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Pauling noble prize winner

Pauling Therapy References


1. NLM CIT. ID: 91067711 2. 3. TITLE: Immunological evidence for the accumulation of lipoprotein(a) in 4. the atherosclerotic lesion of the hypoascorbemic guinea pig. 5. AUTHOR: Rath M; Pauling L 6. ADDRESS: 7. Linus Pauling Institute of Science and Medicine, Palo Alto, CA 8. 94306-2025. 9. PUBLICATION TYPES: 10. JOURNAL ARTICLE 11. LANGUAGE: Eng 12. REGISTRY NUMBERS: 13. 0 (Antibodies) 14. 0 (Lipoprotein(a)) 15. 0 (Lipoproteins) 16. ABSTRACT: 17. Lipoprotein(a) [Lp(a)] is an extremely atherogenic lipoprotein. 18. Lp(a) has been found in the plasma of humans and other primates, 19. but until now only in a few other species. The mechanism by which 20. it exerts its atherogenicity is still poorly understood. We 21. observed that Lp(a) has been found in the plasma of several 22. species unable to synthesize ascorbate and not in other species. 23. We have now detected apoprotein(a) in the plasma of the guinea 24. pig. We induced atherosclerosis in this animal by dietary 25. ascorbate depletion and, using SDS/PAGE and subsequent 26. immunoblotting, we identified Lp(a) as accumulating in the 27. atherosclerotic plaque. Most importantly, adequate amounts of 28. ascorbate (40 mg per kg of body weight per day) prevent the 29. development of atherosclerotic lesions in this animal model and 30. the accumulation of Lp(a) in the arterial wall. We suggest an 31. analogous mechanism in humans because of the similarity between 32. guinea pigs and humans with respect to both the lack of 33. endogenous ascorbate production and the role of Lp(a) in human 34. atherosclerosis. 35. MAIN MESH HEADINGS: 36. Lipoproteins/ANALYSIS/*METABOLISM 37. Atherosclerosis/COMPLICATIONS/*METABOLISM/PATHOLOGY 38. Ascorbic Acid Deficiency/COMPLICATIONS/*METABOLISM 39. ADDITIONAL MESH SUBJECTS: 40. Support, Non-U.S. Gov't 41. Muscle, Smooth, Vascular/METABOLISM/PATHOLOGY 42. Guinea Pigs 43. Female 44. Electrophoresis, Polyacrylamide Gel 45. Blotting, Western 46. Aorta/METABOLISM/PATHOLOGY

47. Antibodies 48. Animal 49. SOURCE: Proc Natl Acad Sci U S A 1990 Dec;87(23):9388-90

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51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. NLM CIT. ID: 91031571 TITLE: Lipoprotein(a) in the arterial wall. AUTHOR: Beisiegel U; Rath M; Reblin T; Wolf K; Niendorf A ADDRESS: Medizinische Kernklinik und Poliklinik, Universitatskrankenhaus Eppendorf, Hamburg, F.R.G. PUBLICATION TYPES: JOURNAL ARTICLE LANGUAGE: Eng REGISTRY NUMBERS: 0 (Apoproteins) 0 (Lipoprotein(a)) 0 (Lipoproteins) 0 (Triglycerides) 57-88-5 (Cholesterol) ABSTRACT: We compared CHD patients with healthy blood donors to confirm the 69. role of Lp(a) as an independent risk factor. More important, we 70. performed biochemical and immunohistochemical studies to evaluate 71. the potential mechanism by which Lp(a) causes CHD. We measured 72. the Lp(a) concentration in comparison with other lipoprotein 73. parameters in fresh human arterial wall biopsies and, in autopsy 74. tissue, we localized apo (a) and apo B, as well as fibrin, with 75. immunohistochemical methods in different vessel areas. Density 76. gradient ultracentrifugation was used to analyse lipoprotein 77. fractions isolated from human arterial wall. Lp(a) accumulates in 78. the intima, preferentially in plaque areas, dependent on the 79. serum Lp(a) level. Most of the Lp(a) can be located 80. extracellularly, but apo(a) can also be detected in foam cells. A 81. strong co-localization has been observed for apo(a) and apo B; 82. only a few areas containing only apo B were detected. Moreover, a 83. striking co-localization for apo(a) and fibrin was found. The 84. possibilities for the pathways by which Lp(a) enters the arterial 85. wall and accumulates extracellularly are discussed on the basis 86. of the present data and recent data published by other groups. 87. MAIN MESH HEADINGS: 88. Lipoproteins/*ANALYSIS 89. Endothelium, Vascular/*CHEMISTRY 90. Coronary Disease/*METABOLISM 91. Aorta/*CHEMISTRY 92. ADDITIONAL MESH SUBJECTS: 93. Triglycerides/ANALYSIS 94. Support, Non-U.S. Gov't 95. Proteins/ANALYSIS 96. Middle Age

