Effects of photodynamic therapy in combination with Adriamycin.

The combination of photodynamic therapy (PDT) and Adriamycin (ADM) was studied in the animal model system. Photohem (PH) was used as a photosensitizer. Mice bearing carcinoma epidermoides LL of the lung received PH once at a dose 10 mg/kg and after 24 h ADM was injected i.p. at a dose 3 mg/kg and tumors were illuminated with laser light after three different time intervals, 15 min, 3 and 24 h. To evaluate the effect of PDT and PDT combined with ADM the intensity of lipid peroxidation in tumor tissue and in blood serum was determined using the thiobarbituric acid assay. PDT induces an increase of malondialdehyde (MDA) concentration in tumor tissue as well as in blood serum. When PDT is combined with ADM, the MDA level in tumor tissue is similar to the level of this product as in the PDT alone. No enhancement of the efficiency of the combined treatment was observed at these experimental conditions. This is also confirmed by the tumor growth dynamics, survival time of animals and flow cytometric DNA analysis of tumor cells. For the successful combination of PDT with chemotherapy it is suggested to apply the drugs at the regimen which will allow to avoid the interaction between two agents since the ground state interaction between PH and ADM is stated spectroscopically. It should lead to the conclusion that the sequence of the combination of two treatment modalities is an important factor for synergistic effect.

Influence of ethyl alcohol on the carcinogenic activity of N-nitrosonornicotine.

The present paper describes an experiment designed to investigate the effects of the combined action of different doses of N-nitrosonornicotine (NNN) and ethyl alcohol in BDVI rats. Dose-response relationships of NNN was clearly shown. Ethyl alcohol did not appear to increase, to a great degree, the tumour incidence of NNN. However, ethyl alcohol did shorten the tumour latency period in the groups given NNN in alcoholic solution. In addition, an infiltration of the olfactory tumours to the brain was observed more frequently in both males and females given the high dose of NNN in alcoholic solution.

Influence of ethyl alcohol on carcinogenesis with N-nitrosodimethylamine.

This paper presents the results of an experiment on the combined action of nitrosodimethylamine and ethyl alcohol in C57BL mice. As shown, alcohol can act to change the target organ of that liver carcinogen by favouring development of olfactory neuroepitheliomas, which infiltrate the frontal lobe of the brain.

Investigation on the combined action of N-nitrosodiethylamine with other carcinogens.

The results of this experiment suggest that chemical carcinogens other than N-nitrosamines, even at levels that are very low and not effective when given singly, can in some way contribute to th carcinogenicity of NDEA.

Carcinogenicity of dapsone of mice and rats.

Dapsone (4,4'-diamino-diphenyl sulfone) has been tested for possible carcinogenicity in long-term animal experiments. BDIV rats and C7 Bl mice received a 3.5% aqueous suspension of dapsone by intragastric intubation. Treatment was started in pregnant females during the last part of pregnancy, continued during lactation, then given to the offspring after weaning, five times a week for 104 weeks. The dose administered was 100 mg/kg to both rats and mice; total doses ranged from 10-16 g per rat and 1.2-1.4 g per mouse. Separate groups of animals received a combined treatment of dapsone with urethane or benzo (alpha) pyrene, to investigate the possible additive or synergistic action of dapsone with known carcinogens, as well as the possible inhibiting effect of dapsone on carcinogenesis. Unusual tumors, viz. spleen sarcomas (related to severe fibrosis of the spleen) were detected in male rats, and higher morbidity from C-cell thyroid carcinomas was observed in treated rats of both sexes than in control rats. There was no evidence that dapsone can modify the action of other chemical carcinogens. It was noted that: (1) although the increase in the incidence of tumours in dapsone-treated animals over that observed in untreated controls is statistically significant, the increase is relatively low; (2) the tumours appeared after lifetime treatment with maximum tolerated doses; (3) in rats, spleen sarcomas were observed mostly in males; this may indicate a possible hormone-dependence of the observed carcinogenic effect. The present results therefore provide only limited evidence of carcinogenicity of dapsone in rats.

[Research on the etiological factors of oesophageal cancer in the West of France (author's transl)]. / Recherches concernant les factuers étiologiques du cancer de l'oesophage dans l'Ouest de la France.

There is strong epidemiological evidence that oesophageal cancer in the West of France is related to alcohol consumption. Various laboratory studies have been undertaken in connection with this finding. Samples of the spectrum of alcoholic drinks consumed in the region, notably apple cider and its distillates, were collected from retail outlets and from farms: several distillates produced under experimental conditions in the laboratory were also examined. These samples were analysed for the presence of selected nitrosamines; small amounts were found for the most part in beer, which is little consumed in Normandy and Brittany. Mutageniticy tests on the apple cider based drinks and on other commercially available alcoholic beverages (beer excepted), have shown a weak response, for the most part in farm distillates, that can be attributed neither to nitrosamines nor to polycyclic aromatic hydrocarbons, but to some other as yet unidentified compounds.

