Enhancement of murine bone marrow ablation by combining whole body hyperthermia with total body irradiation and cyclophosphamide

Abstract

Bone marrow ablation using combined whole body hyperthermia (WBH), total body irradiation (TBI), and cyclophosphamidel (Cy) was investigated in C3H f/Sed mice to demonstrate cytotoxic synergism between the three modalities. TBI was given on day 0. WBH treatment was for 1 hr at 41.8°C, given in daily sessions for 1, 2 or 3 consecutive days following TBI. Total cyclophosphamide doses were 160 and 240 mg/kg given in 2 daily injections on days 1 and 2 following TBI. Polymorphonuclear leukocyte and lymphocyte numbers were determined by differential cell counts. The total peripheral blood cell counts were also determined. WBH alone, given in daily sessions for 3 days, did not reduce the total peripheral blood cell counts. However, when WBH was added to TBI (6.3 Gy) peripheral blood cellularity was reduced on day 2, but no significant heat/radiosensitization was evident after day 2. WBH (3 (daily sessions) significantly reduced the peripheral blood cellularity and resulted in bone marrow ablation when it was combined with TBI and Cy. CY (160–240 mg/kg) combined with TBI (5.4 Gy) resulted in bone marrow ablation and subsequent death in 14–22% of mice treated; 60–100% of mice died from bone marrow ablation when WBH was added to TBI (5.4 Gy) and Cy (160–240 mg/kg). Femoral and vertebral tissue sections showed total loss of progenitor cells when WBH, TBI (5.4 Gy), and Cy (240 mg/kg) were combined whereas lessor treatment was associated with histologically verified reconstitution of progenitor cells inside the marrow cavities. These studies indicate that bone marrow ablation can be achieved when using WBH in combination with lower doses of TBI and Cy.