PubMed Health⌕ Search

Biomedical subjects

R M Hicks

Publications and source records attributed to R M Hicks.

At least 37 records · Page 2Linked to original sources
PubMed1984

Metabolism of 2-naphthylamine and benzidine by rat and human bladder organ cultures.

The metabolism of benzidine and 2-naphthylamine, two aromatic amines which are carcinogenic for the human, was investigated in human and rat bladder organ cultures. There was little oxidative metabolism of either carcinogen in either species. In particular, N-hydroxy-2-naphthylamine, a proximate carcinogen of 2-naphthylamine could not be detected. In contrast, large amounts of the acetylated metabolites, N-acetylbenzidine, N,N-diacetylbenzidine and N-acetyl-2-naphthylamine were formed both in rat and human bladder cultures. The results suggest that metabolism of these carcinogens in situ in the bladder is unlikely to contribute to their carcinogenic effect but instead may have a positive protective role.

2-Naphthylamine↗
PubMed1983

The induction of urothelial hyperplasia by methyl methanesulphonate and ethyl methanesulphonate.

The early and late morphological changes induced in rat bladder urothelium by intravesicular administration of the alkylating agents methyl methanesulphonate (MMS) and ethyl methanesulphonate (EMS) are described. In the short-term, both compounds produced dose-related toxic damage followed by a regenerative hyperplasia of the urothelium. At any given dose-level, the effects of MMS were more severe than those of EMS. Two years after administration of multiple doses of 2.5 mg MMS or 7.5 mg EMS the majority of animals had dose-related simple urothelial hyperplasias with occasional mild dysplasia. However, in three MMS-treated animals the hyperplasias had progressed to well-differentiated transitional-cell carcinomas. No bladder neoplasms were seen in EMS-treated animals. The urothelial response of the rat to MMS and EMS is discussed with reference to the known chemical reactivity of these compounds. It is concluded that EMS is a mitogen for the urothelium and that the few carcinomas which develop following topical exposure of the bladder to MMS do not necessarily reflect any initiating potential in this compound. Rather it is argued that the results are consistent with MMS acting as a promoter in cells which have either been previously initiated or which carry a latent oncogene.

Animals↗
PubMed1983

Effect of promoters on incidence of bladder cancer in experimental animal models.

Multistage models of carcinogenesis proposed to account for the observed patterns of tumor development in the skin, liver, lung, bladder and other organs involve initiation of neoplastic change in a few cells by a threshold dose of carcinogen followed by conversion of these latent tumor cells into an autonomous cancer by further doses of the same and/or other carcinogens, and/or noncarcinogenic promoting agents. In the rat urinary bladder, neoplastic change can be initiated by a few weeks treatment with low doses of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) or N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or by a single, low dose, intravesicular instillation of N-methyl-N-nitrosourea (MNU). Very few animals treated thus will develop bladder cancer unless exposed subsequently to some further regime which will promote tumor growth from the initiated cells. Many different factors will stimulate tumor growth in the initiated rat bladder, including further low doses of complete bladder carcinogens, dietary factors such as metabolites of tryptophan or deficiency of vitamin A, the food additives saccharin and cyclamate and some alkylating agents such as cyclophosphamide and methylmethane sulfonate. New and published evidence is reviewed which supports the belief that these and other factors are promoters or later stage carcinogens in the bladder. The difficulties of defining a promoter and of identifying markers of promotion, i.e., of distinguishing the second from the later stages of carcinogenesis in the urinary bladder, are discussed with reference to the action of promoters in the mouse skin initiation/promotion model. However, in terms of their effect on an initiated population on the risk of developing cancer, it is suggested that such a distinction is largely irrelevant. Since both second and later stage carcinogens accelerate tumor development in an initiated urothelium, they both have the potential to lower the age at which bladder cancer becomes symptomatic. They are thus as important as are initiating carcinogens in determining the patterns of age-related neoplastic disease in any population.

Adenocarcinoma↗
PubMed1983

Long-term organ culture of normal human bladder.

