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Biomedical subjects

C Borek

Publications and source records attributed to C Borek.

At least 55 records · Page 3Linked to original sources
PubMed1985

Thyroid hormone modulation of transformation induced by Kirsten murine sarcoma virus.

We have investigated the effect of triiodothyronine (T3) on the transformation of normal rat kidney (NRK) cells by the Kirsten strain of murine sarcoma virus (Ki-MSV). When NRK cells were grown and infected with Ki-MSV in medium lacking T3, the yield of transformed foci was about one-half that observed in the cultures supplemented with T3. Individual foci appeared somewhat later in cells grown out in medium devoid of T3. The yield of Ki-MSV released from transformed NRK cells was lower when these cells were maintained in T3-depleted medium. The results cannot be attributed to cell growth modification by T3. Normal and Ki-MSV-transformed NRK cells grew equally well in mono-layer culture in medium containing or lacking T3. Selective maintenance and removal of T3 during various phases of the transformation process indicated that T3 exerted its maximum effect on transformation rates when added to the medium 24 h prior to virus infection. T3 was less effective in modulating transformation when added simultaneously with virus infection and was ineffective if added 24 h after virus infection. The results indicate that thyroid hormone is a required factor for optimal transformation by Ki-MSV and that the hormone exerts its effects during the early phase of Ki-MSV-induced transformation.

Animals↗
PubMed1984

Inhibition of malignant transformation in vitro by inhibitors of poly(ADP-ribose) synthesis.

Malignant transformation in vitro of hamster embryo cells and mouse C3H 10T 1/2 cells by x-rays, ultraviolet light, and chemical carcinogens was inhibited by benzamide and by 3-aminobenzamide at concentrations that are specific for inhibition of poly(ADP-ribose) formation. These compounds slow the ligation stage of repair of x-ray and alkylation damage but not of ultraviolet light damage. At high concentrations they also inhibited de novo synthesis of DNA purines and DNA methylation by S-adenosylmethionine. The suppression of transformation by the benzamides is in striking contrast to their reported effectiveness in enhancing sister chromatid exchange, mutagenesis, and killing in cells exposed to alkylating agents. Our results suggest that mechanisms regulating malignant transformation are different from those regulating DNA repair, sister chromatid exchange, and mutagenesis and may be associated with changes in gene regulation and expression caused by alterations in poly(ADP-ribosyl)ation.

Animals↗
PubMed1984

Methylating and ethylating carcinogens have different requirements for poly(ADP-ribose) synthesis during malignant transformation.

Transformation of mouse C3H 10T1/2 cells by various alkylating carcinogens can be modulated by inhibiting poly(ADP-ribose) synthesis with a low concentration of 3-amino-benzamide, which induces no additional toxicity or reported side effects. Transformation by methylating agents was decreased by 3-aminobenzamide, whereas transformation by ethylating agents was increased. These results confirm earlier work on transformation by methylating agents, X-rays and u.v. light. Transformation by ethylating agents, however, appears to proceed by a different mechanism.

Alkylating Agents↗
PubMed1984

Inhibition of X-ray- and ultraviolet light-induced transformation in vitro by modifiers of poly(ADP-ribose) synthesis.

Neoplastic transformation in vitro of hamster embryo cells and mouse C3H 10T1/2 cells by X rays and ultraviolet light was suppressed by benzamide or 3-aminobenzamide, agents which inhibit poly(ADP-ribose) polymerization. Suppression was observed under conditions in which the inhibitors reduce poly(ADP-ribose) polymerization by about 75% and increase sister chromatid exchange frequencies, but have no influence on repair of X-ray and uv damage and reportedly have no detectable side effects on nucleotide precursor metabolism. These findings suggest that the mechanisms regulating neoplastic transformation differ from those regulating mutagenesis and sister chromatid exchanges and are mediated via alterations in poly(ADP-ribosylation), causing changes in gene control and expression.

Animals↗
PubMed1983

X rays may be twice as potent as gamma rays for malignant transformation at low doses.

