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Heat Radiosensitization and the Level of DNA Polymerases and ß of Human Colony-forming Unit-Granulocyte-Macrophage and Myeloid Leukemias Sensitive and Resistant to Chemotherapeutic Agents¹

Department of Radiation Research [N. F. M.] and Biochemical Pharmacology [H. M., K. J. S.], City of Hope National Medical Center, Duarte, California 91010

In these studies, heat radiosensitization in normal human colonyforming unit-granulocyte-macrophage (CFU-GM) and several different leukemic cell lines sensitive or resistant to chemotherapeutic agents were measured. Extent of heat radiosensitization was then correlated with the level of DNA polymerases and ß in control and heat-shocked cells in order to examine whether there is a positive correlation between the degree of heat radiosensitization and the level of these enzymes. Our results show that human bone marrow CFU-GM have an x-ray response with D₀ of 1.56 Gy and a small amount of heat radiosensitization with a thermal enhancement ratio (TER) of 1.2. K562, a human erythroleukemic cell, showed a D₀ of 1.32 ± 0.2 Gy and TER of 1.4. However, in contrast to normal CFU-GM which showed no shoulder in the X-ray survival curve, K562 cells showed a small shoulder with a quasi-threshold dose, (D_q) of 2 Gy and n of 2. K562 cells resistant to chemotherapeutic drugs such as 1-ß-D-arabinofuranosylcytosine and etoposide (VP-16) showed D₀ of 1.47 ± 0.13, and 1.77 ± 0.18 Gy; D_q of 4 and 0 Gy; and n of 5 and 1; and TER of 1.6 and 2, respectively. The level of DNA polymerases and ß activity and their respective mRNA levels were approximately the same in all cells. The reduction in the level of DNA polymerase ß after heat treatment however, correlated with the TER obtained for various leukemic cells.

These studies indicate that normal CFU-GM and variety of human leukemic cells show only a small amount of heat radiosensitization. However, drug-resistant leukemic cells show a higher amount of heat radiosensitization than their drug-sensitive parent line. This suggests that hyperthermia may be beneficial in eradicating drug-resistant leukemic cells when combined with X-ray. Furthermore, the inactivation of DNA polymerase ß activity results in a higher amount of heat radiosensitization.

¹ This work was supported by NIH Grant CA-33572 and the American Cancer Society Grant CH265.

² To whom requests for reprints should be addressed, at Radiation Oncology Research Laboratory, CED-200, University of California, San Francisco, San Francisco, CA 94143.

³ Scholar of the Leukemia Society of America.

Received 5/ 3/89. Revised 10/23/89.