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325. Carcinogens in sea plants
CANCER RESEARCH
321
work raises the possibility that a variety of N-methylated carcinogens, which include the aminostilbenes, are converted in the body into N-hydroxymethyl derivatives which act as alkylating agents, in the same way as the nitrosamines and a variety of other classes of compounds displaying carcinogenic propensities. Roberts, J. J. & Warwick, G. P. (1963). Azo dye liver carcinogenesis: Reaction of hydroxymethylaminoazobenzene with nucleic acids in vitro. Nature, Lond. 197, 87. 324. Urinary tract effects of naphthalenesulphonamides The ability to induce hyperplasia (a localized cell multiplication) in the epithelium of the urinary tract of mice was studied with the following substituted naphthalenes: in position 1, -SO2NHRI, where R I = H , methyl or piperidyl; in position 4,-SO2R2, where R2=methyl, ethyl, propyl or isopropyl. The combinations R t = H with R2=methyl (I), ethyl (II) or isopropyl (III) produced compounds which were active while they were being fed but within a week of cessation of treatment the hyperplasia regressed. A similar effect was seen in the rat and possibly the rabbit but not in the guinea-pig. The remaining compounds, and a benzene analogue with R ~ = H and R2=ethyl were inactive. After 40 weeks of continuous treatment, III produced two bladder papillomas (benign tumours) and I produced bladder carcinoma in one mouse. The administration of II resulted in hyperplasia but no tumours. Accordingly the tumour-promoting action of II was tested in combination with a weak carcinogen, 2-amino-l-naphthol hydrochloride, acting as an initiator (see explanation of the two-stage mechanism of carcinogenesis (Cited in F.C.T. 1963, 1, 106). An increase in the incidence of bladder tumours was obtained with II. [Since the technique used involved implantation into the mouse bladder of.a paraffin pellet containing the initiator, control experiments should have been carried out with paraffin pellets containing no initiator. Until this is do he, the mechanism of turnout production remains somewhat uncertain. As usual, it had originally been suggested that the hyperplasia of the urinary tract was related to bladder stones or to phosphate crystals in the urine. Once again this hoary old legend was laid to rest by showing no correlation whatever between these phenomena.] Sen Gupta, K. P. (1962). Hyperplasia of urir~ary tract epithelium induced by continuous administration of sulphonamide derivatives. Brit. J. Cancer 16, 1 I0. Sen Gupta, K. P. (1962). Tumour-promoting action of 4-ethylsulphonyl-naphthalene-lsulphonamide. Nature, Lond. 194, 1185. 325. Carcinogens in sea plants Continuing their investigations on the occurrence of carcinogenic substances in water and soil the authors turned their attention to the phytoplankton (1) (minute plants which float or drift near the'surface of seas and lakes) taken from the Bodensee in Germany. Paper chromatography of dried benzene extracts of I revealed the presence of a number of aromatic and polycyclic hydrocarbons, half of which are known carcinogens. Many of these compounds were further characterized by means of ultraviolet absorption and spectrofluorimetric techniques. The concentrations of these compounds were determined and are expressed in ppm of dried I as follows: fluoranthene (300); 1,2-benzanthracene (20); 3,4benzpyrene (2); 1,-12 benzfluoranthene (100) and 3,4-, 10,11-, and 11,12-benzfluoranthene (100, 50 and 20 respectively). Six unidentified fluorescing polycyclic hydrocarbons at concentrations of 10, 50, 20, 20, 20, and 2 ppm were also present in dried I. [The phytoplankton are of great ecological and economic importance providing food for fish and whales. The carcinogenic hydrocarbons found in I are therefore likely to make their way into fish and whales and possibly eventually to man. Further experiments must be undertaken to elucidate the sources of these substances in I.]
322
TERATOGENESIS
Borneff, J. & Fischer, R. (1962). Kancerogene Substartzen in Wasser und Boden. X. Untersuchung von Phytoplankton eines Birmensees auf polyzyklische, aromatische Kohlenwasserstoffe. Arch. Hyg., BerL 146, 334. 326. Carcinogens in German soils According to a previous report (Cited in F.C.T. 1963, 1, 135) 3,4-benzpyrene (BP) occurs in Swiss soil to the extent of 21 ppm while samples of soils taken from Massachusetts and Connecticut contained between 0.04-1.3 ppm of BP. The presence of BP and other carcinogenic hydrocarbons in the soils was attributable to the decomposition of vegetable organic matter or soil organisms. Now comes the news that dried benzene extraots of samples of soil taken in 3 forested areas south of Darmstadt, Germany, were found to contain seven fluorescent polycyclic aromatic hydrocarbons. These were fluoranthene, 11,12benzfluoranthene, 1,12-benzperylene and four carcinogenic compounds, 3,4-benzfluoranthene, BP, 10,11-benzfluoranthene, and indeno (1,2,3cd)-pyrene. These were identified by means of chromatography, ultraviolet and spectrofluorimetric techniques. The concentrations of these substances in soils varied from 4 ppm in Buchenwald to 1300 ppm in Mischwald, and the authors estimated that the upper layers of the soil contain between 100-200 ppm of carcinogenic hydrocarbons. The areas, from which the samples of soil were taken, were so far removed from industrial areas and human habitation that the presence of these compounds in the soil poses the question whether plants contribute to their formation. [Once again the sources of these compounds will need to be thoroughly investigated.] Borneff, J. & Fischer, R. (1962). Kanzerogene Substanzen in Wasser und Boden. XI. Polyzyklisehe, aromatische Kohlenwasserstoffe in Walderde. Arch. Hyg., BerL 146, 430.
