Monoterpenes, including
limonene and its in vivo rat plasma metabolites, have been shown to be inhibitors of protein isoprenylation of
small G proteins, including
p21 ras. In addition, dietary
limonene has been shown to be capable of preventing the development and causing the regression of chemically induced mammary
carcinomas, many of which contain activated ras oncogenes. On the basis of these observations, it was hypothesized that a possible mechanism by which
limonene exerts its effects on the
chemoprevention and regression of mammary
tumors involves the inhibition of protein isoprenylation of the
small G protein p21. In the first study, we asked whether dietary
limonene was able to prevent the development of mammary
carcinomas which were induced using direct retroviral gene transfer of v-Ha-ras into the mammary parenchyma in situ.
Limonene modified neither the rate of gene transfer nor the stability of gene expression. However,
limonene did greatly inhibit the formation of mammary
carcinomas induced by the insertion of activated ras. In a follow-up study, we asked whether
chemoprevention by
limonene was preferentially effective against a subset of chemically induced mammary
carcinomas with activated ras. Rats were fed
limonene to prevent the development of N-nitroso-N-
methylurea-induced mammary
tumors, a majority of which contain the activated Ha-ras oncogene. As expected,
limonene administration increased the latency period and lowered the frequency of mammary
carcinoma development as compared to controls. However,
tumor characterization revealed that
limonene treatment did not alter the percentage of
carcinomas with activated ras. These studies are consistent with the above studies in that
limonene is effective in preventing mammary
carcinomas with activated ras. Interestingly,
carcinomas without activated ras were prevented to the same extent as those with the activated oncogene.