Pauling Noble Prize Winner

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Pauling noble prize winner

Pauling Therapy References1. NLM CIT. ID: 910677112. 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 L6. ADDRESS:7. Linus Pauling Institute of Science and Medicine, Palo Alto, CA8. 94306-2025.9. PUBLICATION TYPES:10. JOURNAL ARTICLE11. LANGUAGE: Eng12. 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. We21. observed that Lp(a) has been found in the plasma of several22. species unable to synthesize ascorbate and not in other species.23. We have now detected apoprotein(a) in the plasma of the guinea24. pig. We induced atherosclerosis in this animal by dietary25. ascorbate depletion and, using SDS/PAGE and subsequent26. immunoblotting, we identified Lp(a) as accumulating in the27. atherosclerotic plaque. Most importantly, adequate amounts of28. ascorbate (40 mg per kg of body weight per day) prevent the29. development of atherosclerotic lesions in this animal model and30. the accumulation of Lp(a) in the arterial wall. We suggest an31. analogous mechanism in humans because of the similarity between32. guinea pigs and humans with respect to both the lack of33. endogenous ascorbate production and the role of Lp(a) in human34. atherosclerosis.35. MAIN MESH HEADINGS:36. Lipoproteins/ANALYSIS/*METABOLISM37. Atherosclerosis/COMPLICATIONS/*METABOLISM/PATHOLOGY38. Ascorbic Acid Deficiency/COMPLICATIONS/*METABOLISM39. ADDITIONAL MESH SUBJECTS:40. Support, Non-U.S. Gov't41. Muscle, Smooth, Vascular/METABOLISM/PATHOLOGY42. Guinea Pigs43. Female44. Electrophoresis, Polyacrylamide Gel45. Blotting, Western46. Aorta/METABOLISM/PATHOLOGY


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47. Antibodies48. Animal49. SOURCE: Proc Natl Acad Sci U S A 1990 Dec;87(23):9388-9050. 51. NLM CIT. ID: 9103157152. 53.

TITLE: Lipoprotein(a) in the arterial wall.

54. AUTHOR: Beisiegel U; Rath M; Reblin T; Wolf K; Niendorf A55. ADDRESS:56. Medizinische Kernklinik und Poliklinik, Universitatskrankenhaus57. Eppendorf, Hamburg, F.R.G.58. PUBLICATION TYPES:59. JOURNAL ARTICLE60. LANGUAGE: Eng61. REGISTRY NUMBERS:62. 0 (Apoproteins)63. 0 (Lipoprotein(a))64. 0 (Lipoproteins)65. 0 (Triglycerides)66. 57-88-5 (Cholesterol)67. ABSTRACT:68. We compared CHD patients with healthy blood donors to confirm

the

69. role of Lp(a) as an independent risk factor. More important, we70. performed biochemical and immunohistochemical studies to

evaluate

71. the potential mechanism by which Lp(a) causes CHD. We measured72. the Lp(a) concentration in comparison with other lipoprotein73. parameters in fresh human arterial wall biopsies and, in autopsy74. tissue, we localized apo (a) and apo B, as well as fibrin, with75. immunohistochemical methods in different vessel areas. Density76. gradient ultracentrifugation was used to analyse lipoprotein77. fractions isolated from human arterial wall. Lp(a) accumulates

in78. the intima, preferentially in plaque areas, dependent on the79. serum Lp(a) level. Most of the Lp(a) can be located80. 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. The84. possibilities for the pathways by which Lp(a) enters the

arterial

85. wall and accumulates extracellularly are discussed on the basis86. of the present data and recent data published by other groups.87. MAIN MESH HEADINGS:88. Lipoproteins/*ANALYSIS89. Endothelium, Vascular/*CHEMISTRY90. Coronary Disease/*METABOLISM91. Aorta/*CHEMISTRY92. ADDITIONAL MESH SUBJECTS:93. Triglycerides/ANALYSIS94. Support, Non-U.S. Gov't95. Proteins/ANALYSIS96. Middle Age


