There have been relatively few animal experiments examining the potential anti-cancer activity of dietary BC (Rogers and Longnecker 1988; Moon et al. 1989; Rogers et al. 1993; Kelloff et al. 1994). Several reports (Rogers and Longnecker 1988; Moon et al. 1989; Rogers et al. 1993; Kelloff et al. 1994) have stated that this lack of experimentation has been due to the inability of rodent species to absorb sufficient BC into their bodies without converting it into retinol (vitamin A). However, Mathews-Roth et al. (1977) fed a diet high in BC to mice and guinea pigs. These workers found that unconverted BC accumulated in the skin and in several organs and tissues, including liver, ovary, spleen, adrenal, kidney and body fat. They concluded that the difference between 'yellow- fat' species (such as man) that are good accumulators of carotenoid, and those which do not readily store carotenoids ('white-fat' species, such as mice, guinea pigs and rats) is a quantitative rather than a qualitative one. Furthermore, Mathews-Roth et al. (1977) stated that if 'white-fat' species are given a diet high in carotenoids for a significant period of time, they will eventually accumulate carotenoid in skin and other organs. Komhauser et al. (1986) reported BC accumulation in rats and mice fed a carotene-fortified diet for extended periods. Furthermore, Komhauser et al. (1986) reported that the levels of BC in the blood and skin of rats fed such a diet established this species as a useful animal model for studying the protective effects of dietary BC. Hicks et al. 984) fed a high level (5 mM) of BC to B6D2F1 mice pre-treated with the
carcinogen BBN, to examine the effect of dietary BC upon the incidence of
experimentally-induced urinary bladder carcinomas. In this study, these workers found high plasma levels of unconverted BC in mice given the carotenoid in the diet (Turton 1995).
Furthermore, at post-mortem the body fat and certain internal organs of these mice, but not of the controls, appeared yellow/orange in colour, indicating that BC had been absorbed into the tissues. Thus, it has been shown that appreciable amounts of unconverted BC can be absorbed by the common laboratory rodents provided they are given a sufficiently high level of BC in the diet.
All the available reports of laboratory animal investigations into the potential anti-cancer activity of BC have been reviewed by Peto et al. (1981), Greenberg et al. (1985), Mathews-Roth (1985), Rogers and Longnecker (1988), Moon (1989), and Krinsky (1992).
A small number of experimental studies have been reported in the literature which indicate that dietary carotenoid supplements can inhibit the process of cancer induction in animals (Moon 1989;
Krinsky 1992). These studies have included carotenoids, such as BC, which exhibit provitamin A activity, and others, such as canthaxanthin, which are not metabolised to vitamin A
Early carotenoid experimentation involved the prevention of tumours induced in rats and mice by either UV alone (Epstein 1977; Mathews-Roth 1983; Mathews-Roth and Krinsky 1987), a combination of UV and chemical carcinogens such as DMBA (Mathews-Roth 1982), BP
(Santamaria et al. 1983), or MNNG (Santamaria et al. 1985). Other groups have used dietary or environmental carcinogens in experimental animals supplemented with carotenoids (Krinsky 1992). Under these experimental conditions, BC or canthaxanthin have protected against either DMBA-induced salivary tumours in mice (Alam et al. 1984; Alam and Alam 1987; Alam et al. 1988), or dimethylhydrazine (DMH)-induced colon tumours in mice (Temple and Basu 1987; Basu et al. 1988). Topical administration of BC not only inhibited (Suda et al. 1986) but also reversed (Schwartz et al. 1986) squamous cell carcinoma produced in the hamster buccal pouch by treatment with topical DMBA. Similar results were obtained with oral administration of either BC or canthaxanthin (Schwartz et al. 1988).
BC was reported by Lambert et al. (1990) to protect against two-stage skin carcinogenesis (DMBA/TPA) in Skh mice, although under the same conditions no significant protection was obtained in SENCAR mice. In similar experiments, Steinel and Baker (1990) reported that BC induced a significant inhibition of skin papillomas, but not of the ultimate development of
malignant tumours, in Skh mice treated with DMBA and TPA. These results led these workers to conclude that BC was active during the TPA promotion phase of carcinogenesis.
Rettura et al. (1984) reported that dietary BC inhibited the development of rat mammary tumours induced by DMBA Canthaxanthin, a carotenoid lacking vitamin A activity, was reported by Grubbs et al. (1991) to induce a 65% reduction in the incidence of mammary tumours in rats treated with DMBA, when fed for 3 weeks prior to administration of the carcinogen. Furthermore, these authors showed that the results obtained with canthaxanthin were no different to the
reduction by VAA in mammary tumour incidence in rats treated with MNU. In this instance, the experimentalists concluded that the carotenoid was not inhibiting promotion (Krinsky 1992).
Moon (1989) considered the reports of Reider et al. (1983) and Dorogokulpa et al. (1973) to, perhaps, most simulate human carotenoid exposure in relation to carcinogenesis. These studies
involved feeding experimental animals a diet which consisted primarily or entirely of carrots. Reider et a l (1983) reported that feeding carrots alone for 4 or 5 days each week significantly delayed hepatoma-related mortality in rats treated with diethylnitrosamine (DEN). It is probable that during this study intake of protein, fat and most micronutrients was inadequate, although,
surprisingly, body weights of carrot-fed and control animals were reported to be similar. Dorogokupla et al. (1973) reported that feeding unlimited amounts of carrots inhibited sarcoma development and prolonged tumour latency in mice given DMBA.
In addition to the lack of protection afforded by BC against DMBA/TPA treatment in SENCAR mice reported by Lambert et al. (1990), several other negative results have been reported in trials of the anti-cancer activity of carotenoids. Imaida et al. (1990), found only weak organ-specific effects of BC against carcinogenesis induced in F344 rats by DMH followed by MNU. In another report (Mathews-Roth et al. 1991), BC or canthaxanthin was fed for 5 weeks before, and 26 weeks after treatment with BBN, and only the mice receiving the supplemental BC showed significant protection against the development of bladder tumours. In contrast to the protective effect of BC against the development of bladder tumours reported by Mathews-Roth et al. (1991), Hicks et a l (1984) demonstrated no effect of BC on urinary bladder carcinomas, when the carotenoid was given to B6D2F1 mice after the administration of BBN. These results are supported by unpublished data from Moon's laboratory (cited by Moon 1989), who found no effect of BC, given by intraperitoneal injection, on BBN-induced bladder tumours in mice. Unpublished data from other animal tumour models cited by Moon (1989) demonstrated no effect of BC in the MNU rat mammary tumour model, and no effect on lung tumours induced in
hamsters by either MNU or DEN. However, when retinol was given in the diet, in addition to the dietary BC supplement, inhibition of DEN-induced hamster lung tumours was observed (Moon
1989).
6 POSSIBLE MECHANISMS OF THE ANTI-CANCER ACTIVITY OF BC AND