Prevention and therapy of mammary cancer by monoterpenes.

Monoterpenes, found in a wide variety of plants, are a major component of plant essential oils. The unsubstituted monocyclic monoterpene limonene has been shown to prevent carcinogen-induced mammary cancer at both the initiation and the promotion/progression stages. This terpene also causes the complete regression of the majority of advanced rat mammary cancer when added to the diet. Modification of limonene by hydroxylation at various positions increases both its chemopreventive and therapeutic efficacy. For example, the naturally occurring hydroxylated limonene analog perillyl alcohol is 5-10 times more potent than limonene and has a similar therapeutic index. Several cellular, metabolic and molecular activities are associated with terpene exposure. These include induction of phase I and II hepatic detoxification enzymes, selective inhibition of protein isoprenylation, inhibition of CoQ synthesis, and induction of the mannose 6-phosphate/IGFII receptor and TGF beta. Due to the therapeutic efficacy of monoterpenes in experimental model systems, clinical evaluation of this class of compounds has begun in advanced cancer patients. A Phase I trial of limonene is in progress in the UK. Efforts in the US will target perillyl alcohol for Phase I testing. Pre-IND toxicology is currently being completed. Phase I trails are anticipated to begin in the Spring of 1995. We feel that the results of these therapeutic trials, if positive, will facilitate the development of current terpenes and more potent analogs for future chemoprevention trials.