97. Lipids/ANALYSIS 98. Immunohistochemistry 99. Human 100. Cholesterol/ANALYSIS 101. Apoproteins/ANALYSIS 102. SOURCE: Eur Heart J 1990 Aug;11 Suppl E:174-83

103.
104. NLM CIT. ID: 90349583 105. 106. TITLE: Hypothesis: lipoprotein(a) is a surrogate for ascorbate 107. [published erratum appears in Proc Natl Acad Sci U S A 1991 Dec 108. 15;88(24):11588] 109. AUTHOR: Rath M; Pauling L 110. ADDRESS: 111. Linus Pauling Institute of Science and Medicine, Palo Alto, CA 112. 94306. 113. PUBLICATION TYPES: 114. JOURNAL ARTICLE 115. LANGUAGE: Eng 116. REGISTRY NUMBERS: 117. 0 (Antioxidants) 118. 0 (Lipoprotein(a)) 119. 0 (Lipoproteins) 120. 50-81-7 (Ascorbic Acid) 121. ABSTRACT: 122. The concept that lipoprotein(a) [Lp(a)] is a surrogate for 123. ascorbate is suggested by the fact that this lipoprotein is found 124. generally in the blood of primates and the guinea pig, which have 125. lost the ability to synthesize ascorbate, but only rarely in the 126. blood of other animals. Properties of Lp(a) that are shared with 127. ascorbate, in accordance with this hypothesis, are the 128. acceleration of wound healing and other cell-repair mechanisms, 129. the strengthening of the extracellular matrix (e.g., in blood 130. vessels), and the prevention of lipid peroxidation. High plasma 131. Lp(a) is associated with coronary heart disease and other forms 132. of atherosclerosis in humans, and the incidence of cardiovascular 133. disease is decreased by elevated ascorbate. Similar observations 134. have been made in cancer and diabetes. We have formulated the 135. hypothesis that Lp(a) is a surrogate for ascorbate in humans and 136. other species and have marshaled the evidence bearing on this 137. hypothesis. 138. MAIN MESH HEADINGS: 139. Lipoproteins/*PHYSIOLOGY 140. Cardiovascular Diseases/*PHYSIOPATHOLOGY 141. Ascorbic Acid/*METABOLISM 142. ADDITIONAL MESH SUBJECTS: 143. Wound Healing 144. Neoplasms/PHYSIOPATHOLOGY 145. Human 146. Evolution 147. Disease Models, Animal 148. Diabetes Mellitus/PHYSIOPATHOLOGY 149. Atherosclerosis/PHYSIOPATHOLOGY

