Among the carotenoids, P-carotene has been expected to be the most promising candidate as a cancer preventive agent. Thus, P-carotene has been tested for cancer-preventive activity in interventional trials; i.e., two Linxian trials (Linxian 1 and Linxian 2), the Alpha-Tocopherol Beta-Carotene (ATBC) cancer prevention study, the P-Carotene and Retinol Efficacy Trial (CARET), the Physicians' Health Study (PHS), and the Skin Cancer Prevention Study (SCPS). In addition to these studies, we have recently completed an intervention trial with supplementation of a mixture of natural carotenoids (lycopene, P-carotene, a-carotene, and others) plus a-tocopherol (Jinno, K., Nishino, H. et al., patent pending: 2002-022958, 2002.1.31; see Section 4.3.8).
4.3.1 P -Carotene (Synthetic)
In the Linxian 1 study, a protective effect of supplemental P-carotene, vitamin E, and selenium was reported with regard to the incidence and mortality rates of gastric cancer when compared with untreated subjects. In the Linxian 2 study, the relative risk for cancer mortality was 0.97 in men and 0.92 in women (not significant). At the end of follow-up in the ATBC cancer prevention study, 894 cases of lung cancer were reported. The numbers of lung cancer cases by intervention group were 204 in the a-tocopherol group, 242 in the P-carotene group, 240 in the a-tocopherol plus P-carotene group, and 208 in the placebo group. The group receiving P-carotene had a 16% higher incidence of lung cancer than those not given P-carotene. The excess risk associated with P-carotene supplementation was concentrated mainly among people who currently smoked more than 20 cigarettes per day and who drank more than 11 g/day of ethanol.
In the CARET, the relative risk of lung cancer incidence was 1.3 in the group treated with P-carotene and retinal (p = 0.02), 1.4 in the current smoker group treated with P-carotene and retinal, and 1.4 in the asbestos-exposed group treated with P-carotene and retinal. In the PHS, no significant modification in risk was found. In the SCPS, the relative risk for skin cancer was 1.4 in the smoker group treated with P-carotene.
4.3.2 a-Carotene a-Carotene has been proved to induce Gj-arrest of cells in the cell cycle. As various agents that induce G1-arrest have been proved to have cancer preventive activity, we evaluated the anticarcinogenic activity of a-carotene. a-Carotene showed higher activity than P-carotene to suppress the tumorigenesis in skin, lung, liver, and colon.4
In the skin tumorigenesis experiment, a two-stage mouse skin carcinogenesis model was used. First, 7-week-old female ICR mice had their backs shaved with electric clipper. From 1 week after initiation by 100 |g of 7,12-dimethyl-benz[a]anthracene (DMBA), 1.0 |g of 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied twice a week. a-Carotene or P-carotene (200 nmol) was applied with each TPA application. The higher potency of a-carotene than P-carotene was observed. The percentage of tumor-bearing mice in the control group was 69%, whereas the percentages of tumor-bearing mice in the groups treated with a- and P-carotene were 25 and 31%, respectively. The average number of tumors per mouse in the control group was 3.7, whereas the a-carotene-treated group had 0.3 tumors per mouse (p < 0.01, Student's i-test). P-Carotene treatment also decreased the average number of tumors per mouse (2.9 tumors per mouse); however, the difference from the control group was not significant.
The higher potency of a-carotene compared to P-carotene in the suppression of tumor promotion was confirmed by another two-stage carcinogenesis experiment, i.e., 4-nitroquinoline 1-oxide (4NQO)-initiated and glycerol-promoted ddY mouse lung carcinogenesis model. 4NQO (10 mg/kg body weight) was given by a single subcutaneous injection on the first experimental day. Glycerol (10% in drinking water) was given as the tumor promoter from experimental week 5 to week 30 continuously. a-Carotene or P-carotene (at the concentration of 0.05%) or vehicle as a control was mixed as an emulsion into drinking water during the promotion stage. The average number of tumors per mouse in the control group was 4.1, whereas the a-carotene-treated group had 1.3 tumors per mouse (p < 0.001). P-Carotene treatment did not show any suppressive effect on the average number of tumors per mouse, but rather induced a slight increase (4.9 tumors per mouse).
In a liver carcinogenesis experiment, a spontaneous liver carcinogenesis model was used. Male C3H/He mice, which have a high incidence of spontaneous liver tumor development, were treated for 40 weeks with a- and P-carotene (at the concentration of 0.05%, mixed as an emulsion into drinking water) or vehicle as a control. The mean number of hepatomas was significantly decreased by a-carotene treatment as compared with that in the control group; the control group developed 6.3 tumors per mouse, whereas the a-carotene-treated group had 3.0 tumors per mouse (p < 0.001). On the other hand, the P-carotene-treated group did not show a significant difference from the control group, although a tendency toward a decrease was observed (4.7 tumors per mouse).
As a short-term experiment to evaluate the suppressive effect of a-carotene on colon carcinogenesis, the effect on colonic aberrant crypt foci formation (ACF) induced by N-methylnitrosourea (MNU, three intrarectal administrations of 4 mg in week 1) was examined in Sprague-Dawley (SD) rats. a-Carotene or P-carotene (6 mg, suspended in 0.2 ml of corn oil, intragastric gavage daily) or vehicle as control were administered during weeks 2 and 5. The mean number of colonic ACF in the control group was 63, whereas a- or P-carotene-treated group had 42 (significantly lower than that in the control group, p < 0.05) and 56, respectively. Thus, a greater potency of a-carotene compared to P-carotene was again observed.
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Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.