[Methods of identifying carcinogenic factors in medication, food and cosmetics]. / Méthodes de dépistage du pouvoir cancérogène des médicaments, des aliments et des cosmetiques.

The removal of carconogenic factors would be a most efficient measure to prevent cancer. As far as known chemicals are concerned, every effort is made to avert them, or at least to reduce the exposure to such compounds, but is necessary to detect unknown chemicals, especially those, drugs and foodstuffs for example, to which large populations are exposed. Giving suspected chemicals to laboratory animals is a standard carcinogenicity test. Studies of the carcinogenicity of unknown chemicals in animals are time consuming, expensive and cumbersome. This is why other means of establishing carcinogenicity are sought for. Several rapid tests are available to-day to select suspected carcinogens. These methods aim primarily at determining with chemicals--at the cell or tissue level--certain changes that would appear essential to trigger the carcinogenic process, such as somatic mutations. Studies are used on the mutagenicity of chemicals for bacteria of the Salmonella type, for yeast and cultured mammalian cells, together with the induction of recessive lethal mutations in Drosophila and of the unscheduled repair synthesis of DNA and the transformation of mammalian cells in vitro. Although there is an unequivocal correlation between the activity of chemicals in such tests and their carcinogenicity, discrepancies are found. Thus, the in vivo tests on laboratory animals remain the most reliable method to determine carcinogenicity. Whereas direct extrapolation of experimental data to human pathology is impossible, the experimental evidence of the carcinogenicity of any chemical should allow us to draw constructive conclusions. We shall never be able to reject drugs which produce the expected results and cannot be replaced by other drugs. But we can must the drugs whose beneficial effects are not exceptional and which can be replaced by other chemicals. As for the chemicals used in food additives and cosmetics, and recognized as carcinogenic in animals, they should be totally given up. Any decision made should be based on animal studies.

[Carcinogens in food (author's transl)]. / Les substances cancérogènes dans les aliments.

There is no evidence at present that certain chemicals are responsible for certain human cancers (with the exception of aflatoxin, which is the most suspect agent in the development of primary liver cancer in some districts of Africa and in Thailand). A number of chemicals which are carcinogenic to animals are present in human food. Any chemical which induces tumours in animals should be considered as a potential human carcinogen. But special studies must be undertaken before the role played by these substances in the development of human cancer can be definitely evaluated. First priority should be given to polycyclic aromatic hydrocarbons and N-nitroso compounds by reason of their general distribution in the human environment and their high efficiency in animal experiments. An appropriate approach to such studies would be the establishment of correlations between cancer morbidity data and the data on levels of these chemicals in special environments and, if possible, their total intake. This approach has proved fruitful in the aflatoxin intake studies carried out in countries where liver cancer is endemic. The IARC is currently carrying out a study of this kind in areas of high oesophageal cancer morbidity in Iran and in the north of France.

[N-nitroso compounds. Analysis and possible carcinogenicity in man]. / Les composés N-nitrosés. Analyse et carcinogénicité eventuelle chez l'homme

Much work has been carried out on N-nitroso compounds but their role in human pathology has still to be elucidated. We cannot extrapolate experimental data to the human situation but we do have indirect evidence that nitroso compounds can be carcinogens in man. Although some nitrosamines are organ-specific, the nitroso group induces the development of many different types of cancer in animals It is probable that the same phenomenon occurs in human pathology, and we cannot therefore expect to have special case reports on their carcinogenicity in man. Therefore, an alternative approach to the study of the role of nitrosamines in human pathology would be to establish a correlation between cancer morbidity in some regions and amounts of N-nitroso compounds in the environment. In view of the complexity of the problem of in vivo nitrosamine formation, it is more realistic nowadays to measure exogenous nitrosamines. Many laboratories are currently engaged on studies on N-nitroso compounds, although systematic information on their presence in the environment is scant. Furthermore, the data acquired by different laboratories has been obtained using a variety of methods for sampling, storage, clean-up and identification and estimation, with the result that it is not known to what extent these results are comparable.Therefore, the standardization and determination of comparability of methods for the identification of N-nitroso compounds is the first step towards their quantitation in the environment. Adequate methods are now available for the determination of volatile nitrosamines, down to the mug/dg level, but methods for non-volatile nitrosamines are still in the development stages. In order to avail all interested laboratories of information on analytical methods for volatile nitrosamines, IARC's analytical chemistry laboratory has organized a three part collaborative study using samples of canned luncheon meat. The results of this study were encouraging, and the European Sub-Committee for the Guidance of Collaborative Studies, at its last meeting, recommended that such studies be continued and extendedto include non-volatile nitrosamines. In parallel with the perfection of analytical techniques, IARC has initiated studies on the measurement of volatile nitrosamines in the environment in conjuction with the epidemiological studies on oesophageal cancer at present being carried out. The data collected up to now is far from being complete but it is important in that it represents the first step towards the evaluation of the risk to health of N-nitroso compounds, which constitute a part of the total carcinogenic load in the human environment.