IMedical Hypotheses

Protein-Induced Hyperthermia for Liver Cancer Treatment E. J. NORMAN Hem&o&y-Ontwbgy 45267-0562, USA

Divisbn, University of Cincinnati Medical School, 231 Bethesda Ave, Cincinnati, OH

Abstract - It is suggested that the thermic effect of protein be exploited as a means of hyperthermia therapy in the treatment of liver cancer. Oral ingestion of high amounts of protein or intravenous amino acid therapy could generate heat directly within the hepatocytes primarily through urea synthesis. This approach could enhance the effects of conventional hyperthermia or radiation therapy.

Introduction Primary hepatocellular cancer (PHC) and metastatic liver cancer that are unresectable are presently incurable (1). PHC is rare in the US and Europe but may be the most common malignancy in the world due lo a high incidence in Africa and Asia (2, 3). The pathogenesis of liver cancer in man is unknown (4). Hepatitis B virus infection, afiatoxin consumption and protein malnutrition have been implicated as etiologic factors (4, 5.6). PHC has not been found to be common in regions where kwashiorkor is rare (4). Populations on a high protein diet such as Eskimos in Greenland (7) and Canada (8) have a low incidence of PHC. However, it is more common in Alaskan natives and is associated with hepatitis B virus infection (9). Hyperthermia in liver cancer treatment

Hyperthermia treatment of cancer is based on the principle that malignant cells are selectively more Date received 27 __May _ 1991 ___ Date scceped 28 June 1991

sensitive to heat than normal cells (10). It has been used to enhance the effects of radiation therapy (11, 12). Radiofrequency hyperthermia (13) and hyperthermic liver perfusion (1) have been employed in the treatment of malignant liver tumors. Failure to produce disease-free states and toxicities suffered by normal tissue suggest that other treatment approaches be explored. Protein ina!uced hypertkrmia

Protein has a thermic effect greater than other nutrients. The rise in metabolism after ingestion of carbohydrate or fat is only about 6%. However, the increase in metabolism after consuming protein is about 30%. The extra energy set free generates heat (14). Krebs attributed the thermic effect of protein to heat produced from urea production and amino acid degradation in the liver (15). Four moles of ATP are hydrolyzed for every mole of urea produced, liberating 7.3 kcals per mole of ATP (16, 17). Dauncey and Bing-

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ham demonstrated that amino acids significantly influence metabolism to a greater extent than glucose (18). In addition, they found a close correlation between heat production and urea excretion, indicating urea synthesis in the liver accounts for part of the extra heat production (18). Individuals consuming 225 g of protein during 24 h produced an average of 1.8 moles of urea (18). Furthermore, it has been shown that there is a linear relationship between urea production and serum amino acid concentration (19). Gastrointestinal tolerance of the high protein meal was the factor limiting urea production rather than the liver’s synthetic ability (19). Ingestion of excess protein is not harmful provided approximately 750 ml of water per 100 g of protein is given to prevent dehydration (20, 21, 22). A protocol to achieve maximum serum amino acid concentrations through oral protein ingestion has been described (19).

cancer. Cancer Research

5. Doll R. The epidemiology 6.

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8.

9.

10. 11. 12. 13.

Conclusion Protein-induced hyperthermia either through diet or IV. amino acid mixture may produce liver tumor remission. More likely it may exert a synergistic effect when combined with other modalities of therapy such as hyperthermic hepatic perfusion, radiation or chemotherapy. Potentially it offers a simple, specific, and non-toxic hy-perthennic therapy for the treatment of liver cancer.

14. 15.

16. 17. 18.

References 19. Skibba J L. Quehbeman E J. Tumoricidal effects and patient survival after hyperthermic liver perfusion. Arch Surg 121: 1266-1271. 1986. El-Domeiri A A, Huvos A G, Goldsmith H S. Foote F W. Primary malignant tumors of the liver. Cancer 27: 7-11.1971. Heyward W L. Lamer A P, Bender T R, Hardison H H. Dohan P H, McMahat B J, Francis D P Primary heptocellular carcinoma in Alaskan natives, 1969-1979. Int J Cancer 28: 47-50. 1981. Higginson J. ‘Ihe Geographical pathology of primary liver

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2% 1624-1633,1%3. of cancer. Cancer 45: 2475-2485,

1980. Falk H. Liver. pp668-682 in Cancer Epidemiology and hevmtion (D Scholtenfeld and J F Fraumeni. eds) W B Saunders Co. 1982 Skinhoj P, Hansen J P H, Nielsen N H, Mikkelse F. Occurrence of cirrhosis and primary liver cancer in an Eskimo population hyperendenicaIIy infected with heaptitis virus. Amer J Epidemiol 108: 121-125, 1978. Schaefer 0. Hildes J A, Medd L M, Cameron D G. The changing pattern of necplastic disease in Canadian Eskimos. Can Med Assoc J 112: 1399-1404, 1975. Lamer A P, McMahon B J, Alberts S R, Popper H, Heyward W L. Primary liver cancer in Alaskan Natives, 198&1985. Cancer 60: 1915-1920. 1987. Anderson R L, Kapp D S. Hypcrthermia in cancer therapy: current status. Med J of Australia 152: 310-315. 1990. Langlands A. Hypertbcmria in the treatment of cancer. Med J of Australia 152: 283-284, 1990. Reinhold H S, Gvergaard J. Hyperthermia in clinical oncology. Eur J Cancer 26(8): 915-916, 1990. Nagata Y, Hiraoka M, Akuta K. Abe M. Takahashi M. Jo S. Nishimura Y, Masunaga S, Fukuda M, Imura H. Radiofrequency thermotherapy for malignant liver tumors. Cancer 65: 173G-1736, 1990. Bogen L J, Briggs G M. Calloway D H. Nutrition and Physical Fitness. W B Saunders Co, 1%7. Krebs H A. The metabolic fate of amino acids. pp125-176 in Mammalian Protein Metabolism, VoI 1 (H N Munro and J B Allison, eds) Academic Ptess. New York, 1%4. Lehninger A L. Biochemistry. Worth Publishers Inc. New York. 1970. Stryer L Biochemistry. W H Freeman & Co, New York, 1988. Dauncey M J. Bingham S A. Depmknce of 24 h energy expenditure in man on the composition of the nutrient intake. Br J NUL 50: l-13. 1983. Rafoth R J, On&d G R. Urea synthesis after oral protein ingestion in man. 56: 1170-1174,-1975. Paraira M D. Conrad E J. Hicks W. Ebnan R. ‘Iberaneutic nutrition with tube feeding. J Am M&I Assoc 156: 8ld-816. 1954. Wilson W S, Meinert J K. Extraccllular hyperosmolarity secondary to high-protein nasogastric tube feiding. Ann Med 47: 585-590. 1957. Gault M H, Dixon M E, Doyle M, Cohen W M. Hypematremia, atiemia, and dchydraticn due to high-protein tube feeding. Ann Intern Med 68: 778-791, 1968.

Protein-induced hyperthermia for liver cancer treatment.

It is suggested that the thermic effect of protein be exploited as a means of hyperthermia therapy in the treatment of liver cancer. Oral ingestion of...
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