Thesis (M. Phil.)--University of Hong Kong, 1983.

Thesis (M.Phil.)--University of Hong Kong, 1983. / Also available in print.

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published_or_final_version / Biochemistry / Master / Master of Philosophy

Cell proliferation plays an important role in multistage chemical carcinogenesis. Again, several reports demonstrated that upregulation of metallothionein (MT) expression is associated with increased cell proliferation that may contribute to the pathogenesis of preneoplastic phenotype to frank malignancy. In this study, we evaluated the roles of early DNA damage, altered expressions of liver MT and Ki-67 nuclear antigen, and altered hepatic levels of zinc (Zn) and copper (Cu) on cell proliferation and the progression of hepatocarcinogenesis through premalignant, late premalignant and malignant transformation phases in male Sprague-Dawley rats. We have further studied the association between MT expression and cell proliferation in hepatocarcinogenesis. There was substantial induction of DNA single-strand breaks (SSBs) (P < 0.001) and development of hepatocellular premalignant lesions along with significant decrease in hepatic levels of Zn and increase in Cu content following a single, necrogenic, intraperitoneal (i.p.) injection (200 mg/Kg body weight) of diethylnitrosamine (DEN) at week 4 of the experimental protocol. Moreover, DEN + phenobarbital (PB)-treatment significantly elevated MT-, Ki-67-, and BrdU-immunoexpressions along with their immunolabeling indices. Furthermore, positive correlations between MT- and Ki-67- labeling (P = 0.0006) at various time intervals, as well as, between MT immunoreactivity and 5'-bromo-2'-deoxyuridine-labeling index (BrdU-LI) (P = 0.0007) indicate that, MT expression might be associated with Ki-67 expression and cell proliferation thereby. The study suggests that DEN treatment may lead to alteration of Zn and Cu levels resulting in early DNA damage along with elevation of MT expression that may ultimately lead to hepatic cell proliferation. The results thus provide evidence in support of the role of MT as a potential positive regulator of cell growth during the early stages of hepatocellular transformation in rats.

No description available.

We previously observed that postnatal exposure of mice to the procarcinogen 4-aminobiphenyl (ABP) produced liver tumors only in wild-type males, while arylamine N-acetyltransferase deficient males and females of either strain were protected. Others have also observed a sex difference in liver tumors in mice using the procarcinogen diethylnitrosamine (DEN). Reasons for these sex and strain differences are unclear, but differences in acute hepatotoxicity and inflammation may be involved. In this thesis we found that neither ABP nor DEN produced overt hepatotoxicity in postnatally exposed mice, and only DEN caused an increase in levels of the pro-inflammatory cytokine interleukin-6 but was not sex-dependent. The lack of sex difference suggests that sex hormone modulation of inflammation following sexual maturation might favour growth of initiated cells in males. However, the lack of detectable inflammation following ABP exposure may be due to localized responses, or that inflammation may be a DEN-specific effect.

We previously observed that postnatal exposure of mice to the procarcinogen 4-aminobiphenyl (ABP) produced liver tumors only in wild-type males, while arylamine N-acetyltransferase deficient males and females of either strain were protected. Others have also observed a sex difference in liver tumors in mice using the procarcinogen diethylnitrosamine (DEN). Reasons for these sex and strain differences are unclear, but differences in acute hepatotoxicity and inflammation may be involved. In this thesis we found that neither ABP nor DEN produced overt hepatotoxicity in postnatally exposed mice, and only DEN caused an increase in levels of the pro-inflammatory cytokine interleukin-6 but was not sex-dependent. The lack of sex difference suggests that sex hormone modulation of inflammation following sexual maturation might favour growth of initiated cells in males. However, the lack of detectable inflammation following ABP exposure may be due to localized responses, or that inflammation may be a DEN-specific effect.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

