Effect of anthraquinone-laxatives on the proliferation and urokinase secretion of normal, premalignant and malignant colonic epithelial cells.

Even though 1,8-dihydroxyanthraquinone (DHA)-laxatives have been implicated in colon carcinogenesis, the available information is still inconclusive. The aim of this study was to demonstrate the effect of the DHA-laxatives, danthrone, rhein, aloe-emodin and sennidine, on colorectal tumour cells. In SW480 carcinoma cultures, dose-dependent induction of urokinase secretion into the medium was the predominant effect. Simultaneously, cell numbers were decreased by DHA-aglycones, but not by sennoside or the biphenylic laxative bisacodyl. DNA synthesis was not similarly reduced: 0.4-4 microM danthrone and sennidine even stimulated 5-bromo-2'-desoxyuridine (BrdU) uptake into DNA. When uptake was normalised to cell number, danthrone and sennidine doubled BrdU uptake/10(6) cells, 18 microM rhein and 0.7 microM aloe-emodin induced increases of 37 and 50%, respectively. This may at least partially be due to selective resistance of S-phase cells to DHA-caused cell loss. In VACO235 adenoma cells, sennidine and aloe-emodin did not affect urokinase secretion, but stimulated growth. Both cell numbers and DNA synthesis were increased. In contrast to SW480 carcinoma cells, VACO235 cells were also sensitive to sennoside and bisacodyl. No effects of DHA were observed in normal colorectal epithelial cells. The biological effects were preceeded by specific phosphorylation of cellular proteins with molecular weights of 110, 78, 63, 57 kDa, indicating the specific induction of a cellular signalling cascade by the laxatives.

Carcinogenicity testing of some constituents of black pepper (Piper nigrum).

In mice, injection of safrole, tannic acid or methylcholanthrene (MCA) during the preweaning period induced tumors in different organs. Safrole and tannic acid (constituents of black pepper) were weak carcinogens when compared with MCA which was used as a carcinogenic control substance. Force feeding of d-limonene (one of the pepper terpenoids) for a long time to the mice which were injected with any of the above 3 substances reduced their carcinogenic activity, while force feeding of piperine (one of black pepper alkaloids) was ineffective.

Carcinogenesis induced by black pepper (Piper nigrum) and modulated by vitamin A.

Painting and feeding of mice with 2mg of an extract from black pepper on 3 days a week for 3 months results in a significant increase of the number of tumor-bearing mice. Tumor incidence is reduced in those groups of experimental animals receiving 5 or 10mg Vitamin A-palmitate twice weekly for 3 months by feeding or painting during and subsequent to application of pepper extract. Feeding of mice with powder of black pepper in diet (50g/3kg food) has no impact on carcinogenesis.

Melatonin circadian-stage-dependently delays breast tumor development in mice injected daily for several months.

Breast tumor incidence is compared in C3CF1 mice, receiving at one of 6 different circadian stages, daily injections of melatonin or of a vehicle or no treatment, the latter in a slightly cooler environment. Results are summarized when approximately 33% of all animals have a breast tumor. Vehicle treatment increases tumor incidence. This environment-handling-vehicle effect is reduced by injecting melatonin, as indicated by life table analysis. A circadian-stage-dependence of the melatonin effect is suggested by the statistical significance of a 12-h component fitted to the tumor incidence data. The administration time of melatonin is an indispensable complement to dosing, notably when effects upon tumorigenesis are involved.

Prevention of transplacentally induced malignant diseases.

Administration of vitamin A (retinol palmitate) causes a reduction of transplacentally induced leukemias. Subsequent to a transplacental application of ENU, addition of vitamin A as a suspension to drinking water leads to a reduction of leukemia incidence to 50% as well as to a corresponding decrease of this disease as a cause of death. Yet there is no influence of vitamin A on the adenomas of the lung arising in this experimental design.

Establishment of slowly growing lung tumor cell model by aspiration of tumor cells.

In male BDF1 mice, aspiration of suspended Lewis lung tumor cells at a certain concentration leads to the occurrence of lung carcinomas after 30 days. Under the chosen experimental conditions tumor incidence is about 70%. Within 20 days, animals die from this slowly growing tumor. Furthermore, the experimental conception offers a model which seems suitable for investigations into growth regulation of lung tumors.

Influence of vitamin A on the formation of ethylnitrosourea (ENU)-induced leukemias.

In mice, administration of ethylnitrosourea (120 mg/kg body weight) on day 14 of pregnancy leads to a transplacentally induced and transplantable leukemia in a high percentage of the offspring. Moreover, 100% of the offspring develop, later on, adenomas of the lung. Application of retinol palmitate (daily dose 170,000 IU/kg) reduces leukemogenesis up to 50%, yet without influencing formation of lung adenomas.

Induction of a slowly growing transplantable adenocarcinoma metastasizing into the lungs.

In male Long Evans rats Dibutylnitrosamin induces adenocarcinomas of the lung. Transplantation of a tumor cell suspension prepared from the tumor leads in 100% of cases to death by metastases from adenocarcinoma of the lung after an average of 24 weeks when applied i.m. in a syngeneic system.

Active experimental inhibition of cancer by corynebacterium parvum.

It has been demonstrated that 5 microgram Corynebacterium parvum (Mérieux, Lyon) applied i.v. once weekly in mice of the strain C 3 H X Swiss Albino F 1 after three pregnancies effectively inhibits tumour growth. At this time those mice are 100% at risk. The appearance of tumours in the treated group is significantly delayed.