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Biomedical subjects

C Borek

Publications and source records attributed to C Borek.

At least 73 records · Page 4Linked to original sources
PubMed1981

Cellular transformation by radiation: induction, promotion, and inhibition.

Mammalian cell cultures offer powerful tools for evaluating qualitatively and quantitatively the oncogenic potential of radiation over a wide range of doses with particular importance at the low dose range that is relevant to human exposure and risk. Our studies have shown that early events in the process of radiation induced transformation in both rodent and human cells requires initial replication for fixation of transformation as a hereditary property of cells and further clonal expansion for full expression. Early events (fixation) are inhibited by cell-cell contact and high cell density but can be modified at low temperature where repair processes are slowed. Cell-cell contact and communication in tissue organization may be in part responsible for our findings that radiation oncogenesis induced in utero in hamsters is expressed at a lower frequency than that induced in vitro. Quantitative studies carried out on hamster embryo cells indicate that neutrons are more effective in their carcinogenic potential than x-rays but also more toxic, that splitting the dose of x-rays at low doses leads to enhanced transformation, but that at high doses protracted radiation has a sparing effect. At all dose ranges survival was increased by protracting the radiation dose, thus suggesting that different repair processes must be involved for survival and transformation. Similar observations were seen when the protease inhibitor Antipain was found to enhance transformation in rodent and human cells when present at the time of radiation, but was protective when added after radiation. Survival was not modified under any of those conditions, and Antipain did not affect DNA replication and repair. In our qualitative studies, once cells are transformed by radiation, they exhibit a wide range of structural and functional phenotypic changes, some of which are membrane-associated and are expressed within days after induction. Our current studies on nutritional and hormonal influences on radiation transformation indicate the following: Pyrolysate products from broiled protein foods act in synergism with radiation to produce transformation, whereas vitamin A analogs are powerful, preventive agents. Retinoids inhibit both x-ray-induced transformation and its promotion by TPA; these modifications (enhancement by TPA, inhibition by retinoids) are not reflected in sister chromatid exchanges, but are reflected in the level of membrane associated enzymes Na/K ATPase. Whereas retinoids modify late events (expression, promotion), we find that thyroid hormone plays a crucial role in the early phases of radiation and chemically induced transformation. Under hypothyroid conditions no transformation is observed. The addition of triiodothyronine at physiological levels results in a transformation rate that is dose-related. Our recent success in transforming human skin fibroblasts will enable quantitative and qualitative studies of radiation carcinogenesis in a system relevant to man.

Animals↗
PubMed1981

Protease inhibitors neither damage DNA nor interfere with DNA repair or replication in human cells.

Human fibroblasts were exposed to antipain or leupeptin at concentrations up to 2.5 mM and the presence of DNA damage and repair was assayed by several different methods. These did not reveal DNA damage or repair after exposure to either antipain or leupeptin, even in the presence of rat-liver microsomal S9 mix. Antipain also had no significant effects on the repair or replication of DNA after ultraviolet or X-irradiation. The demonstrated potentiation of radiation-induced transformation of human cells and the selective killing of repair-deficient cells by antipain must therefore occur by mechanisms that do not involve direct interaction of antipain with DNA.

Antipain↗
PubMed1981

The interaction of ionizing radiation and food pyrolysis products in producing oncogenic transformation in vitro.

Short term cultures of golden hamster embryo cells were exposed to X-irradiation and/or to 3-amino-1-methyl-5H-pyrido[4,3,-b]indole (Trp-P-2), a pyrolysis product of GL-tryptophan. Oncogenic transformation was scored following treatment with radiation and the pyrolysate, alone or in combination. Pre-treatment of the cells with 50 rad or 150 rad and subsequent exposure to 0.5 microgram/ml Trp-P-2, resulted in a higher transformation frequency as compared to that observed following exposure to the single agents. The enhanced frequency was related to the absorbed dose of radiation. The data suggest a synergistic interaction between X-rays and the pyrolysis product in their oncogenic action.

Animals↗
PubMed1981

Crucial role of thyroid hormone in x-ray-induced neoplastic transformation in cell culture.