TERATOGENESIS 327. The fate of thalidomide in the body Thalidomide (I) differs markedly from all other types of sedatives that have so far been synthesized, in its chemistry and pharmacology. I is unique in that it does not contain the grouping RxR2C-CO'N< (RI and R2----alkyl or aryl radicals) which is present in other sedatives, and that it is a derivative of a naturally-occurring amino acid, glutamic acid. Also unlike most other sedatives I does not possess any anaesthetic or anticonvulsant activity. Most interesting of all I has a very low order of acute oral toxicity, so low, that it was impossible to determine the lethal dose value. Bearing in mind the fact that when given to adults an oral therapeutic dose of 100 mg I gives rise to maximum blood levels of 0.9/~g I/ml, it appears that only a few t~g suffice to produce a teratogenic effect. This is hard to reconcile with I's low acute toxicity and prompts the question whether I or one of its metabolites is responsible for producing foetal malformations. An investigation of the metabolism of I was therefore undertaken. In the first part of the study single oral doses of 100 mg/kg of I labelled with ~4C in the earbonyl groups of the phthaloyl moiety was administered to rats and dogs. The amount of 14C excreted in the expired air was less than 0.1 ~o of the total dose administered; this indicated to the authors that I was not subject to radical degradation by either animal. After the ingestion of single 100 mg/kg or 50 mg/kg daily doses for 28 days I was found to be evenly distributed throughout almost all organs of the body. In addition I readily passed across the placental membrane, since the embryos of pregnant animals given I had present in their organs similar concentrations to those in adults.
321
work raises the possibility that a variety of N-methylated carcinogens, which include the aminostilbenes, are converted in the body into N-hydroxymethyl derivatives which act as alkylating agents, in the same way as the nitrosamines and a variety of other classes of compounds displaying carcinogenic propensities. Roberts, J. J. & Warwick, G. P. (1963). Azo dye liver carcinogenesis: Reaction of hydroxymethylaminoazobenzene with nucleic acids in vitro. Nature, Lond. 197, 87. 324. Urinary tract effects of naphthalenesulphonamides The ability to induce hyperplasia (a localized cell multiplication) in the epithelium of the urinary tract of mice was studied with the following substituted naphthalenes: in position 1, -SO2NHRI, where R I = H , methyl or piperidyl; in position 4,-SO2R2, where R2=methyl, ethyl, propyl or isopropyl. The combinations R t = H with R2=methyl (I), ethyl (II) or isopropyl (III) produced compounds which were active while they were being fed but within a week of cessation of treatment the hyperplasia regressed. A similar effect was seen in the rat and possibly the rabbit but not in the guinea-pig. The remaining compounds, and a benzene analogue with R ~ = H and R2=ethyl were inactive. After 40 weeks of continuous treatment, III produced two bladder papillomas (benign tumours) and I produced bladder carcinoma in one mouse. The administration of II resulted in hyperplasia but no tumours. Accordingly the tumour-promoting action of II was tested in combination with a weak carcinogen, 2-amino-l-naphthol hydrochloride, acting as an initiator (see explanation of the two-stage mechanism of carcinogenesis (Cited in F.C.T. 1963, 1, 106). An increase in the incidence of bladder tumours was obtained with II. [Since the technique used involved implantation into the mouse bladder of.a paraffin pellet containing the initiator, control experiments should have been carried out with paraffin pellets containing no initiator. Until this is do he, the mechanism of turnout production remains somewhat uncertain. As usual, it had originally been suggested that the hyperplasia of the urinary tract was related to bladder stones or to phosphate crystals in the urine. Once again this hoary old legend was laid to rest by showing no correlation whatever between these phenomena.] Sen Gupta, K. P. (1962). Hyperplasia of urir~ary tract epithelium induced by continuous administration of sulphonamide derivatives. Brit. J. Cancer 16, 1 I0. Sen Gupta, K. P. (1962). Tumour-promoting action of 4-ethylsulphonyl-naphthalene-lsulphonamide. Nature, Lond. 194, 1185. 325. Carcinogens in sea plants Continuing their investigations on the occurrence of carcinogenic substances in water and soil the authors turned their attention to the phytoplankton (1) (minute plants which float or drift near the'surface of seas and lakes) taken from the Bodensee in Germany. Paper chromatography of dried benzene extracts of I revealed the presence of a number of aromatic and polycyclic hydrocarbons, half of which are known carcinogens. Many of these compounds were further characterized by means of ultraviolet absorption and spectrofluorimetric techniques. The concentrations of these compounds were determined and are expressed in ppm of dried I as follows: fluoranthene (300); 1,2-benzanthracene (20); 3,4benzpyrene (2); 1,-12 benzfluoranthene (100) and 3,4-, 10,11-, and 11,12-benzfluoranthene (100, 50 and 20 respectively). Six unidentified fluorescing polycyclic hydrocarbons at concentrations of 10, 50, 20, 20, 20, and 2 ppm were also present in dried I. [The phytoplankton are of great ecological and economic importance providing food for fish and whales. The carcinogenic hydrocarbons found in I are therefore likely to make their way into fish and whales and possibly eventually to man. Further experiments must be undertaken to elucidate the sources of these substances in I.]
