| Background and objective:Since 1960s, many researches on radiosensitizer have been carried out and a series of in vivo and in vitro protocols for testing radiosensitization have been established. Though a large number of agents had shown significant radiosensitize effect in vivo and in vitro, their clinical efficacies are disappointing. Up to now, MISO(misonidazole) is the only agent that has entered the phase III clinical trial. However, serious neurotoxicity limits its further clinical application.Arsenic trioxide (As2O3) has shown itself to be an effective and relatively safe agent for the treatment of acute promyelocytic leukemia (APL). A complete remission rate of 80-90% has been achieved among the patients with refractory or relapsed APL The main mechanism lies in the induction of apoptosis and the inhibition of proliferation. Further study has shown that As203 can inhibit variant solid tumor as well. After the analysis of someliteratures published previously, we were surprised to find that As203 in fact is a good potential of radiosensitizer for solid tumors.Firstly, almost all the researches have concluded that As203 is able to induce phase G2/M cell cycle arrest while decreasing the proportion of phase S cell. Since phase G2/M cells are the most sensitive to radiation while phase S cells are tolerant, the arrest of G2/M cells means the increase of radiosensitivity of the tumor.More and more literatures have showed that glutathione(GSH) is involved in the mechanism of apoptosis induced by As203. It reacts with arsenic trioxide to form a type of oxidized GSH(GSSG) and cause the depletion of intracellular GSH. As it has been well demonstrated, GSH can repair the radio-induced organic radicals by hydrogen donation. The depletion of intracellular GSH results in a decrease of cell repair ability and an increase of radiosensitivity. And this is the second reason the As203 may be a candidate of radiosensitizer.It has been confirmed that AsA triggers apoptosis through a mechanism associated with the down-regulation expression of bcl-s gene. It is now quite certain thatbcl-2 gene was associated with radiosensitvity. The down -regulation of its expression causes an increase of radiosensitivity.The study results mentioned above all imply a possibility that As203 may be a promising novel radiosensitizer. Further more, the clinical safety of the As203 has been proven through a large number of treatments in APL patients. This enables us to avoid the embarrassment met during the exploitation of MISO: a promising radiosensitizer, which we have spent a lot of energy on in the laboratory, could not be applied clinically because of its fatal toxicity.In this study, in vitro and in vivo radiosensitivity of As203 was detected and the pilot clinical application was conducted. Method and materials In vitro studyCNE-1 cell line derived from nasopharyngeal squamous carcinoma was exposed to As203 of different concentration ranging from 0 to 2.5 y mol/L for 48h. MTT assay and clone forming assay were carried out to test the cytotoxicity ofAs2O3, and the concentration needed to inhibit 50% of cellsurvival (IC50) was calculated. DNA flow cytometry was performed to access the influence of As203 on cell cycle distribution. A concentration below IC50 was then chosen in the radiosensitivity assay. Cell survival curve was analyzed using multitarget single hit model. Radiosensitivity ability was determined by the parameter of Do and Dq derived from cell curve. In vivo studySCID mice bearing CSNET-1 cell were used in this study. CSNET-1 was a poorly differentiated squamous nasopharyngeal carcinoma cell line established by our laboratory. Twelve days after the inoculation of tumor mass into the right armpit of the mice, all the mice were randomized into control group and experimental group. Each group was further divided into 4 subgroups that would receive irradiation of 0,2,4 and 6 Gy, respectively. As203 at a dosage of 4mg/kg body weight were administered i.p. for consecutiv...
|
PDF Full Text Request