150. Antioxidants/METABOLISM 151. Animal 152. SOURCE: Proc Natl Acad Sci U S A 1990 Aug;87(16):6204-7

153.
154. NLM CIT. ID: 90312898 155. 156. TITLE: Morphological detection and quantification of lipoprotein(a) 157. deposition in atheromatous lesions of human aorta and coronary 158. arteries [published erratum appears in Virchows Arch A Pathol 159. Anat Histopathol 1991;418(1):86] 160. AUTHOR: Niendorf A; Dietel M; Beisiegel U; Arps H; Peters S 161. Wolf K; Rath M 162. ADDRESS: 163. Institut fur Pathologie, Universitat Hamburg, Federal Republic 164. of Germany. 165. PUBLICATION TYPES: 166. JOURNAL ARTICLE 167. LANGUAGE: Eng 168. REGISTRY NUMBERS: 169. 0 (Apolipoproteins A) 170. 0 (Apolipoproteins B) 171. 0 (Lipoprotein(a)) 172. 0 (Lipoproteins) 173. ABSTRACT: 174. Lipoprotein(a), as an atherogenic particle, represents an 175. independent risk factor for coronary heart disease. In the 176. present study the morphological distribution of apoprotein (a) 177. and apoprotein B within the arterial wall is described. 178. Apoprotein B, a constituent of very low-density lipoprotein, 179. low-density lipoprotein and lipoprotein(a) has previously been 180. demonstrated in atheromatous lesions. Lipoprotein(a) possesses an 181. additional protein, designated apoprotein (a). Autopsy material 182. (n = 74) from the left coronary artery and from the thoracic 183. aorta has been examined by means of immunohistochemistry and both 184. apoprotein (a) and apoprotein B were detected, primarily 185. associated with the extracellular matrix and accumulating in 186. lesions in the arterial wall. The staining pattern for both 187. antigens was almost always found to be congruent, suggesting that 188. the detection of (a)-antigen has to be attributed at least in 189. part to the presence of lipoprotein(a). It is concluded that both 190. low-density lipoprotein and lipoprotein(a) have an important role 191. in the pathogenesis of atherosclerosis. 192. MAIN MESH HEADINGS: 193. Lipoproteins/*METABOLISM 194. Coronary Disease/*METABOLISM/PATHOLOGY 195. Atherosclerosis/*METABOLISM/PATHOLOGY 196. Arteriosclerosis/*METABOLISM 197. Aortic Diseases/*METABOLISM/PATHOLOGY 198. ADDITIONAL MESH SUBJECTS: 199. Tissue Distribution 200. Middle Age

201. Infant, Newborn 202. Infant 203. Immunohistochemistry 204. Human 205. Coronary Vessels/METABOLISM/PATHOLOGY 206. Comparative Study 207. Child, Preschool 208. Child 209. Apolipoproteins B/METABOLISM 210. Apolipoproteins A/METABOLISM 211. Aorta/METABOLISM/PATHOLOGY 212. Aged, 80 and over 213. Aged 214. Adult 215. Adolescence 216. SOURCE: Virchows Arch A Pathol Anat Histopathol 1990;417(2):105-11

Is Vitamin C Harmful to Cancer Patients?


Stephen Lawson LPI Administrative Officer Linus Pauling Institute

In a recent presentation at the American Cancer Society meeting, Dr. David Golde of Memorial Sloan-Kettering Cancer Center speculated that supplemental vitamin C may be harmful to cancer patients. Dr. Golde had previously shown how vitamin C gets into and accumulates in cancer cells. Golde and others are concerned that the extra vitamin C in cancer cells may enhance their growth or protect them from the cell-killing free radicals produced by radiation and some chemotherapeutic drugs. While different cancer cells may respond differently to vitamin C, it is important to view these concerns in the context of the experimental cell culture, small animal, and human clinical studies. In some cell culture and small animal studies, vitamin C has enhanced cancer cell growth. Dr. Chan Park has found that the growth of leukemic cells from some leukemia patients put into culture was enhanced by vitamin C. The growth of cells

taken from other leukemia patients was either inhibited or unaffected by vitamin C. It is unknown whether similar effects would have been observed in the same patients taking supplemental vitamin C. Dr. Joel Schwartz of the National Institutes of Health has published studies in which supplemental vitamin C enhanced the growth of tumors induced in hamsters by a chemical carcinogen. Interestingly, the growth of tumors was significantly inhibited by supplemental vitamin E and by a mixture of antioxidants, including betacarotene, vitamin E, and vitamin C. Studies published by LPI scientists since the 1970s have demonstrated that supplemental vitamin C delayed the onset of tumors in mice that developed spontaneous mammary tumors, in mice exposed to ultraviolet radiation, and in guinea pigs implanted with liver cancer cells. In these experiments, vitamin C did not appreciably affect the growth rate of tumors once they formed. Other studies published by Dr. Constance Tsao and her colleagues at LPI showed that supplemental vitamin C (sometimes combined with oxidation products of vitamin C) inhibited the growth of human colon, lung, and mammary tumors implanted into mice. LPI investigations also demonstrated that vitamin C and its derivatives have anticancer effects against a number of cancer cell lines in culture. What about clinical studies on vitamin C in cancer patients? Dr. Pauling and his medical collaborator, Dr. Ewan Cameron, former Chief of Surgery at Vale of Leven Hospital in Scotland, published numerous papers on the response of cancer patients given large doses of supplemental vitamin C as an adjunct to the appropriate conventional treatment for cancer. In their book Cancer and Vitamin C, they concluded that supplemental vitamin C is of benefit to most cancer patients. The benefit ranged from an increased sense of wellbeing to a prolongation of survival time in terminal patients to rare complete regressions. However, two clinical studies carried out by Drs. Edward Creagan and Charles Moertel of the Mayo Clinic and published in 1979 and 1985 showed no benefit from supplemental vitamin C on survival time. As Drs. Cameron and Pauling pointed out, however, the patients in the first Mayo Clinic study had undergone extensive chemotherapy that damaged their immune systems prior to the use of vitamin C. In the second study supplemental vitamin C was abruptly stopped after only about two months. There was also evidence that some of the patients in the placebo group were taking extra vitamin C, thus muddying the differences between groups. When Cancer and Vitamin C was first published in 1979, Drs. Cameron and Pauling noted that little information was available on the interaction between vitamin C and chemotherapeutic drugs. They cautioned that patients undergoing aggressive chemotherapy expected to be curative should refrain from taking large doses of vitamin C at the same time in case the vitamin

