Failure to demonstrate chemoprevention by the monoterpene perillyl alcoholduring early rat hepatocarcinogenesis: a cautionary note

The monoterpene perillyl alcohol (PA) is being considered as a useful chemo preventive and therapeutic agent against human cancers, However, no data ar e available on the effects of PA in the first stages of hepatocarcinogenesi s. To study such effects, putatively initiated cells and preneoplastic foci in hepatocarcinogenesis were used as a model, Male Wistar rats were treate d with a single dose of N-nitrosomorpholine (NNM), Between days 4 and 91 af ter NNM, subgroups of rats received either PA (1 g/kg body wt/day) or pheno barbital (PB) (50 mg/kg body wt/day) in the diet, Since PA treatment reduce d food intake, one control group was fed ad libitum, while a second control was pair fed between days 4 and 91, In order to enhance any treatment effe cts, all groups, including the controls, were treated with the potent tumor promoter PB after day 91 until the end of the experiment at day 266, Rats were killed at multiple time points and putatively initiated cells and pren eoplastic foci were identified by staining positively for placental glutath ione S-transferase (G+), The following results were obtained. (i) A few day s after NNM treatment single G+ cells emerged; a considerable portion of wh ich developed into foci, (ii) Treatment with PB resulted in an increase in number and size of G+ foci, (iii) YA treatment failed to reduce the number of G+ cells; it somewhat lowered rates of apoptosis in G+ foci and clearly increased their average size. (iv) Eighty-seven days of PA revealed no prot ective effect on day 266, but, similar to PB treatment, increased the growt h of foci, In conclusion, PA exerted no detectable chemopreventive effect i n the early stages of rat hepatocarcinogenesis. It rather exerted a PB-like tumor promoting activity. These data argue against a recommendation of PA as a chemopreventive agent for healthy humans.