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Analysis and knowledge of individual strain susceptibility of experimental animals to induction of carcinogenesis is important especially in regard to possibility of transfer of these facts to human pathology, first of all to chemopreventive projects. Our group (AHLERS et al. [1]) reported very low sensitivity of female Wistar:Han rats to induction of mammary carcinogenesis by 7,12-dimethylbenz(a)anthracene (DMBA) and by N-methyl-N-nitrosourea (NMU). The aim of this paper was to increase the sensitivity of females of this strain to mammary carcinogenesis induction by repeated administration of NMU in a dose 50 mg/kg of b.w. in critical periods: on 3-4 postnatal days, on 21 day (critical period for development of ductal parts of mammary gland) and between 50-55 days (maximal proliferation of whole gland). In comparison with 38% incidence of mammary tumors after the single dose and 65% incidence after 3 subsequent doses between 50-60 days, the combination of administration (only) on 21 day and between 50-55 postanatal days resulted in 88% incidence the sensitivity of animals reached the level of highly susceptible rat strains. The latency period was significantly increased in groups with NMU given on 3-4, 21 days and between 45-55 days respectively, on 21 day and between 45-55 days in comparison with control group (one dose of NMU). The tumor frequency per group and per animal in all groups with repeated NMU administration was significantly higher than that of control group. The volume of tumors was not influenced either by repeated carcinogen application or by time of its administration. These results expand the possibilities of analysis of carcinogen effects in individual periods of rat postnatal development.

The primary cancer chemoprevention is an important topic of experimental oncology. We have analyzed the possible oncostatic properties ofmelatonin in a combined model of radiation plus chemocarcinogen-induced mammary carcinogenesis. Virgin female rats of Wistar:Han strain were continuously irradiated with daily dose 96 mGy of gamma rays up to 15 days. At the end of irradiation, between 52-60 postnatal days, 7,12-dimethylbenz(a)anthracene was administered by gavage, in three 10 mg/rat consecutive doses. A part of animals drank melatonin in a concentration 100 microg/ml of tap water, continuously from the beginning of irradiation and 26 weeks after its end. The aim of the experiment was to investigate the preventive effect of melatonin on mammary tumor patterns. Relatively low incidence of mammary tumors in the noninfluenced group was probably connected with generally very low sensitivity of Wistar:Han female rats to single dose of chemocarcinogen in mammary carcinogenesis induction. In our trial melatonin decreased markedly the volume of mammary tumors, but did not influence any other tumor characteristics. The chemopreventive effect of melatonin, derived from in vivo realized mammary carcinogenesis study in female Wistar:Han rats was limited. The cancer preventive properties of melatonin should be investigated in the future especially from the standpoint of susceptible strain, effective doses, and mode plus sufficient length of application.

The aim of this project was to evaluate the effect of retinyl acetate (RA), melatonin (Mel) and their combination on N-methyl-N-nitrosourea (NMU)-induced rat mammary carcinogenesis. Female Sprague-Dawley rats were given two intraperitoneal doses of NMU, each of 50 mg/kg of b.w. between 43rd to 57th postnatal day. The administration of RA started 11 days and the administration of Mel 12 days before the first dose of NMU. RA was given daily in a dose of 8.2 mg per animal and day at the base of the tongue. Mel was given as a solution (20 micrograms/ml of tap water) between 3 p.m. and 8 a.m., from 8 a.m. to 3 p.m. the animals were drinking tap water only. The experiment was finished 22 weeks after the first administration of the carcinogen. The tumour incidence in the control group was 88%, in the group treated with RA 80% and in the group treated with Mel 61%. A substantial decrease in tumour incidence to 37% was noted in the group treated with RA plus Mel. Significant differences in incidence were noted in the group treated with the combination of RA and Mel as compared to the control group and the group treated with RA. Chemoprevention lengthened the latency significantly in the group treated with Mel and with the combination of RA and Mel. The decrease in tumour frequency per group was confirmed in the group treated with the combination of RA and Mel; differences between groups in the frequency per tumour-bearing animal were not observed. The volume of mammary tumours in the groups treated with chemopreventive agents was not changed.

One goal of experimental oncology is to find and test effective chemopreventive substances which can suppress malignant transformation of the cells, their accumulation and invasion. Mammary gland tumours were induced by DMBA applied intragastrically (10 mg/rat, three times) every three days between postnatal days 50 and 60 in female Sprague-Dawley rats. One day after the last dose we started chemoprevention with Mel, RA and combination of both drugs, which lasted 25 weeks. Mel was drunk continuously as a solution in tap water (100 micrograms/ml). RA was applied daily in the dose of 8.2 mg/rat at the base of the tongue. There were four experimental groups: 1. control--no chemoprevention, 2. Mel treatment, 3. RA treatment, 4. application RA + Mel. At the end of the experiment the incidence, frequency, latency and average volume of tumours were evaluated. In the group treated with Mel tumour incidence, latency and volume did not differ from controls; the frequency of tumours was decreased. Treatment with RA and with combination RA + Mel decreased mammary tumour incidence to 38% (RA) and 48% (RA + Mel); it also decreased frequency and prolonged latency. Thus chemoprotective effects of RA and combination of RA with Mel were proved in mammary carcinogenesis induced by DMBA. The oncostatic effect of Mel alone was not confirmed. In our recent paper (Bojková et al., 2000) drinking of lower doses of Mel during the late afternoon and night prolonged the latency period and in combination with RA showed an oncostatic effect on mammary carcinogenesis induced by NMU. Further studies are needed to elucidate the conditions of successful chemoprevention with Mel.