Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP145) MIBG plus hyperglycemia sensitizes bone marrow CFU-F but not CFU-C to Cs-137 irradiation in Situ.

O'Hara, M,*,2, Pollard, M.1, Pocceschi, M.1, Leeper, D.1, 2 Center for Devices and Radiological Health, Rockville, MD, USA1 Radiation Oncology, Philadelphia, PA, USA

ABSTRACT- Introduction: Melanoma xenografts are sensitized to hyperthermia, radiation and alkylating agents by hyperglycemia and the respiratory inhibitor meta-iodobenzylguanidine (MIBG). Hyperglycemia and MIBG reduce pHi, pHe, the nucleoside triphosphate:Pi ratio and increase mean pO2 in tumors, but in liver there are only minor changes (Zhou et al., 2000). Axial bone marrow may have hypoxic areas (Allalunis-Turner and Chapman, 1986) and may be chronically acidotic. Thus, bone marrow may be a limiting normal tissue for the techniques that enhance tumor acidification. However, we showed that heating tibias of Balb/c male mice in the presence or absence of hyperglycemia ± MIBG at the same concentrations as used for sensitization of tumors did not sensitize bone marrow to 42°-hyperthermia. Results: To investigate the sensitivity to radiation, bone marrow was irradiated in situ (Cs-137) after administration of 2 g/kg oral glucose ± 22.5 mg/kg MIBG, s.c. After irradiation tibial marrow was flushed out, nucleated cells counted, CFU-C grown in soft agar with colony stimulating factor and CFU-F grown on plastic, and the surviving fraction determined. The radiation survival curve for CFU-C was identical whether bone marrow was irradiated in the presence of excess glucose alone, MIBG alone or excess glucose+MIBG. The Do1.15 Gy and the Dq0.1 Gy. On the other hand, the radiation survival curve for CFU-F exposed to excess glucose alone or MIBG alone was resistant to radiation compared to controls with a Do2.4 Gy and a Dq1.0 Gy compared to a Do1.4 Gy and Dq1.0 Gy for controls. By contrast CFU-F exposed to excess glucose+MIBG exhibited a survival curve without a shoulder, the Do1.4 Gy and the Dq0 Gy. Conclusions: Similar to the results after 42°-hyperthermia, excess glucose plus respiratory inhibition did not sensitize committed precursors to radiation. In CFU-C lactic acidosis and oxygenation either did not occur or had no effect on radiation response. This would suggest an increase in therapeutic gain after thermoradiotherapy. By contrast exposure of CFU-F to excess glucose alone or MIBG alone may lead to hypoxia and radioresistance. In addition CFU-F may be acidified by the combination of glucose+MIBG, which resulted in the inhibition of repair. (Supported in part by USPHS Grant P01 CA56690).

Key words: CFU-C, CFU-F, hyperglycemia, MIBG

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2005 RRS