Inhibition of the alkylation of nucleic acids and of the metabolism of 1,2-dimethylhydrazine by aminoacetonitrile

Pretreatment of rats with aminoacetonitrile inhibited the metabolism of [¹⁴C]1,2-dimethylhydrazine to ¹⁴CO₂ and increased the expiration of [¹⁴C]-azomethane. Alkylation of nucleic acids following administration of 1,2-dimethylhydrazine was reduced by aminoacetonitrile to 5% of control levels in liver, 11% of control levels in kidney and 43% of control levels in colon.     

Inhibition of carcinogenesis by retinoids.

Experimental investigations of the antineoplastic effects of retinoids are reviewed in this paper. In vitro studies have shown that the hyperplastic and metaplastic response to chemical carcinogens of mouse prostate cultures is suppressed by the addition of retinoids to the culture medium, that retinoids can partially inhibit the morphologic transformation of 10T 1/2 cells by physical or chemical carcinogens, and that the growth of some non-neoplastic and some neoplastic cell lines can be inhibited by retinoids. In vivo studies have shown that retinoids can suppress papilloma and carcinoma development (the promotion phase) in the two-stage skin carcinogenesis assay, inhibit mammary and bladder carcinogenesis in mice and rats, and inhibit the growth of some transplantabletumor lines. So far it has not been possible to inhibit predictably tumour formation in the intestinal tract or the respiratory tract of rodents. Almost all the synthetic retinoids have a higher therapeutic index than the natural retinoids in the prevention or treatment of cancer.     

细胞衰老与肿瘤发生

细胞衰老（cell senescence）是指细胞在信号转导作用下不可逆地脱离细胞周期并丧失增殖能力后进入的一种相对稳定的状态。细胞衰老有增殖衰老与早熟衰老两种形式：增殖衰老由端粒缩短激发的信号转导激发,与TP53/CDKN1a（p21^WAF-1/Cip1）/pRB/E2F信号通路密切相关;早熟衰老由细胞内在或外在急慢性应激信号引发,与TP53/CDKN1a（p21^WAF-1/Cip1）/pRB/E2F或CDKN2a（p16^ink4A）/pRB/E2F信号通路相关。目前研究已经证实早熟衰老是细胞在癌变过程中的天然屏障,是继DNA修复、细胞凋亡后的第三大细胞内在抗癌机制,在机体防止肿瘤形成中起重要作用。     

Studies on lung tumours. III. Oxidative metabolism of dimethylnitrosamine by rodent and human lung tissue.

The oxidative metabolism of the carcinogen dimethylnitrosamine (DMN) was studied in mouse, rat, hamster and human respiratory tissue. [14C]DMN was purified by Dowex-1-bisulfite column chromatography to remove a contaminant (probably [14C]formaldehyde) interfering with the enzyme assay. Since formaldehyde and methyl carbonium ions - yielding methanol with water - are considered to be the primary products of DMN metabolism, tissue slices were assayed for the production of [14C]CO2 from 14C-labelled methanol, formaldehyde, formate, and DMN. Oxidation of formaldehyde to formate was not, but oxidation of formate to CO2 was very much rate-limiting. This rate-limiting step was circumvented by introducing quantitative chemical oxidation of formate to CO2 by mercury(II)chloride following the enzymic reaction. Since oxidation of methanol to CO2 proved to be insignificant, production of CO2 from DMN by lung tissue enzymes and HgCl2 may serve as a parameter for N-demethylating activity and the production of the suspected carcinogenically active methyl carbonium ions. The DMN-N-demethylating activities of lung tissue slices of two mouse strains with widely different susceptibilities to formation of lung adenomas by DMN differed significantly, but the difference seemed too small to explain the divergence in tumourigenic response. The enzymatic activities decreased in hamster bronchus, hamster trachea, hamster lung, GRS/A mouse lung, C3Hf/A mouse lung, human lung, Sprague-Dawley rat lung, in that order. The reported resistance of the hamster respiratory system to tumour induction by DMN may therefore not be due to poor DMN-N-demethylating capacity.     

Liver nucleotides in acute experimental liver injury induced by dimethylnitrosamine and by thioacetamide

1. The concentrations of the nicotinamide-adenine dinucleotides in rat liver have been determined at intervals during the period 1-24hr. after feeding adult female rats with dimethylnitrosamine or thioacetamide. 2. The administration of dimethylnitrosamine resulted in a rapid decrease in the sum of NAD+NADH(2). This sum was decreased by 40% 3hr. after dosing. 3. Dimethylnitrosamine administration also produced an overall decrease in the NADP+NADPH(2) but this decrease was not so early nor as marked as that found for NAD+NADH(2). 4. The changes produced by thioacetamide were quite different from those obtained with dimethylnitrosamine. Thioacetamide produced a temporary rise in the NAD+NADH(2) followed by a small fall. The NADP+NADPH(2) was little changed in the early hours after dosing with thioacetamide but had decreased by approx. 15% 18hr. after administration. 5. These changes are discussed in terms of the known hepatotoxic actions of dimethylnitrosamine and thioacetamide, and are compared with previously reported changes found after the administration of carbon tetrachloride.     

Investigations into the hepatic metabolism of dimethylnitrosamine in the rat.

In this paper we report the detection and identification of methanol as an intermediate formed during both the $\text{in vivo}$ and the $\text{in vitro}$ metabolism of dimethylnitrosamine (DMN) in the rat. Methanol was formed in both hepatic 10,000 $\text{g}$ av. supernatant and washed microsomal fractions over a wide range of nitrosamine substrate concentrations. Furthermore the total amounts of methanol and formaldehyde formed largely accounted for the metabolic fate of both methyl moieties of DMN. Although a number of inhibitors of alcohol metabolism profoundly inhibited the hepatic metabolism of DMN they had little effect on the activities of two mixed function oxidase dependent enzymes. The results suggest that DMN and possibly other dialkylnitrosamines are degraded by enzymic pathway(s) not dependent on cytochrome P-450.     

