agents N-hydroxyurethan, N-methyl-N-nitrosourea and N-ethyl-N-nitrosourea. Caffeine effects on neoplasia parallel those on mutation in Escherichia coli; i.e., caffeine diminishes 4NQO-induced mutations by the inhibition of inducible error-prone postreplication repair but does not affect the mispairing mutagenesis by these alkylating agents. The assumptions that caffeine selectively kills cells made tumorigenic or suppresses the change in gene expression for neoplastic conversion and the contribution of cyclic AMP increased by caffeine to reverse tumorigenic cells to normal are ruled out, since is such physiological changes caused by caffeine can suppress neoplasia caffeine would be effective on lung neoplasia, irrespective of the kinds of carcinogens.