These studies are predicated on the hypothesis that the cellular membrane, specifically the organizational integrity of the membrane lipids, is the initial target of hyperthermia. The continuing goals of these studies are to delineate the direct or indirect response subsequent to the membrane insult which leads to cell death, to differentiate the mechanisms responsible for heat and irradiation killing and to develop protocols which enhance thermosensitivity. One test of the hypothesis is to examine the thermosensitivity of cells and tissues grown under protocols which modify in a systematic manner the lipid constituents of their membranes. The thermal and irradiation sensitivities of a series of organisms progressing in biological complexity from a fatty acid auxotroph of E. coli, K1060 to an in vivo solid tumor, the CA755 mammary adenocarcinoma transplanted to a BDF1, mouse will be studied. One protocol which varies the fatty acid supplement of the medium for the L1060 system exerts near absolute control on the biochemical make up and biophysical characteristics of the cell membrane. Another protocol utilizes variation in dietary linoleate initiate adaptive responses for the solid tumor model which tend to maintain host tissue membrane and to a lesser extent tumor membrane properties for optimal function. In this system there are protocols (e.g., local and systemic anesthetics, cholesterol inhibitors) which interfere with the diet-mediated adaptive responses in membrane composition. Falling between these extremes in biological complexity are two models, the E. coli B/r and Bs-1 and V79 and P388 mammalian cells. Each protocol includes the exhaustive analysis of membrane constitutents (phospholipid species, relative proportion, concentrations, and fatty acid patterns; protein concentration and two dimensional PAGE patterns, and when appropriate cholesterol concentration, lipopolysaccharide concentration, fatty acid pattern and microviscosity), the results of which will be examined in relation to shifts in the organisms thermal sensitivity. These models provide a means for comparing the mechanisms of hyperthermia-induced membrane-initiated cell killing and killing by irradiation. These studies of adaptive thermotolerance and hyperthermic lethality are intended to answer questions relevant to the design of clinical studies using hyperthermia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA024872-10
Application #
3166600
Study Section
Radiation Study Section (RAD)
Project Start
1988-06-05
Project End
1991-05-31
Budget Start
1989-06-01
Budget End
1990-05-31
Support Year
10
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Herman, P P; Yatvin, M B (1994) Effect of heat on viral protein production and budding in cultured mammalian cells. Int J Hyperthermia 10:627-41
Wainberg, R H; Walden Jr, T L; Stebler, B A et al. (1991) Effect of diet on hyperthermia-induced cell lethality and prostaglandin release. Prostaglandins 41:501-13
Wainberg, R H; Watkins, D K; Stebler, B A et al. (1990) Effects of heat and other agents on amino acid uptake in Escherichia coli. Int J Hyperthermia 6:597-605
Ianzini, F; Guidoni, L; Simone, G et al. (1990) Effects of decreased pH on membrane structural organization of Escherichia coli grown in different fatty acid-supplemented media: a 31P NMR study. Arch Biochem Biophys 278:1-10
Yatvin, M B; Clark, A W; Siegel, F L (1987) Major E. coli heat-stress protein do not translocate: implications for cell survival. Int J Radiat Biol Relat Stud Phys Chem Med 52:603-13
Yatvin, M B; Vorpahl, J W; Ghosh, S K et al. (1987) Heat sensitivity and membrane properties of metastasizing and non-metastasizing rat mammary tumors. Radiat Environ Biophys 26:89-101
Yatvin, M B; Dennis, W H; Elegbede, J A et al. (1987) Sensitivity of tumour cells to heat and ways of modifying the response. Symp Soc Exp Biol 41:235-67
Yatvin, M B (1987) Influence of membrane-lipid composition on translocation of nascent proteins in heated Escherichia coli. Biochim Biophys Acta 901:147-56
Yatvin, M B; Gipp, J J; Klessig, D R et al. (1986) Hyperthermic sensitivity and growth stage in Escherichia coli. Radiat Res 106:78-88
Yatvin, M B; Smith, K M; Siegel, F L (1986) Translocation of nascent non-signal sequence protein in heated Escherichia coli. J Biol Chem 261:8070-5

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