Membrane Alterations in Cancer Cells:

Radiation, chemicals, and some viruses are known to be environmental causes of cancer. The origin of tumors of different kinds has been associated for a long time to exposure to radiations of different energy.'.' Chemicals also can cause cancer either by a direct action on the cells or by enzymatic conversion to an active carcinogenic form. This process often involves the NADPH-cytochrome P-450 electron transport system, located mainly in the endoplasmic reticulum of the hepatocyte but also of several other tissues.3v4 Free radicals are among the products of this cytochrome P-450-mediated reactions. Substances that give free radical intermediates are halogenoalkanes, nitro-compounds, aromatic amines, quinones, nitrosoamines, polycyclic hydrocarbons, and polyunsaturated fatty acids. These intermediates have been found to play a significant role in chemical carcin~genesis.~*~ Free radicals are indeed responsible for a series of damaging reactions within the cell. Among their targets are DNA, nucleotidecoenzymes, thiol-dependent enzymes and membranes, whose damage is known to be induced by lipid peroxidation, responsible for structural and functional modifications as well as production of toxic intermediates.' It has of course to be considered that highly reactive radicals are very short lived and cannot diffuse far from the site of generation. This consideration is particularly relevant for radicals that may have DNA as a target and are produced far from the nucleus. On the other hand, slow reacting radicals should not have too great a damaging effect even if they can diffuse more freely within cell. Among the damaging effects of free radicals, lipoperoxidation has been studied with particular attention because of a number of important biological consequences. It consists of a chain reaction resulting in the oxidative degradation of unsaturated lipids, particularly of polyunsaturated fatty acid residues of phospholipids that constitute the bilayer of the rnembrane~.'.~ Several are the products of lipoperoxidation: alkanals,

[1]  I. Zbarsky,et al.  A novel type of superoxide generating system in nuclear membranes from hepatoma 22a ascites cells , 1980, FEBS letters.

[2]  G. Milo,et al.  Polyunsaturated fatty acids, vitamin E, and the proliferation of aortic smooth muscle cells. , 1979, Lipids.

[3]  J. Butler.  Free Radicals, Lipid Peroxidation and Cancer , 1982, British Journal of Cancer.

[4]  R. Estabrook,et al.  Cytochrome P-450—Its Role in Oxygen Activation for Drug Metabolism , 1977 .

[5]  D. Cornwell,et al.  Regulation of cell division in a human glioma cell clone by arachidonic acid and alpha-tocopherolquinone. , 1982, Cancer letters.

[6]  T. Galeotti,et al.  Growth-related lipid peroxidation in tumour microsomal membranes and mitochondria. , 1979, Biochimica et biophysica acta.

[7]  S. Kawato,et al.  Microsomal lipid peroxidation causes an increase in the order of the membrane lipid domain , 1982, FEBS letters.

[8]  W. Pryor.  The Involvement of Free Radicals in Chemical Carcinogenesis , 1987 .

[9]  H. Morris,et al.  The deacylation and reacylation of phosphoglyceride in microsomes of Morris hepatoma 7777 and host rat liver. , 1977, Cancer research.

[10]  N. Porter.  Chemistry of lipid peroxidation. , 1984, Methods in enzymology.

[11]  J. Crapo,et al.  Biology of disease: free radicals and tissue injury. , 1982, Laboratory investigation; a journal of technical methods and pathology.

[12]  A. Ottolenghi,et al.  Inhibition of cell division by ultraviolet irradiated unsaturated fatty acid. , 1957, Experimental cell research.

[13]  S. Aust,et al.  Evidence for superoxide generation by NADPH-cytochrome c reductase of rat liver microsomes. , 1972, Biochemical and biophysical research communications.

[14]  E. Cadenas,et al.  Mitochondrial production of superoxide anions and its relationship to the antimycin insensitive respiration , 1975, FEBS letters.

[15]  T. Galeotti,et al.  Different contribution of rat liver microsomal pigments in the formation of superoxide anions and hydrogen peroxide during development. , 1977, Archives of biochemistry and biophysics.

[16]  D. Mills,et al.  NADPH-dependent lipid peroxidation in mitochondria from livers of young and old rats and from rat hepatoma D30 [proceedings]. , 1977, Biochemical Society transactions.

[17]  J. Farber,et al.  Lipid peroxidation increases the molecular order of microsomal membranes. , 1984, Archives of biochemistry and biophysics.

[18]  S. Weiss,et al.  Phagocyte-generated oxygen metabolites and cellular injury. , 1982, Laboratory investigation; a journal of technical methods and pathology.

[19]  H. Forman,et al.  CHAPTER 3 – Superoxide Radical and Hydrogen Peroxide in Mitochondria , 1982 .

[20]  E. Miller,et al.  Mechanisms of chemical carcinogenesis , 1981, Cancer.

[21]  T. Slater,et al.  Free radicals, lipid peroxidation and cancer , 1982 .

[22]  J. Huff,et al.  Lipide peroxide production and inhibition by tumor mitochondria. , 1960, Archives of biochemistry and biophysics.

[23]  T. Galeotti,et al.  Superoxide dismutase content and microsomal lipid composition of tumours with different growth rates. , 1980, Biochimica et biophysica acta.

[24]  K. Utsumi,et al.  Failure of FE2+-induced lipid peroxidation and swelling in the mitochondria isolated from ascites tumor cells. , 1965, Biochimica et biophysica acta.

[25]  R. Holmes,et al.  Peroxisomes: new aspects of cell physiology and biochemistry. , 1977, Physiological reviews.

[26]  K. Wilbur,et al.  Lipid peroxide formation in regenerating rat liver. , 1956, Experimental cell research.

[27]  L. Oberley,et al.  Role of superoxide dismutase in cancer: a review. , 1979, Cancer research.

[28]  B Chance,et al.  The cellular production of hydrogen peroxide. , 1972, The Biochemical journal.

[29]  W. S. Thayer,et al.  Differential effect of lipid peroxidation on membrane fluidity as determined by electron spin resonance probes. , 1983, Biochimica et biophysica acta.

[30]  G. Milo,et al.  Fatty acids and their prostaglandin derivatives: inhibitors of proliferation in aortic smooth muscle cells. , 1977, Science.

[31]  L. Oberley,et al.  Superoxide dismutase and superoxide radical in Morris hepatomas. , 1980, Cancer research.

[32]  A. Upton.  Physical Carcinogenesis: Radiation—History and Sources , 1975 .

[33]  W. Caspary,et al.  CHAPTER 7 – The Involvement of Free Radicals in Chemical Carcinogenesis , 1977 .

[34]  H. Morris,et al.  Microbodies of Morris hepatomas. , 1971, Cancer research.

[35]  T. Galeotti,et al.  Production of superoxide anions and hydrogen peroxide in Ehrlich ascites tumour cell nuclei. , 1977, Biochimica et biophysica acta.

[36]  I. Zbarsky,et al.  Superoxide dismutase and glutathione peroxidase activities in tumors , 1977, FEBS letters.

[37]  T. Galeotti,et al.  Superoxide-dependent lipid peroxidation and vitamin E content of microsomes from hepatomas with different growth rates. , 1985, Archives of biochemistry and biophysics.

[38]  T. Galeotti,et al.  Superoxide radicals and hydrogen peroxide formation in mitochondria from normal and neoplastic tissues. , 1975, Biochimica et biophysica acta.