Incubation of mouse embryo fibroblasts (C3H/10T1/2) in media depleted of thyroid hormone for 1 week rendered the cells completely resistant to the transforming action of an x-ray dose, 4 grays, that yields transformation frequencies (no. foci per surviving cells) of approximately 10(-3) in media supplemented with triiodothyronine (T3) (1 nM). Studies on the timing of the additions or removal of the hormone indicate that T3 was maximally effective when added 12 hr before irradiation and that progression from the time of irradiation to the appearance of foci (6 weeks) was independent of the presence or absence of the hormone. The dependence of x-ray-induced transformation on the concentration of T3 in the medium was virtually the same as that for augmentation of Na+,K+-ATPase activity. The latter effect was used as a measure of T3 induction of protein synthesis. A further indication of the involvement of protein synthesis in the process is the abolition of T3- and x-ray-dependent transformation by cycloheximide at a concentration (100 ng/ml) that inhibits 50% of protein synthesis. We propose that thyroid hormone induces the synthesis of a host protein that is an obligatory participant in x-ray-mediated transformation.

Animals↗
PubMed1981

Antipain and radiation effects on oncogenic transformation and sister chromatid exchanges in Syrian hamster embryo and mouse C3H/10T1/2 cells.

Depending on its time of addition to Syrian hamster embryo or mouse C3H 10T1/2 cells the protease inhibitor antipain (AP) can enhance, or reduce, radiation induced-oncogenic transformations. These opposing influences are not paralleled by changes in sister chromatid exchanges in either cell system. A 24 h treatment with 10 microM AP prior to, and during irradiation, with removal 10 min after irradiation results in greater than a two-fold increase in transformants. Conversely, a 24 h treatment beginning 10 min after irradiation results in about a two-fold decrease in transformants. The utility of AP as an agent for the reduction of tumorigenesis is brought into question, since quite short temporal differences in application can result in near five-fold differences in the frequencies of oncogenic transformations.

Animals↗
PubMed1981

Regulation of retinol-binding protein metabolism by glucocorticoid hormones in cultured H4II EC3 liver cells.

Studies were conducted to explore the effects of glucocorticoid hormones on the regulation of the metabolism of retinol-binding protein (RBP) by H4II EC4 rat hepatoma cells in culture. Cortisol, corticosterone, and the synthetic glucocorticoid analog dexamethasone all induced a 2- to 3-fold increase in accumulation of RBP. Half-maximal stimulation occurred at concentrations of dexamethasone in the range of 1-5 nM. Progesterone in the concentration range of 1-10 microM, inhibited the stimulatory effect of dexamethasone. Progesterone alone in this concentration range had no effect on RBP metabolism. By analogy with the studies of others, these observations with progesterone suggest that glucocorticoid receptors are involved in the effect of dexamethasone on RBP. As previously reported, RBP accumulated in the hepatoma cells when they were incubated in a medium free of serum and of vitamin A. The addition of retinol over a range from 3.5 nM to 3.5 microM stimulated a dose-dependent secretion of RBP from the cells into the medium. In longer experiments, retinol also stimulated the accumulation of RBP. Neither dexamethasone nor retinol had an effect on the accumulation or the cell to medium distribution of rat serum albumin or prealbumin at concentrations which were maximally stimulatory for RBP. When studied over a wide range of concentrations, retinol and dexamethasone incubated together produced approximately additive increases in the accumulation of RBP. Dexamethasone, moreover, did not affect the retinol-induced secretion of RBP. Thus, retinol and dexamethasone appear to function via different and independent mechanisms to regulate the metabolism of RBP by the liver cell.

Animals↗
PubMed1981

Nutritional and hormonal factors in the prevention of carcinogen-induced neoplastic development in vitro.

Cell cultures and in vitro oncogenic transformation offer a powerful tool for exploring conditions and compounds that may inhibit malignant transformation following exposure to environmental or therapeutic agents. We find, using rodent cell cultures, that retinoids inhibit radiation-induced transformation and eradicate the enhancing effect of tumor promotors. These protective effects of the retinoids are not mediated at a chromosomal level but are reflected at the cell membrane level via the membrane-associated transport enzyme Na/K-ATPase. Using these systems, we also find that hypothyroid condition is protective and that thyroid hormone T3 is essential for the induction of both radiation-induced and chemically induced carcinogenesis, and thus may also play a crucial role in cancer induction in vivo.