The introduction in the 1950s of 60Co teletherapy units and megavoltage X-ray accelerators for radiotherapy prompted several studies which showed that the relative biological effectiveness (RBE) of orthovoltage X rays, compared with 60Co gamma rays, was approximately 1.1-1.2 (refs 1, 2). Subsequently, radiation therapists confirmed that the effect of established treatment protocols using orthovoltage X rays could be duplicated with the higher energy radiation by increasing the dose by approximately 10%, when radiation doses are of the order of tens of grays (or thousands of rads). The dependence of biological effectiveness on photon energy led to recommendations in which the quality factor, Q, which is an RBE for radiation protection purposes, was set at unity for X and gamma rays as well as for electrons or other directly ionizing particles having a linear energy transfer (LET) of less than 3.5 ke V microns-1. Over the past decade, however, several studies have shown differences in RBE between various low-LET radiations having LET values within the range designated for standard radiation. Underbrink et al. found an RBE for orthovoltage X rays relative to 60Co gamma rays of approximately 2 at 0.04 Gy, for induction of pink mutations in the stamen hairs of Tradescantia. Schmidt et al. scored chromosome aberrations in human lymphocytes, and at 0.25 Gy found the RBE of 200-k Vp X rays relative to 3-MeV electrons to be also approximately 2. Here we have compared 60Co gamma rays and orthovoltage X rays over the dose range 0.03-1.5 Gy using malignant transformation in mammalian cells in vitro as an end point. Our findings indicate that whereas the transformation incidence seems similar for X and gamma rays at high doses, the malignant potential of X rays is about twice that of gamma rays at 0.03 Gy.

Animals↗
PubMed1983

Critical role played by thyroid hormone in induction of neoplastic transformation by chemical carcinogens in tissue culture.

Incubation of primary cultures of hamster embryo cells (HEC) or mouse fibroblasts (C3H/10T1/2 cells) in media depleted of thyroid hormones does not alter cell growth or survival but renders the cells resistant to neoplastic transformation by benzo[a]pyrene (B[a]P) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), carcinogens which yield transformation rates of 10(-4)-10(-2) in media supplemented with triiodothyronine (T3). In C3H/10T1/2 cells, the times of addition or removal of the hormone indicate that T3 exerts maximum effect when added 12 hr prior to treatment with B[a]P and that the progression of transformation from the time of initiation by the carcinogen to full expression and the appearance of transformed foci was independent of the presence or absence of the hormone in the medium. Dependence of transformation on T3 concentration in the medium was observed over the physiological range of 1 pM to 100 nM in C3H/10T1/2 cells treated with B[a]P. These results were similar to our previous findings on the T3 dose-related induction of radiogenic transformation and of Na+,K+-ATPase activity. The latter effect was used as a measure of T3 induction of protein synthesis. A further indication of the potential involvement of protein synthesis in T3 action is the suppression of T3- and B[a]P-dependent transformation by cycloheximide at concentrations that inhibit protein synthesis by approximately equal to 50% in the C3H/10T1/2 cells. We suggest that thyroid hormone induces the synthesis of a host protein that plays a key role in neoplastic transformation by direct-acting chemical carcinogens and by those requiring metabolic activation. In our previous studies, similar T3-dependent mechanisms were implicated in radiogenic transformations.

Animals↗
PubMed1983

Modifiers of free radicals inhibit in vitro the oncogenic actions of x-rays, bleomycin, and the tumor promoter 12-O-tetradecanoylphorbol 13-acetate.

Using short-term cultures of hamster embryo cells, we have examined the effects of the free-radical scavenger superoxide dismutase (superoxide:superoxide oxidoreductase, EC 1.15.1.1) and the enzyme catalase (hydrogen-peroxide:hydrogenperoxide oxidoreductase, EC 1.11.1.6) on x-ray- and bleomycin-induced transformation and on the enhancement of radiogenic transformation by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA). We find that superoxide dismutase inhibits (i) transformation induced by x-ray and bleomycin and (ii) promotional action of TPA in vitro. The results suggest that the oncogenic action of x-rays and bleomycin and the enhancement of oncogenic transformation by TPA are mediated in part by free radicals. The findings also suggest that superoxide dismutase can serve as an inhibitor of oncogenesis and that its actions, as seen in this in vitro system, are most predominantly on inhibiting late events in the progression of cellular transformation--those associated with promotion.

Animals↗
PubMed1983

Critical biochemical and regulatory events in malignant transformation in vitro.