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97. Lipids/ANALYSIS98. Immunohistochemistry99. Human100. Cholesterol/ANALYSIS101. Apoproteins/ANALYSIS102. SOURCE: Eur Heart J 1990 Aug;11 Suppl E:174-83103. 104. NLM CIT. ID: 90349583105. 106. TITLE: Hypothesis: lipoprotein(a) is a surrogate for ascorbate107. [published erratum appears in Proc Natl Acad Sci U S A 1991 Dec108. 15;88(24):11588]109. AUTHOR: Rath M; Pauling L110. ADDRESS:111. Linus Pauling Institute of Science and Medicine, Palo Alto, CA112. 94306.113. PUBLICATION TYPES:114. JOURNAL ARTICLE115. LANGUAGE: Eng116. 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 for123. ascorbate is suggested by the fact that this lipoprotein is

found

124. generally in the blood of primates and the guinea pig, whichhave

125. lost the ability to synthesize ascorbate, but only rarely in the126. blood of other animals. Properties of Lp(a) that are shared with127. ascorbate, in accordance with this hypothesis, are the128. acceleration of wound healing and other cell-repair mechanisms,129. the strengthening of the extracellular matrix (e.g., in blood130. vessels), and the prevention of lipid peroxidation. High plasma131. Lp(a) is associated with coronary heart disease and other forms132. of atherosclerosis in humans, and the incidence of

cardiovascular

133. disease is decreased by elevated ascorbate. Similar observations134. have been made in cancer and diabetes. We have formulated the135. hypothesis that Lp(a) is a surrogate for ascorbate in humans and136. other species and have marshaled the evidence bearing on this137. hypothesis.138. MAIN MESH HEADINGS:139. Lipoproteins/*PHYSIOLOGY140. Cardiovascular Diseases/*PHYSIOPATHOLOGY141. Ascorbic Acid/*METABOLISM142. ADDITIONAL MESH SUBJECTS:143. Wound Healing144. Neoplasms/PHYSIOPATHOLOGY145. Human146. Evolution147. Disease Models, Animal148. Diabetes Mellitus/PHYSIOPATHOLOGY149. Atherosclerosis/PHYSIOPATHOLOGY


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150. Antioxidants/METABOLISM151. Animal152. SOURCE: Proc Natl Acad Sci U S A 1990 Aug;87(16):6204-7153. 154. NLM CIT. ID: 90312898155. 156.

TITLE: Morphological detection and quantification of lipoprotein(a)

157. deposition in atheromatous lesions of human aorta and coronary158. arteries [published erratum appears in Virchows Arch A Pathol159. Anat Histopathol 1991;418(1):86]160. AUTHOR: Niendorf A; Dietel M; Beisiegel U; Arps H; Peters S161. Wolf K; Rath M162. ADDRESS:163. Institut fur Pathologie, Universitat Hamburg, Federal Republic164. of Germany.165. PUBLICATION TYPES:166. JOURNAL ARTICLE167. LANGUAGE: Eng168. 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 an175. independent risk factor for coronary heart disease. In the176. 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 been180. demonstrated in atheromatous lesions. Lipoprotein(a) possesses

an

181. additional protein, designated apoprotein (a). Autopsy material182. (n = 74) from the left coronary artery and from the thoracic183. aorta has been examined by means of immunohistochemistry and

both

184. apoprotein (a) and apoprotein B were detected, primarily185. associated with the extracellular matrix and accumulating in186. lesions in the arterial wall. The staining pattern for both187. antigens was almost always found to be congruent, suggesting

that

188. the detection of (a)-antigen has to be attributed at least in189. part to the presence of lipoprotein(a). It is concluded that

both

190. low-density lipoprotein and lipoprotein(a) have an importantrole

191. in the pathogenesis of atherosclerosis.192. MAIN MESH HEADINGS:193. Lipoproteins/*METABOLISM194. Coronary Disease/*METABOLISM/PATHOLOGY195. Atherosclerosis/*METABOLISM/PATHOLOGY196. Arteriosclerosis/*METABOLISM197. Aortic Diseases/*METABOLISM/PATHOLOGY198. ADDITIONAL MESH SUBJECTS:199. Tissue Distribution200. Middle Age


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201. Infant, Newborn202. Infant203. Immunohistochemistry204. Human205. Coronary Vessels/METABOLISM/PATHOLOGY206. Comparative Study207. Child, Preschool208. Child209. Apolipoproteins B/METABOLISM210. Apolipoproteins A/METABOLISM211. Aorta/METABOLISM/PATHOLOGY212. Aged, 80 and over213. Aged214. Adult215. Adolescence216. SOURCE: Virchows Arch A Pathol Anat Histopathol 1990;417(2):105-11

Is Vitamin C Harmful to Cancer Patients? Stephen Lawson

LPI Administrative OfficerLinus 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 hadpreviously shown how vitamin C gets into and accumulates in cancer cells.