The absorption and metabolism in rats of small oral doses of dimethylnitrosamine. Implication for the possible hazard of dimethylnitrosamine in human food.

1. Groups of rats were given one dose of the carcinogen dimethylnitrosamine by gastric intubation. The dose was varied between 10mg/kg body wt. and 1 microgram/kg body wt. 2. The dose was rapidly absorbed. 3. The methylation of liver DNA resulting from the administration of this carcinogen was proportional to dose. This suggests that small doses are absorbed from the gut with no more loss than large doses. 4. As the dose was decreased there was a disproportionately greater decrease in the alkylation of kidney DNA, and when the dose was less than 40 microgram/kg body wt. the methylation of kidney DNA was no longer detectable. This possibly explains why small amounts of dimethylnitrosamine in the diet do not induce kidney tumours. 5. Comparison of the relative alkylation of liver DNA and kidney DNA resulting from an oral and from an intravenous dose of dimethylnitrosamine suggest that small amounts of dimethylnitrosamine absorbed into the portal blood from the gut are completely metabolized by the liver and do not enter the general circulation. 6. The implications of these results for the possible hazard of dimethylnitrosamine in human food is discussed.     

Cellular targets and host genes in multistage carcinogenesis

Recent studies indicate that although cellular DNA is the critical target in the action of initiating carcinogens, specific membrane-associated receptors mediate the actions of certain tumor promoters. A stereochemical model is presented to explain how three different types of tumor promoters (phorbol esters, indole alkaloids, and polyacetates) can interact with the same class of cellular receptors. Multistage chemical carcinogenesis might involve progressive alterations in the expression of cellular DNA sequences homologous to oncogenes and regulatory sequences in certain retroviruses. We found that the oncogene c-mos is not rearranged or expressed in a series of carcinogen-transformed murine C3H 10T112 cells. These cells do express, however, a unique set of poly(A)+ RNAs that contain sequences homologous to the Moloney leukemia virus long terminal repeat sequence. Studies are in progress to determine the significance of this finding with respect to the carcinogenic process.     

Cellular search migrations in normal development and carcinogenesis

This review describes the large group of morphogenetic processes designated as search migrations. Search migrations typically include two stages: i) search, when a group of cells or of the cytoplasmic processes migrate over the cell-free spaces, and ii) choice, the stage when migrating cells reach specific loci where they stop and undergo specific differentiations induced by local factors such as cell-cell contacts and humoral agents. Migrating cells that do not meet their targets usually undergo apoptosis. Numerous examples of search migrations range from gastrulation to formation of axon-muscle connections. Critical stages of carcinogenesis such as acquisition of cell ability for invasion may be regarded as the genetic aberration of normal search migration: cancer cells perform an endless search but cannot make final choice.     

Arsenic possibly influences carcinogenesis by affecting arginine and zinc metabolism

The role of arsenic in carcinogenesis is controversial. There is no doubt arsenic can influence carcinogenesis under certain conditions. However, a review of the findings relating arsenic to cancer indicates that arsenic mainly affects carcinogenesis indirectly by influencing other metabolic systems (i.e., immune system) or nutrients (i.e., arginine, zinc) that may have a more direct role in the carcinogenic process. Depending upon the level of exposure, arsenic can either inhibit or activate interferon, an inhibitor of virus replication. Furthermore, arsenic can apparently inhibit some virusinduced tumorigenesis. However, once a tumor is initiated, arsenic enhances tumor growth, possibly by affecting the immune response. Recent experiments in our laboratory demonstrated that arsenic metabolically interacts with arginine and zinc, both of which apparently influence the immune response. Arsenic evidently has a role that strongly influences the metabolism of arginine, which is an immunostimulatory amino acid. Furthermore, the effect of arsenic on arginine metabolism is apparently modified by the zinc status of the animal. Because arsenic can apparently affect cancer development through several indirect or direct mechanisms, probably the only general conclusion that can be made about arsenic and cancer is that arsenic, depending upon dosage, route of administration, and chemical form, modifies the induction or development of some tumors.     

Cellular and molecular effects of vitamin D on carcinogenesis

Epidemiologic data suggest that the incidence and severity of many types of cancer inversely correlates with indices of vitamin D status. The vitamin D receptor (VDR) is highly expressed in epithelial cells at risk for carcinogenesis including those resident in skin, breast, prostate and colon, providing a direct molecular link by which vitamin D status impacts on carcinogenesis. Consistent with this concept, activation of VDR by its ligand 1,25-dihydroxyvitamin D (1,25D) triggers comprehensive genomic changes in epithelial cells that contribute to maintenance of the differentiated phenotype, resistance to cellular stresses and protection of the genome. Many epithelial cells also express the vitamin D metabolizing enzyme CYP27B1 which enables autocrine generation of 1,25D from the circulating vitamin D metabolite 25-hydroxyvitamin D (25D), critically linking overall vitamin D status with cellular anti-tumor actions. Furthermore, pre-clinical studies in animal models has demonstrated that dietary supplementation with vitamin D or chronic treatment with VDR agonists decreases tumor development in skin, colon, prostate and breast. Conversely, deletion of the VDR gene in mice alters the balance between proliferation and apoptosis, increases oxidative DNA damage, and enhances susceptibility to carcinogenesis in these tissues. Because VDR expression is retained in many human tumors, vitamin D status may be an important modulator of cancer progression in persons living with cancer. Collectively, these observations have reinforced the need to further define the molecular actions of the VDR and the human requirement for vitamin D in relation to cancer development and progression.