Low Dose Radiation Increased the Therapeutic Efficacy of Cyclophosphamide on S180 Sarcoma Bearing Mice

Abstract

We examined whether low dose radiation (LDR) exposure (75 mGy) could increase the therapeutic efficacy of cyclophosphamide (CTX) by comparing the effects of tumor suppression, tumor cell apoptosis, cell cycle and proliferation of bone marrow in vivo. Kunming mice implanted with S(180) sarcoma cells were given 75 mGy whole body gamma-ray radiation exposure and CTX (300 mg/kg) by intraperitoneal injection 36 hours after LDR. Proliferation of bone marrow and tumor cells was analyzed by flow cytometry. Cytochrome c leakage from the tumor was measured by Western-blot. We discovered that tumor growth was significantly reduced in the group exposed to CTX add to LDR. The apoptosis of tumor cells increased significantly after LDR. The tumor cells were arrested in G(1) phase in the groups treated with CTX and CTX + LDR, but cell cycle was more significantly arrested in mice exposed to LDR followed by CTX than in mice exposed only to LDR or CTX chemotherapy. Concentration of bone marrow cells and proliferation index in CTX + LDR mice were higher than those in the untreated mice. LDR or CTX + LDR could induce greater cytochrome c levels and caspase-3 activity in tumors. These results suggest that low dose radiation can enhance the anti-tumor effect of the chemotherapy agent CTX markedly. Furthermore, LDR significantly protects hematopoetic function of the bone marrow, which is of practical significance on adjuvant chemotherapy.

Different responses of tumor and normal cells to low-dose radiation

“…Subsequent research on this topic became a hotspot. Studies have found that normal cells including immune cells, blood cells [4–6], and spermatogonial cells [7] induced by LDR could cause an adaptive response. Thus, LDR improved organism immunity and enhanced the tolerance of normal tissue under radiation.…”

“…This method has been extensively documented by many investigators with different experimental models, including cultured cells and experimental animals [8–11]. Experimental studies have proven that low doses of ionizing radiation induce various cancer types with various effects, including radioadaptive response, activation of immune functions, and enhancement of resistance to high-dose radiation at the initial slope of the cell survival curve [4, 12]. In recent years, studies on the effects of LDR have attracted the attention of scientists in radiation research [12, 13].…”

“…The LDR-induced adaptive response has been associated with cell cycle arrest [5, 6, 9]. However, some studies have reported that only a slight correlation exists between the two [4]. A literature review revealed that certain tumor cells are resistant to the LDR-induced radioadaptive response or show a distinct pattern from normal cells for interval times between LDR and subsequently large doses of radiation [21, 22].…”

Low-dose radiation-induced apoptosis in human leukemia K562 cells through mitochondrial pathways

“…Mitochondrial membrane permeability and the alteration of membrane potentials are essential aspects in the apoptotic process, resulting in release of CytoC and initiation of apoptosis by activating the caspase reaction cascade. Yu et al (32) also discovered that LDR exposure (0.0075 Gy) increased the therapeutic efficacy of cyclophosphamide (CTX) to S180 sarcoma cells. The apoptosis of tumor cells increased significantly following LDR.…”

Low-dose Radiation Induces Antitumor Effects and Erythrocyte System Hormesis

“…5 days after implantation of S180 sarcoma cells, the mice's tumor growth was observed every other day by measuring the maximum horizontal diameter (a) and the maximum vertical diameter (b) twice with slide gauge and then the average values were calculated. The tumor's volume (V) was calculated with the formula: V=1/2ab 2 (Yu et al, 2007). Then the tumor's growth graph was drawn.…”