Animals↗
PubMed1981

Modification of sister chromatid exchanges and radiation-induced transformation in rodent cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and two retinoids.

Modification of sister chromatid exchanges and radiation-induced transformation in mouse C3H/10T 1/2 and Syrian hamster embryo cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and two retinoids, the trimethylmethoxyphenyl analog of N-ethyl retinamide and beta-all-trans-retinoic acid, has been studied. 12-O-tetradecanoylphorbol-13-acetate alone enhances, and retinoids alone reduce radiation-induced transformation. When both compounds were present, the retinoids not only reduced the oncogenic effects of radiation but completely eliminated the promoting effects of 12-O-tetradecanoylphorbol-13-acetate. These results were not paralleled by changes in sister chromatid exchange frequencies, indicating that, while sister chromatid exchanges may be useful as indicators of primary carcinogen mutagens, they may have little utility when secondary agents after the response of cells to a primary initiator.

Animals↗
PubMed1980

Thyroid hormone modulation of X ray-induced in vitro neoplastic transformation.

The direct oncogenic potential of X rays has been demonstrated by the in vitro neoplastic transformation of mammalian cells in culture, a technique which permits the study of oncogenesis in the absence of host-specific effects. Although several agents are known to modulate in vitro neoplastic transformation by X rays, little is known of the effects of hormones. We now describe experiments which show that the presence of thyroid hormone is necessary for in vitro neoplastic transformation by X rays in cells of an established mouse fibroblast culture (C3H/10T1/2) and in early-passage diploid hamster embryo cells.

Animals↗
PubMed1980

X-ray induced in vitro neoplastic transformation of human diploid cells.

Techniques have recently been developed to identify and score quantitatively neoplastic transformation caused by X rays in cultured cells derived from rodents. Because of their relevance to estimates of human cancer risk, it is clearly desirable to carry out similar experiments with cultured cells of human origin. The present report describes for the first time the neoplastic transformation in vitro of human diploid cells by X-ray irradiation into cells which can progress in vitro into advanced stages of neoplastic development, namely, to form colonies in agar and give rise to tumours when injected into nude mice.

Adult↗
PubMed1979

Scanning electron microscopy of differentiated liver cells transformed in vitro by chemical carcinogens.

A scanning electron microscopy study was carried out on differentiated liver cells transformed in vitro by three chemical carcinogens into cells that give rise to carcinomas. The results indicate that the transformed cells grow as a rule in tightly adherent monolayers but differ in topography. There is a tendency toward heterogeneity in cell shape compared to the normal and on the whole toward a larger number of surface microvilli in the malignant cell population. However, both in sparse and confluent cultures the topographic differences are often not striking enough to unequivocally distinguish single neoplastic cells from the normal.

Animals↗
PubMed1979

Conditions for inhibiting and enhancing effects of the protease inhibitor antipain on x-ray-induced neoplastic transformation in hamster and mouse cells.

Using cultured normal hamster embryo cells and the heterploid mouse C3H cell line 10T1/2, clone 8, we have studied the effect of the protease inhibitor antipain on x-ray-induced neoplastic transformation. We found in both cell systems that, while there was no effect on cell survival as compared to irradiated controls, the addition of antipain at a concentration of 6 microgram/ml to the cultures 24 hr prior to irradiation resulted in enhanced transformation as compared to the frequency in cultures exposed to radiation alone. Yet the addition of antipain to cultures 10 min after irradiation resulted in a decreased transformation rate. This decrease was not found when antipain was added to the mouse cells 24 hr after irradiation or to the hamster cells 48 hr after irradiation. These results suggest that the protease inhibitor antipain has more than one mechanism of action in modulating the fixation and expression of transformation by x-irradiation, possibly by the modification of DNA repair.

Animals↗