Oncogenic transformation of hamster embryo cells and mouse C3H 10T1/2 can be modified by a variety of agents and conditions which alter events at early stages of initiation and at later stages of promotion. Inhibition of poly(ADP-ribose) synthesis by low concentrations of benzamide and 3-aminobenzamide inhibits the induction of transformation by ultraviolet light, X-rays, and chemical carcinogens as well as inhibiting the enhancement of transformation by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). The suppression of transformation by the benzamides is observed under conditions where the inhibitors reduce poly(ADP-polymerization) by about 75%, have no influence on damage induced by X-rays or alkylating chemicals and enhance sister chromatid exchanges. A modification of the physiological state of the cells by rendering them hypothyroid also results in an inhibition of transformation by radiation and chemical carcinogens and a suppression of promotion by teleocidin and TPA. When thyroid hormone is added to the medium radiogenic transformation and its dramatic enhancement by the tumor promoters is observed, with teleocidin being over 100 times as effective as a promotor as TPA. Our results suggest that mechanisms regulating initiation and promotion are associated with alterations in poly(ADP-ribosylation), causing changes in gene control and expression and may differ from those associated with the induction of sister chromatid exchanges. The results also suggest that genetic events taking place in both the early events (initiation) and late events (promotion) in malignant transformation are highly dependent on the presence of thyroid hormones.

Animals↗
PubMed1983

Poly(ADP-ribose): spectator or participant in excision repair of DNA damage.

Inhibition of poly(ADP-ribose) synthesis by 3-aminobenzamide in various human and hamster cell types influenced the responses to DNA damage from methyl methanesulfonate (MMS), but not from UV light. Excision of the major alkylation products and pyrimidine dimers was unaffected by 3-aminobenzamide. After exposure of cells to methyl methanesulfonate, 3-aminobenzamide increased the strand break frequency in all cell types studied, but stimulated repair replication only in lymphoid and HeLa cells, suggesting these are independent effects. 3-Aminobenzamide also inhibited the pathway for de novo synthesis of DNA purines, suggesting that some of its effects, particularly on repair replication, may be due to disturbance of precursor pathways. 3-Aminobenzamide stimulated sister chromatid exchange formation and mutagenesis but inhibited transformation, suggesting that some of these endpoints involve ADP-ribosylation by ways other than repair. Poly(ADP-ribose) synthesis appears to regulate the ligation stage of repair of alkylation damage by modulating a dynamic balance between incision and ligation, so as to minimize the frequency of DNA breaks.

Animals↗
PubMed1982

Hormones and the single cell: a relationship prerequisite for transformation.

The direct oncogenic potential of radiation and chemicals is demonstrable in cell cultures, where host-mediated influences do not prevail. These systems afford the opportunity of investigating factors that modulate neoplastic transformation. Agents such as retinoids modulate late events and inhibit the expression of transformation and the promotional effects of 12-O-tetradecanoylphorbol-13-acetate. Thyroid hormones play a role in early events, in initiation of transformation. Interaction of triiodothyronine (T3) in a culture medium with single cells is a prerequisite for the initiation of transformation following exposure to X-rays and to benzo[a]pyrene. When cloned hamster embryo cells and mouse 10T 1/2 cells are maintained in a medium containing serum without thyroid hormones (hypothyroid conditions) and exposed to 3 or 4 Gy X-rays, no transformation is observed, although cell survival and cell growth are unaffected by thyroid hormone level. Supplementation of the medium with 10-12M to 10-7M T3 12 h before exposure to X-rays results in a transformation frequency related to the dose of T3, with a peak at 10-10M. The curve is similar to that induced by Na/K ATPase. Addition of T3 at the time of radiation results in a lower transformation frequency; if it is added after radiation no transformation is observed. The effect of T3 in the process of initiation is not mimicked by reverse T3 and is abolished by addition of 100 ng cyclohexamide. The data suggest that the effect of T3 in rendering the cell competent to transform involves synthesis of a cellular 'transforming protein'. Ongoing experiments indicate that exposure to 1 microgram/ml benzo[a]-pyrene results in transformation only in the presence of T3. Under hypothyroid conditions, no transformation is observed.

Animals↗