Study of Low Dose Irradiation Enhancing the Effect of Chemotherapeutic Agents against Leukemia and Its Mechanism / 中国实验血液学杂志

ABSTRACT

For effectively enhancing the anti-leukemia effect of chemotherapeutic agents, and meanwhile decreasing the side effect of these agents, the study has been made to explore the synergistic effect of low dose irradiation (LDI) combined with Ara-C on murine leukemia and its mechanism. Firstly, an optimal scheme of low dose total body irradiation combined with Ara-C was established in L615 leukemia (T lymphocytic leukemia) mouse model. The machanism of the enhancing effect was explored by patho-morphological observation, examination of residual leukemia cells, the expression of GM-CSF on the surface of marrow stromal cells and in the bone marrow cultural supernatants. The results showed that the optimal scheme was 300 cGy irradiation at 4 days after inoculation of leukemic cells followed by Ara-C 30 mg/kg x 3 days in an interval of 1, 2 or 3 days after irradiation. The mean survival time of the L615 leukemia mice in LDI + Ara-C combined treatment groups was longer than that of control groups. The percentage of long-term survival mice (> 30 days) was the highest (58% - 72%), too. 17% of the mice were be cured. The numbers of blood leukocytes and marrow nucleated cells were transiently decreased in combined treatment group, and then recovered rapidly. Slight myelosuppression and marrow sinus dilation and congestion were seen after 300 cGy irradiation. The expression of GM-CSF either on the stromal cells or in marrow cultural supernatant after irradiation increased strikingly (P < 0.05). Therefore, LDI combined with Ara-C possesses synergistic effect. The mechanism is possibly related to three facts LDI could increase the permeability of bone marrow sinus; LDI could promote marrow stromal cells to produce some cytokines (such as GM-CSF, etc.) which drive leukemia cells into cell cycle to make the cells more sensitive to chemotherapeutic agents; and LDI could augment Ara-C-induced cytotoxicity through the mechanism of apoptosis.