O Carcinoma de células escamosas é o tipo histológico mais comum das neoplasia esofágicas no mundo.Tem sua origem no epitélio escamoso do esôfago e é achado com maior frequência no terço médio do órgão. A carcinogênese esofágica é um processo que resulta do acúmulo de mutações envolvendo diferentes genes, como o TP53. Este está mutado em mais de 50% dos tumores esofágicos. Inúmeras pesquisas têm sido direcionadas para restaurar a função da proteína p53, as quais resultaram na descoberta da PRIMA-1. Neste estudo, foram pesquisados possíveis efeitos protetores da PRIMA-1 no epitélio do esôfago sob efeito carcinogênico químico evitando o desenvolvimento neoplásico e induzindo involução da carcinogênese. Para testar esta hipótese, realizamos estudo, com utilização da PRIMA-1, em um modelo experimental de carcinogênese esofágica por dietilnitrosamina com indução de carcinoma de células escamosas. O estudo experimental foi realizado com 6 grupos de animais, onde os grupos I e II foram considerados controles, sendo diferenciados por uso da PRIMA-1. E os grupos III e IV, e Va e Vb, foram considerados estudos, os quais receberam dietilnitrosamina por 3 dias consecutivos semanalmente. Enquanto os grupos III e IV, foram diferenciados pelo uso de PRIMA-1 prévio ao início da carcinogênese, os grupos Va e Vb, foram diferenciados pelo uso de PRIMA-1 ao final da carcinogênese. O estudo apresentou data de eutanásia com colheita de peças esofágicas, aos 150 dias, grupos I, II, III e IV, e 180 dias, grupos Va e Vb, devido ao período de observação após uso tardio da PRIMA-1. Não foram detectadas alterações histopatológicas nos grupos controles, grupo I (DEN-/PRIMA-) e II (DEN-/PRIMA+). Não foram detectadas diferenças nas alterações histopatológicas estatisticamente significativas entre os grupos III (DEN+/PRIMA-) e IV (DEN+/ PRIMA+ inicial). Foram detectadas diferenças nas alterações histopatológicas estatisticamente significativas entre os grupos Va (DEN+/PRIMA-) e Vb (DEN+/PRIMA+ tardio). A análise imunohistoquímica do p53 evidenciou diferença estatística nos grupos que utilizaram a PRIMA-1, em relação as seus controles. A análise imunohistoquímica do Ki-67 demonstrou diferença estatística somente entre os dois grupos controles. Conclue-se que a PRIMA-1 teve efeito de redução da gravidade histopatológica em esôfago de camundongos previamente induzidos a carcinogênese com dietilnitrosamina e aumento da expressão imuno-histoquímica da proteína p53. / The esophageal squamous cell carcinoma is the most common histological type in the world. It is origin in the squamous epithelium of the esophagus and is found more often in the middle third of the organ. The esophageal carcinogenesis is a process that results from the accumulation of mutations in different genes such as TP53. This is mutate in more than 50% of esophageal tumors. Numerous researches have been directed to restore the function of the p53 protein, which resulted in the discovery of PRIMA-1. In this study, we investigated the possible protective effects of PRIMA-1 in the epithelium of the esophagus under chemical carcinogenic effect preventing neoplastic development and inducing regression of carcinogenesis. To test this hypothesis, a study with use of PRIMA-1 in an experimental model of esophageal carcinogenesis induced by diethylnitrosamine with squamous cell carcinoma. The experimental study was performed wth six groups of animals, where the groups I and II were considered controls being differentiated by the use of PRIMA-1. And the groups III and IV, and Va and Vb, were considered studies, which received diethylnitrosamine for 3 consecutive days weekly. While the groups III and IV, were differentiated by the use of PRIMA-1 prior to the beginning of carcinogenesis, the Va and Vb groups were differentiated by the use of PRIMA-1 at the end of carcinogenesis. The study presented date of euthanasia with crop esophageal parts, at 150 days, groups I, II, III and IV, and 180 days, Va and Vb groups because of the observation period after late use of PRIMA-1. Histopathological changes were detected in the control groups, Group I (DEN-/PRIMA-) and II (DEN-/PRIMA+). There were no statistically significant differences in pathological changes between the groups III (DEN+/PRIMA-) and IV (DEN+/PRIMA- first). Differences were found in statistically significant histopathological changes between Va groups (DEN+/PRIMA-) and Vb (DEN+/PRIMA+ late). Immunohistochemical analysis of p53 showed a statistically significant difference in the groups using PRIMA-1, compared to their controls. Immunohistochemical analysis of Ki-67 showed statistical difference only between the two control groups. It concludes that the PRIMA-1 was reduced by histopathological effect of gravity previously induced esophageal carcinogenesis in mice diethylnitrosamine and increased immunohistochemical expression of p53 protein.