Normal adult human bladder obtained at cystoscopy has been maintained in long-term organ culture. Several media were tested for their ability to maintain viability and normal tissue morphology. The optimum medium was Ham's F-12 nutrient mixture, supplemented with 10% fetal calf serum, hydrocortisone (1 microgram/ml), and FeSO4, (0.45 microgram/ml). During the first 28 days in vitro, epithelial damage incurred at biopsy and during preparation of the cultures was repaired, and epithelialization of cut stromal surfaces occurred. A wave of cell proliferation was identified by [3H]thymidine autoradiography, 24-h labeling indices rising to a peak of up to 50% on the cut sides of the cultures between 7 and 21 days and falling to 0 to 5% by 21 to 28 days. The regenerating epithelium showed all the normal features of urothelial cell differentiation when examined by scanning and transmission electron microscopy. From 28 days, histology and scanning and transmission electron microscopy showed the cultured urothelium in most cultures to resemble closely that in the normal bladder in vivo, and in this mature state cultures were maintained for 100 days. Urothelium derived from certain patients, although showing normal surface maturation, developed enlarged intercellular spaces or intraepithelial mucin-containing acini. A study of the cytology of cells shed into the medium at different stages in culture showed that culture viability and epithelial differentiation could be monitored easily in long-term culture by this nondestructive means.

Adult↗
PubMed1982

Association of bacteriuria and urinary nitrosamine formation with Schistosoma haematobium infection in the Qalyub area of Egypt.

In Egypt, bladder cancer incidence is high in areas where the prevalence and intensity of Schistosoma haematobium infection is also high. Experimental evidence shows bladder carcinogenesis to be a multi-stage process which can be accelerated by many factors. N-nitroso compounds, some of which are known bladder carcinogens, can be formed from amine precursors and nitrate in urine during some bacterial infections. In experimental animals the growth of nitrosamine-induced urothelial cancers is accelerated by damage to the urothelium caused by S. haematobium infections, and by analogy in man this could account for the lower peak age of incidence of this cancer in Egypt by comparison with Europe. The present study was designed to investigate whether bacterial infection of the urinary tract was common in areas of endemic schistosomiasis and whether N-nitrosamines were regularly found to be associated with bacteriuria. Urine samples from young men in the Qalyub area of Egypt and from an adjacent Delta region were analysed for S. haematobium ova, the nature and intensity of any bacterial infection, nitrate and nitrite, and total N-nitroso compounds plus volatile N-nitrosamines. A relatively high prevalence of bacteriuria was found in young men with schistosomiasis and low levels of N-nitroso compounds were present in all specimens. When the groups were sub-divided on the basis of the ability of their bacterial flora to reduce nitrate to nitrite (the latter is required for the nitrosation of amine precursors to N-nitroso compounds), significantly higher levels of N-nitroso compounds were found in S. haematobium-infected individuals also infected with nitrate-reducing bacteria by comparison either with uninfected controls (p less than 0.0005) or with those infected with non-nitrate-reducing bacteria (p less than 0.001). The results show N-nitroso compounds to be present in the urines of young men in areas of endemic S. haematobium infection in Egypt, and elevated levels of urinary N-nitroso compounds to be associated with infection of the urinary tract by various species of nitrate-reducing bacteria.

Adolescent↗
PubMed1982

Early and late morphological changes (including carcinoma of the urothelium) induced by irradiation of the rat urinary bladder.

Effects of X-irradiating the urinary bladder of female F344 rats with a single dose of 20 Gy were studied by light and electron microscopy. The animals were killed 1 week-20 months post-irradiation, and all tissues of the bladder wall were found to be affected by the irradiation. In the urothelium, damage was initially restricted to the basal cells but slowly extended to intermediate cells, and by 6 months post-irradiation the urothelium was focally hyperplastic. Twenty months post-irradiation, transitional-cell carcinomas were found in 10 of the surviving 17 animals (59%). The blood vessels in the bladder wall showed damage to both the endothelial cells and the smooth muscle. The fibroblasts in the connective tissue of the bladder wall appeared to show increased secretion after irradiation, and there was abundant collagen deposition, resulting in severe fibrosis of the bladder wall. After a latent period of a few months, focal degeneration and extensive necrosis of the smooth muscle cells were seen, leading to severe destruction and disorganization of the muscular coats of the bladder wall. Thus, a single dose of irradiation of 20 Gy was sufficient to produce severe fibrosis of the bladder wall with smooth muscle degeneration and to induce carcinoma of the urothelium in most of the treated animals within 20 months.