interfered with the drug action. There is some evidence that vitamin C increases the activity of liver enzymes that detoxify xenobiotics, including drugs. When the chemotherapy was merely palliative, they did not believe that the use of concurrent vitamin C was contraindicated. They believed that vitamin C potentiates radiation, and even many clinicians who disagree on this point nevertheless agree that supplemental vitamin C given after radiation ameliorates radiation sickness. In the early 1990s, Dr. Pauling published two papers with Dr. Abram Hoffer, who developed a regimen for use in cancer patients that includes B vitamins, vitamin E, large doses of vitamin C, beta-carotene, selenium, zinc, and other substances. The statistical analysis of their data revealed that about 40% of the cancer patients survived five years or more after the initiation of the regimen. (A new book by Dr. Hoffer, Vitamin C & Cancer, features major contributions by Linus Pauling and further discussion of these results.) Only about 10% of the patients treated by Dr. Cameron in Scotland with vitamin C alone survived as long, although all of the Scottish study patients had terminal cancer. These studies, as well as Dr. Cameron's studies in Scotland, were not designed as placebo- controlled, randomized, double-blind trials because of ethical concerns and practical problems concerning appropriate placebos. Interestingly, Dr. Hoffer's regimen is remarkably similar to that recommended by Dr. Kedar Prasad of the University of Colorado and his colleagues, who advocate the use of a combination of B vitamins, large doses of calcium ascorbate (vitamin C), vitamin E, and beta-carotene for cancer patients undergoing either chemotherapy or radiation. Dr. Prasad acknowledges the accumulation of antioxidant vitamins in cancer cells, but argues that this has favorable biochemical effects, including the inhibition of oncogenes and the induction of factors that inhibit cell growth, favor differentation, or induce apoptosis (programmed cell death). In an extensive and well-referenced recent review published in the Journal of the American College of Nutrition, Dr. Prasad presented results from cell culture experiments demonstrating that the killing effect of many cancer drugs or radiation on mouse and human cancer cells is enhanced in the presence of vitamins C or E. Of course, cell culture studies (or animal studies) cannot always predict what will happen in humans. In another extensive review published in Alternative Medicine Review in 1999, Drs. Lamson and Brignall reached conclusions similar to those of Dr. Prasad. These authors noted that "considerable data exists showing increased effectiveness of many cancer therapeutic agents, as well as a decrease in adverse effects, when given concurrently with antioxidants." A Finnish non-randomized clinical study published in Anticancer Research in

1992 by Dr. Jaakkola and colleagues showed that the provision of B vitamins, large doses of vitamins C and E, beta-carotene, fatty acids, and minerals in combination with chemotherapy and radiation to patients with small-cell lung cancer resulted in significantly prolonged survival, especially when started early. These patients were compared to patients in other studies who were treated only with chemotherapy and radiation. Another clinical study by Dr. Emmanuel Cheraskin published in 1968 showed that the response to radiation among women with cervical carcinoma was enhanced by daily supplements of 750 mg of vitamin C given during radiation. What can we conclude about vitamin C and cancer? While the theoretical speculation by Dr. Golde seems plausible, there is no clinical evidence that supplemental antioxidant vitamins, including vitamin C, harm cancer patients. Indeed, much of the recent cell culture and clinical research suggests that a combination of antioxidant vitamins and minerals as an adjunct to conventional therapy may have benefit. This is a complex issue, however, and there is clearly more to learn from controlled clinical trials about the use of these modalities in treating cancer before definitive conclusions can be drawn. For more information on vitamin C, see the Linus Pauling Institute's Micronutrient Information Center.