Golde and others are concerned that the extra vitamin C in cancer cells mayenhance 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 cellculture, small animal, and human clinical studies. In some cell culture and

small animal studies, vitamin C has enhanced cancer cell growth. Dr. ChanPark has found that the growth of leukemic cells from some leukemia

patients put into culture was enhanced by vitamin C. The growth of cells


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taken from other leukemia patients was either inhibited or unaffected byvitamin C. It is unknown whether similar effects would have been observedin the same patients taking supplemental vitamin C. Dr. Joel Schwartz of theNational 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 bysupplemental vitamin E and by a mixture of antioxidants, including beta-carotene, 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 developedspontaneous 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 theyformed. Other studies published by Dr. Constance Tsao and her colleagues

at LPI showed that supplemental vitamin C (sometimes combined withoxidation products of vitamin C) inhibited the growth of human colon, lung,

and mammary tumors implanted into mice. LPI investigations alsodemonstrated 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 andhis 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 adjunctto the appropriate conventional treatment for cancer. In their book Cancer

and Vitamin C , they concluded that supplemental vitamin C is of benefit tomost cancer patients. The benefit ranged from an increased sense of well-being to a prolongation of survival time in terminal patients to rare completeregressions. However, two clinical studies carried out by Drs. Edward

Creagan and Charles Moertel of the Mayo Clinic and published in 1979 and1985 showed no benefit from supplemental vitamin C on survival time. As

Drs. Cameron and Pauling pointed out, however, the patients in the firstMayo Clinic study had undergone extensive chemotherapy that damaged

their immune systems prior to the use of vitamin C. In the second studysupplemental vitamin C was abruptly stopped after only about two months.

There was also evidence that some of the patients in the placebo group weretaking extra vitamin C, thus muddying the differences between groups.

When Cancer and Vitamin C was first published in 1979, Drs. Cameron andPauling noted that little information was available on the interaction betweenvitamin C and chemotherapeutic drugs. They cautioned that patientsundergoing aggressive chemotherapy expected to be curative should refrain

from taking large doses of vitamin C at the same time in case the vitamin


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interfered with the drug action. There is some evidence that vitamin Cincreases the activity of liver enzymes that detoxify xenobiotics, includingdrugs. When the chemotherapy was merely palliative, they did not believethat 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 afterradiation 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 othersubstances. 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 majorcontributions by Linus Pauling and further discussion of these results.) Only

about 10% of the patients treated by Dr. Cameron in Scotland with vitaminC 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 appropriateplacebos.

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, largedoses of calcium ascorbate (vitamin C), vitamin E, and beta-carotene for

cancer patients undergoing either chemotherapy or radiation. Dr. Prasadacknowledges the accumulation of antioxidant vitamins in cancer cells, butargues that this has favorable biochemical effects, including the inhibition ofoncogenes and the induction of factors that inhibit cell growth, favor

differentation, or induce apoptosis (programmed cell death). In an extensiveand well-referenced recent review published in the Journal of the American

College of Nutrition, Dr. Prasad presented results from cell cultureexperiments demonstrating that the killing effect of many cancer drugs or

radiation on mouse and human cancer cells is enhanced in the presence ofvitamins C or E. Of course, cell culture studies (or animal studies) cannot

always predict what will happen in humans. In another extensive reviewpublished 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 cancertherapeutic 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


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1992 by Dr. Jaakkola and colleagues showed that the provision of Bvitamins, large doses of vitamins C and E, beta-carotene, fatty acids, andminerals in combination with chemotherapy and radiation to patients withsmall-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. Anotherclinical study by Dr. Emmanuel Cheraskin published in 1968 showed that theresponse 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 theoreticalspeculation 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 researchsuggests 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 definitiveconclusions can be drawn.

For more information on vitamin C, see the Linus Pauling

Institute's Micronutrient Information Center.
http://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/index.htmlhttp://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/index.htmlhttp://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/index.htmlhttp://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/index.html

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