Animals↗
PubMed1982

The induction of rat bladder cancer by 2-naphthylamine.

The widely held belief that 2-naphthylamine is not carcinogenic for the rat has been re-examined. Twenty female Wistar rats were dosed by gastric intubation weekly for 57 weeks with 2-naphthylamine, 300 mg/kg body wt, in arachis oil and 20 controls were given arachis oil alone. Animals which became moribund were killed during the course of the experiment and the remainder after 100 weeks. A 2-naphthylamine-treated animal died at 21 weeks; all others survived 57 weeks or longer. The urinary tracts of all but two 2-naphthylamine-treated animals, which were found dead and cannibalized, were examined histologically.No neoplastic disease of the urinary tract was present in control animals. In 10 of the 2-naphthylamine-treated rats there was neither neoplasia nor hyperplasia of the urothelium, but 4 of the 18 examined histologically had large, macroscopically visible bladder cancers; one of these also had bilateral transitional cell tumours of the kidney calyces and multiple tumours in both ureters. Another animal had bilateral urothelial cancers in the ureters. The histology and ultrastructure of these urothelial cancers were comparable to those of rat transitional-cell carcinomas experimentally induced with other chemical carcinogens.These results, considered in the context both of early and more recently published biochemical studies of 2-naphthylamine metabolism in the rat, support the possibility that production of the active carcinogenic metabolite in this species may be influenced by a pH-dependent, non-enzymic mechanism in the urine, which could account for individual, strain- and diet-related variations in response in the rat.

2-Naphthylamine↗
PubMed1982

Induction of bladder cancer in rats by fractionated intravesicular doses of N-methyl-N-nitrosourea.

Experiments were conducted to determine the dose response of rat bladder urothelium to a range of different single and fractionated intravesicular doses of the carcinogen, N-methyl-N-nitrosourea (MNU). A dose-related response of bladder-tumour incidence to single graded doses of MNU was found, and a threshold does suitable for use of multistage carcinogenesis experiments was derived from these data. For any given total dose of MNU, the tumour incidence was greater if the MNU had been administered in several small fractions than if it had been administered in fewer larger ones. Extending the interval between doses did not reduce the tumour incidence. It is argued that these results support the multistage theory of carcinogenesis. The histopathology and cell-surface alterations which characterize the development of MNU-induced bladder cancer are described and the contribution of hyperplasia and calculi are discussed.

Animals↗
PubMed1982

Urothelial abnormalities in the obstructed bladder.

Bladder mucosa from patients undergoing prostatectomy was examined histologically for evidence of pre-malignant change. The mucosal appearances were compared with tissue taken from control patients without bladder outlet obstruction. The appearances in patients with uncomplicated obstruction and in control patients were found to be similar and dysplastic change was uncommon. However, dysplasia was found relatively frequently in patients with bladder outlet obstruction complicated by the presence of infection, catheters or stones. In all, 10 out of 74 patients were found to have dysplasia and 7 of these agreed to have a further cystoscopy and biopsy taken at an interval of between 10 and 28 months after the first examination. Persistent dysplasia was found in all 7 cases and in 3 of these it had progressed from mild to moderate in severity. The significance of these findings is discussed.

Adult↗
PubMed1982

Metabolism and binding of benzo(a)pyrene and 2-acetylaminofluorene by short-term organ cultures of human and rat bladder.

