Cocarcinogenesis.
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2-Acetylaminofluorene↗
Biomedical subjects
A Sivak
Publications and source records attributed to A Sivak.
Overview and status of in vitro transformation.
The development of standardized assay procedures has permitted the exploitation of cell culture systems as bioassay tools for the detection of chemical carcinogens. These systems fall generally into 3 classes: diploid cell strains, Syrian hamster embryo cells; cell lines, mouse BALB/c-3T3 and mouse C3H-10T1/2; and cells+virus, Fischer rat cells infected with Rauscher leukemia virus and Syrian hamster embryo cells infected with adenovirus. The results accumulated to date show a good correlation between transformation response in cell culture and carcinogenicity of chemicals in whole animal studies. The major advantages of these systems are their relative brevity (10 days-6 weeks) and resultant low costs, their agreement with whole animal bioassays, and their direct biological relevance to the carcinogenic process. The present major disadvantages are the uncertain nature of the metabolic capabilities of the target cells and the lack of a metabolic activation system that is reliable and adaptable for routine bioassays. The development of epithelial cell systems such as breast, liver, lung, and skin may solve the problem of carcinogen metabolism as well as provide target cells that are representative of major organ sites for cancer in man. The rational use of cell culture bioassays for neoplastic transformation is a valuable component of the toxicological armamentarium to assess risk to humans from exposure to chemicals.
Adenoviridae↗
Zinc deficiency and methylbenzylnitrosamine-induced esophageal cancer in rats.
Dietary zinc deficiency increases the incidence of and shortens the lag time for induction of esophageal tumors in rats by methylbenzylnitrosamine (MBN). Groups of control and zinc-deficient outbred Charles River CD rats were given 24, 17, 8, or 4 doses of MBN, administered twice weekly by intragastric intubation at doses of 2 mg/kg body weight. Between 58 and 93 days after the beginning of treatment, all rats were killed and examined. The frequency of esophageal tumors in the zinc-deficient groups was significantly higher than in the corresponding control groups. Following ip injection of [methyl-14C]MBN, DNA and RNA of esophagus and liver were more noticeably labeled than kidney, lung, and small intestine, which exhibited only modest labeling. In vitro incubation with [14C]MBN of tissue slices from esophagus, liver, kidney, and small intestine produced similar results. This pattern correlates well with the results of our studies of MBN-induced esophageal tumorigenesis.
Animals↗
Induction of cell division in BALB/c-3T3 cells by phorbol myristate acetate or bovine serum: effects of inhibitors of cyclic AMP phosphodiesterase and Na+-K+-ATPase.
Cell division is induced in stationary cultures of BALB/c-3T3 mouse embryo cells without renewal of medium by addition of the tumor promoter, phorbol myristate acetate (PMA), or bovine serum. The addition of dbcAMP (10(-3) M) or other inhibitors of cAMP phosphodiesterase, papaverine (6.7 X 10(-6) M), Persantin (5 X 10(-5) M) or RO-20-1724 (10(-4) M), prevents cell replication induced by PMA or serum. In contrast, ouabain (10(-4) M) and N,N'-dicyclohexylcarbodiimide (10(-5) M), inhibitors of Na+-K+-ATPase activity, block the PMA-stimulated effect but do not inhibit serum-stimulated cell division. Several stages in the cell cycle are sensitive to dbcAMP addition. One is early in the G1 phase at the time of reinitiation of the cell cycle from a stationary (Go) phase, a second is associated with the G1-S transition, and a third with passage of cells from a post-S phase to mitosis. Based on observations of early morphological changes, responses of plasma membrane enzymes and effects of enzyme inhibitors, the stimulation of cell division in BALB/c-3T3 cells by PMA or serum appears to involve several membrane functions which may act in a cooperative manner.
3',5'-Cyclic-AMP Phosphodiesterases↗
Comparison of the biological activity of the tumor promotor phorbol myristate acetate and a metabolite, phorbolol myristate acetate, in the cell culture.
Phorbolol myristate acetate, a metabolite of the tumor promotor phorbol muristate acetate in mouse skin, has one-fiftieth the potency of the parent molecule for the induction of cell division in stationary cultures of BALB/c-3T3 mouse embryo cells. Similarly, in a mixed cell culture assay devised for detection of tumor-promoting agents, phorbolol myristate acetate exhibited only a small fraction of the activity of unmetabolized phorbol ester. The results indicate that the biological activity of phorbol esters either does not require metabolic conversion or is converted by the cells used in this system and that phorbolol myristate acetate would be a tumor promotor of low potency for mouse skin compared to phorbol myristate acetate.
3T3 Cells↗
Regression kinetics of mouse skin papillomas.
The persistence and proliferation rate of mouse skin papillomas were studied in HA/ICR mice initiated with 7,12-dimethylbenz(a)anthracene and promoted three times weekly with phorbol myristate acetate. When the promoter treatments were stopped, rapid (half-time, 24 days) and slow (half-time, greater than 140 days) components of papilloma regression were observed. When the promoter dose was increased, the major effect was an increase among the rapidly regressing papillomas. Increases in the epidermal pulse-labeling index and the number of dermal inflammatory cells produced by phorbol myristate acetate in normal skin were reversible when the phorbol myristate acetate was stopped, but high pulse-labeling index values in papillomas were not reversible. Antithymocyte serum had no effect on regression, although ethylphenylpropriolate, a nonpromoting irritant, slowed the regression sufficiently to increase the half-time from 24 to 57 days. The action of the promoter in overcoming the regression tendency of the papillomas may explain certain features of the role of nonspecific irritation and the importance of promotion frequency in determining tumor yield.
9,10-Dimethyl-1,2-benzanthracene↗
The effect of aging and interval between primary and secondary treatment in two-stage carcinogenesis on mouse skin.
Two-stage carcinogenesis experiments on mouse skin (female ICR/Ha Swiss mice) were done by initiating mice at three age levels (6, 44, and 56 weeks) and promoting after a 2-week interval. In another series, mice were initiated at age 6 weeks, and three time intervals (2, 36, and 56 weeks) were used between initiation and promotion. The initiating agent was 7, 12-dimethylbenz(a)anthracene and the promoting agent was phorbol myristate acetate in all experiments. The results showed a general decrease in tumor production with increasing age at the time of promotion. However, the initiating effect persisted even when the interval between initiation and promotion was 56 weeks.
Aging↗
Induction of unusual tumors in vivo by rat fibroblasts treated with diepoxybutane.
Diploid rat embryo fibroblasts exposed to diepoxybutane, a carcinogenic alkylating agent, exhibited chromosome aberrations and a high proportion of tetraploid cells immediately after treatment. Following a prolonged period of carcinogen-free growth, a diepoxybutane-treated cuture showed morphologic transformation and produced transplantable malignant tumors upon inoculation into neonatal rats. Morphologic and histochemical characteristics of the tumors derived from cells exposed to diepoxybutane in culture were also found in tumors of animals exposed directly to this carcinogen. The tumors from diepoxybutane-treated cell cultures were composed of highly anaplastic giant cells with centrally located cytoplasmic inclusions. Clusters of identical cells were found in some of the tumors obtained by direct in vivo treatment of rats with diepoxybutane. The morphologic similarities of these tumors suggest that similar processes of cellular evolution to malignancy occur in cell culture systems and in vivo.
Alkylating Agents↗