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Hyperthermia is an effective adjuvant in radiation oncology. While presently used as a local therapy, regional and systemic hyperthermia are under active investigation. However, little is known of the effects of hyperthermia on bone marrow stem cells. Since blood flow in marrow is via a sinusoidal vascular network, the various heating modalities may be much more effective raising the temperature of bone marrow compared to other normal tissues. Furthermore, a reduction in pH in marrow may result leading to marked sensitization of cells to heat. Therefore, bone marrow could be the limiting normal tissue in systemic or regional hyperthermia where substantial marrow is included the field.

This investigation will determine: 1. The response of murine tibial bone marrow stem cells (CFU-GM) heated in situ to temperatures of 41 degrees- 45 degrees C; 2. The development and decay of thermotolerance in marrow stem cells; 3. The effect of stimulating stem cell proliferation on the hyperthermia response (e.g., 24 hr after 150 cGy or 48 hr post-injection of 200 mg/kg AraC); 4. The kinetics of stepdown heating, and 5. The effect of pH and the importance of blood flow to the heat response of marrow stem cells. The development and decay of thermotolerance will be examined after priming temperatures of 40 degrees and 42 degrees (relevant to whole-body hyperthermia) and 44 degrees (relevant to local and regional hyperthermia). The impact of stepdown heating (15 min @ 44 degree + 40.0 degree or 42 degree for up to 4 hr) on the development of thermotolerance and on subsequent heat sensitivity will be determined.

Tibial marrow will be heated by waterbath immersion with mice under barbiturate anesthesia. CFU-GM colonies will be grown in soft agar with lung conditioned medium. The percent of CFU-GM in the S phase will be assayed by hydroxyurea suicide. Immigration of circulating stem cells will be eliminated by irradiation of the whole animal with 850 cGy while shielding the tibia. Hyperthermia dose-effect curves will be constructed to establish Do, Dq, & n, and alpha & beta. Marrow pH will be determined with microelectrodes in cross sections of the tibia, and blood flow will be determined by radiolabeled microspheres in heated vs. the unheated tibia.

Little is known of the impact of thermotolerance, stepdown heating, pH or rate of proliferation on the parameters of marrow stem cell hyperthermia sensitivity or on the outcome of fractionated therapy. The results of this study have the potential for influencing the design of clinical heat/radiation and heat/chemotherapy protocols, particularly for regional or whole-body hyperthermia.
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