Augustinus Ong

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.

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.

THE MODULATING EFFECT OF RETINOIDS AND A TUMOR PROMOTER ON MALIGNANT TRANSFORMATION, SISTER CHROMATID EXCHANGES, AND Na/K ATPase

Within the last decade a variety of vitamin A analogs (retinoids) have been shown to inhibit the expression of malignancy both in experimental systems and in the clinic [for recent review see ref. 17) At the same time there has been a revived interest and increased awareness of the effectiveness of substances, mostly of plant origin and called tumor promoters, in promoting carcinogenesis.2 One of these compounds TPAt: [ 12-0 tetradecanoyl-phorbo113-acetate)10 has been used extensively in studies utilizing all culture systems.36 While an antagonism between TPA and retinoids has been recognized in some carcinogenesis systems, in growth-related enzymatic systems in vivo and in vitro and in differentiation in vitro (for review see ref. 16) no studies have been carried out where the effects of retinoids and TPA, alone and in combination were evaluated on oncogenic transformation in vitro. In earlier reports we have shown that a vitamin A analog inhibits radiationinduced transformation in vitrog and that retinoids and TPA exert antagonistic effects on vitamin A-binding protein production.6 Since the tumor promoter TPA has been reported to enhance radiation-induced transformati~n,LZ,~~ it seemed a logical step to follow up these various studies and to investigate whether:

In vivo-in vitro systems in multistage carcinogenesis.

Of particular importance are the long-term genetic effects which ensue following transplacental exposure of embryos or fetuses to radiation. The damage produced by these exposures and the genetic lesions differ depending on the stage of gestation of the exposed embryo, the genetic sensitivity of the cells to be transformed to malignancy and a variety of homeostatic permissive and protective factors which may modulate the outcome of the genetic insult (BEIR, 1972; Borek, 1984a, 1987).

A Role for Poly(ADP-Ribose) in Radiogenic and Chemically-Induced Malignant Transformation and Mutagenesis

3-aminobenzamide (3AB) is a nicotinamide analog which was first introduced as an inhibitor of poly(ADP-ribose) synthesis [29]. 3AB has a multitude of effects on cells previously exposed to DNA damaging agents, which have been taken to indicate a role for poly(ADP-ribose) synthesis in DNA repair [1–3, 9, 10, 12, 13, 15–17, 22–27, 31–33]. Other side effects suggest, however, that 3AB may not be as specific as supposed [9, 10, 14, 18, 21]. 3AB also inhibits malignant transformation by radiation and methylating agents in human, mouse, and hamster cells [5–7, 19]. We have now compared the effects of low concentrations of 3AB on mutagenesis and transformation, in view of the supposed similarities in these processes.

In Vitro Transformation of Human Cells by Radiation

A variety of consumer and industrial products yield ionizing radiation or contain radioactive materials. These include television sets, luminous dial watches, airport luggage x-ray inspection systems, smoke detectors, high voltage vacuum switches, cardiac pacemakers, tobacco smoke, fossil fuels and building materials containing radionuclides. Other sources of exposure are airborne radon and radon daughter products that evolve from ground water supplies used in the home, from cosmic radiation during airline travel and exposure which results from transportation of radioactive material (BEIR, 1972, 1980).

Ozone Carcinogenesis and Co-Carcinogenesis and its Prevention

Ozone (O3), a reactive species of oxygen, is an important natural constituent of the atmosphere (1). Background levels of ozone in the lower atmosphere may range up to 0.1 ppm and are modified by geographic elevation, solar radiation and climatic conditions (2). Since some ozone effects are radiomlmetic its actions may be enhanced in the presence of ionizing radiation from background and/or man-made sources (3,4).

Detecting Dominant Transforming Genes in Cells Transformed in Utero

In earlier reports we described an in vivo-in vitro system which consists of exposing mid-term hamster embryos in utero and cloning the embryonic cells in vitro to assay for transformed cells with malignant potential (Borek et al., 1977, 1987a). Recent developments in molecular biology have made it possible to identify the presence of dominant transforming genes (oncogenes) in cells exposed to a variety of carcinogens (Land et al., 1983; Paroda and Weinberg, 1983; Guererro et al., 1984; Borek et al., 1987b). The methods of DNA-mediated gene transfer (transfection) led to the identification of dominant transforming genes in a variety of human neoplastic cells (Cooper, 1982; Land et al., 1983; Guerrero et al., 1984; Borek et al., 1987b).

Sodium Bisulfite Protects Against Radiogenic and Chemically Induced Transformation in Hamster Embryo and Mouse C3H/10T-1/2 Cells

Pretreatment of hamster embryo cells or mouse C3H/10T-1/2 cells with sodium bisulfite (0.5, 2.5, 5.0 and 100 ppm) inhibits the oncogenic transformation of the cells following their exposure to x-rays or benzo(a)pyrene. The results suggest that low doses of bisulfite, a widely used food additive, can serve as a radioprotective and chemopreventive agent with anticarcinogenic potential.