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      Selective Killing of Transformed Fibroblasts by Combined Treatment with Cycloheximide and Aphidicolin

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          Abstract

          The possibility of selective killing of transformed cells in a mixed population of untransformed and transformed cells was examined using a cell culture system of rat 3Y1 fibroblasts (parental 3Y1 cells, 3Y1 cells transformed with either SV40, polyoma virus, Rous avian sarcoma virus, E1A gene of adenovirus type 12, or H‐v‐ ras oncogene). The principle of the selective killing is as follows. Under suboptimal culture conditions, untransformed cells are inhibited from progressing through G1 phase and retain viability, while transformed cells are not arrested. When DNA synthesis is inhibited for a long period, both types of cells in S phase die. Therefore, if we administer inhibitors of G1 progression and of DNA synthesis simultaneously to a cell population consisting of untransformed and transformed cells, most untransformed cells are arrested in G1 phase, retaining viability, while transformed cells leak from the G1 phase, cease DNA synthesis, and gradually die. The present study shows that all types of transformants in stationary‐phase cultures (consisting of cells mainly with a G1 DNA content) were killed to higher extents compared with untransformed cells, during incubation at lower cell densities with a combination of cycloheximide (G1 inhibitor) and aphidicolin (DNA‐synthesis inhibitor). However, cycloheximide reduced the killing effect of aphidicolin by changing the irreversible DNA‐synthesis inhibition to a reversible inhibition. The availability of G1 inhibitors that do not interfere with the irreversibility of inhibition of DNA synthesis is required for the treatment of cancer based on this idea.

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          Most cited references 17

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          Aphidicolin prevents mitotic cell division by interfering with the activity of DNA polymerase-alpha.

           H Nagano,  Y Mano,  M Ohashi (1978)
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            Rat cell line 3y1 and its virogenic polyoma- and SV40-transformed derivatives

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              Selective killing of transformed baby hamster kidney (BHK) cells.

              We report here that certain drugs can protect Syrian baby hamster kidney cells (BHK) in culture against the lethal agents cytosine arabinonucleoside, hydroxyurea, and colcemid. Polyoma virus-transformed BHK cells (PyBHK) are killed under the same conditions. The protective drugs include caffeine and streptovitacin A. Kinetic studies show that these drugs act specifically in G1, and that they shift BHK cells from G1 into the G0 state at the restriction point, similar to the effects of high cell density or serum deprivation. These drugs do not block the growth of PyBHK cells nearly as effectively, consistent with a reduced effectiveness of restriction point control in virus-transformed cells. Consequently, the transformed cells around their cycle and are killed by the cell cycle phase-specific toxic agents, in contrast to the arrested BHK cells. These findings provide a model for studies on differential killing of tumor versus normal cells in vivo.
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                Author and article information

                Journal
                Jpn J Cancer Res
                Jpn. J. Cancer Res
                10.1111/(ISSN)1349-7006a
                CAS
                Japanese Journal of Cancer Research : Gann
                Blackwell Publishing Ltd (Oxford, UK )
                0910-5050
                1876-4673
                May 1989
                : 80
                : 5 ( doiID: 10.1111/cas.1989.80.issue-5 )
                : 452-458
                Affiliations
                [ 1 ]Department of Virology, Medical Institute of Bioregulation, Kyushu University 69, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812
                Article
                CAE452
                10.1111/j.1349-7006.1989.tb02335.x
                5917752
                2546909
                Page count
                References: 18, Pages: 7
                Product
                Categories
                Article
                Custom metadata
                2.0
                May 1989
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.6.9 mode:remove_FC converted:04.11.2015

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