The ability of organ cultures of normal human and rat bladder to metabolize the polycyclic hydrocarbon, benzo(a)pyrene (BP), and the arylamine, 2-acetylaminofluorene, has been studied. Cultures were maintained for 0 to 6 days in a chemically defined medium before incubation with [3H]BP (0.3 to 0.5 microM) or 2-[14C]acetylaminofluorene (18 to 25 microM) for 24 hr. Ethyl acetate-soluble and water-soluble metabolites were produced from both compounds by both species. The ethyl acetate extracts from [3H]BP-treated human cultures contained 9,10-dihydro-9,10-dihydroxybenzo(a)pyrene, 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene, and 3-hydroxybenzo(a)pyrene. Rat bladder cultures produced similar metabolites but in slightly different proportions. Ethyl acetate-soluble products of 2-[14C]acetylaminofluorene from human cultures contained 7-hydroxy-2-acetylaminofluorene, 9-hydroxy-2-acetylaminofluorene, 2-aminofluorene, and N-hydroxy-2-aminofluorene. Rat bladder cultures produced similar metabolites, but 2-aminofluorene was found in relatively higher proportion. Hydrolysis by beta-glucuronidase of the water-soluble products produced from both carcinogens gave ethyl acetate-extractable derivatives. These hydrolyzable glucuronide conjugates were relatively more abundant following metabolism of the carcinogens by the rat than by the human cultures. Covalent binding to DNA occurred with [3H]BP in both human (19.7 +/- 13 pmol/mg DNA) and rat cultures (22.8 +/- 8.6 pmol/mg DNA). As with other human tissues, considerable variation (50-fold) was observed between individuals. The results demonstrate that both human and rat bladder epithelium can metabolize known potent carcinogens and, in the case of BP, can effect covalent binding between the products of metabolism and the urothelial cell DNA. In theory, carcinogenesis in the urinary bladder could thus be initiated by carcinogens produced or excreted in the urine without the necessity for their prior metabolism elsewhere in the body.

2-Acetylaminofluorene↗
PubMed1981

Surface ultrastructure of the epithelia lining the normal human lower urinary tract.

The finding of cells with pleomorphic microvilli in urinary sediments has been proposed as an indicator for urothelial neoplasia. Recently, in addition to such cells, others with less bizarre, non-pleomorphic microvilli have also been found in urothelial cancers, and these cells are similar in appearance to others detected in the urinary sediments of healthy people. When using scanning electron microscopy as a diagnostic tool, these cells are a possible source of confusion. The entire lower urinary tracts from people free of urothelial neoplasia have therefore been examined to delineate the normal surface appearance of all cell types which could appear in the urine. There are 4 predominant cell types: the large, flat squamous cells of the urethral meatus which have abundant microridges; cells with mucus-coated, short, stubby microvilli lining the urethra and renal papilla; immature urothelial cells with chains and ridges of bleb-like processes in the ureters and bladder; and, also in the ureters and bladder, mature urothelial cells with microridges or ruffles. The lining epithelia of the normal urethra and renal papilla may thus contribute cells with non-pleomorphic stubby microvilli to urine sediments, which cannot be differentiated by scanning electron microscopy alone from similar cells derived from urothelial neoplasms. However, the normal complement of cells lining the adult lower urinary tract does not include any with prolific, long, pleomorphic microvilli such as characterize transitional-cell carcinomas of the urothelium.

Adolescent↗
PubMed1981

Diffuse neoplastic change in urothelium from tumour-bearing human lower urinary tract.

In nine patients, who underwent radical cystectomy for transitional cell carcinoma of the bladder, detailed maps were prepared of results of the light microscopic findings and of the surface features of the urothelium as observed by scanning electron microscopy. Scanning electron microscopy revealed a more widespread distribution of residual neoplastic disease than suspected by light microscopy alone. This observation is based on the presence of abnormal cells carrying pleomorphic microvilli in association with other cells infrequently seen in normal healthy urothelium. Such changes have been directly related to neoplastic transformation in numerous experimental studies and have also been observed in human transitional cell carcinoma. This widespread distribution of these markers for neoplastic transformation explains the multiple recurrences of transitional cell carcinoma which characterises neoplastic disease of the bladder.

Adult↗