322
TERATOGENESIS
Borneff, J. & Fischer, R. (1962). Kancerogene Substartzen in Wasser und Boden. X. Untersuchung von Phytoplankton eines Birmensees auf polyzyklische, aromatische Kohlenwasserstoffe. Arch. Hyg., BerL 146, 334. 326. Carcinogens in German soils According to a previous report (Cited in F.C.T. 1963, 1, 135) 3,4-benzpyrene (BP) occurs in Swiss soil to the extent of 21 ppm while samples of soils taken from Massachusetts and Connecticut contained between 0.04-1.3 ppm of BP. The presence of BP and other carcinogenic hydrocarbons in the soils was attributable to the decomposition of vegetable organic matter or soil organisms. Now comes the news that dried benzene extraots of samples of soil taken in 3 forested areas south of Darmstadt, Germany, were found to contain seven fluorescent polycyclic aromatic hydrocarbons. These were fluoranthene, 11,12benzfluoranthene, 1,12-benzperylene and four carcinogenic compounds, 3,4-benzfluoranthene, BP, 10,11-benzfluoranthene, and indeno (1,2,3cd)-pyrene. These were identified by means of chromatography, ultraviolet and spectrofluorimetric techniques. The concentrations of these substances in soils varied from 4 ppm in Buchenwald to 1300 ppm in Mischwald, and the authors estimated that the upper layers of the soil contain between 100-200 ppm of carcinogenic hydrocarbons. The areas, from which the samples of soil were taken, were so far removed from industrial areas and human habitation that the presence of these compounds in the soil poses the question whether plants contribute to their formation. [Once again the sources of these compounds will need to be thoroughly investigated.] Borneff, J. & Fischer, R. (1962). Kanzerogene Substanzen in Wasser und Boden. XI. Polyzyklisehe, aromatische Kohlenwasserstoffe in Walderde. Arch. Hyg., BerL 146, 430.
TERATOGENESIS 327. The fate of thalidomide in the body Thalidomide (I) differs markedly from all other types of sedatives that have so far been synthesized, in its chemistry and pharmacology. I is unique in that it does not contain the grouping RxR2C-CO'N< (RI and R2----alkyl or aryl radicals) which is present in other sedatives, and that it is a derivative of a naturally-occurring amino acid, glutamic acid. Also unlike most other sedatives I does not possess any anaesthetic or anticonvulsant activity. Most interesting of all I has a very low order of acute oral toxicity, so low, that it was impossible to determine the lethal dose value. Bearing in mind the fact that when given to adults an oral therapeutic dose of 100 mg I gives rise to maximum blood levels of 0.9/~g I/ml, it appears that only a few t~g suffice to produce a teratogenic effect. This is hard to reconcile with I's low acute toxicity and prompts the question whether I or one of its metabolites is responsible for producing foetal malformations. An investigation of the metabolism of I was therefore undertaken. In the first part of the study single oral doses of 100 mg/kg of I labelled with ~4C in the earbonyl groups of the phthaloyl moiety was administered to rats and dogs. The amount of 14C excreted in the expired air was less than 0.1 ~o of the total dose administered; this indicated to the authors that I was not subject to radical degradation by either animal. After the ingestion of single 100 mg/kg or 50 mg/kg daily doses for 28 days I was found to be evenly distributed throughout almost all organs of the body. In addition I readily passed across the placental membrane, since the embryos of pregnant animals given I had present in their organs similar concentrations to those in adults.