WR-2721,PF4 Provides Hematopoietic Protection From Total Body Irradiation In Mice

Up to now there are four primary methods to treat malignant tumors, including Operation, radioherapy, chemotherapy, and biootherapy. But patients are likely to experience acute or chronic side effects resulting from radioherapy and chemotherapy. After several decades of preclinical and clinical research, WR-2721(Amifostine), the first approved radioprotective drug, has been introduced into the clinic and applied in auxiliary therapy of many kinds of tumors. Amifostine is a selective broad-spectrum cytoprotector of normal tissues. It is converted by alkaline phosphatase found on the cytomembrane of normal endothelium to the active compound WR-1065 in vivo. WR-1065 protects normal cells by scavenging free radicals and binding to active derivatives of antineoplastic agents. The selectivity of Amifostine for normal tissue is a result of the absence of alkaline phosphatase on thetumorous endothelium cell and the acid environment of the tumor decreasing WR-1065 intake. In clinical studies, it has been demonstrated that Amifostine can decrease the hematologic toxicity, nephrotoxicity, ototoxicity and neurotoxicity induced by antineoplastic drug. Amifostine has FDA-approved labeling for patients suffering from advanced ovarian cancer and non-small-cell lung cancer to reduce cumulative renal toxicity of cisplatin. The recommended dose in adults is 910 mg/m2, administered 30 minutes before the start of chemotherapy.Platelet factor 4 (PF4) is a 7.8-kDa protein synthesized by megakaryocytes, stored in a -granules as a noncovalent tetramer and released from activated platelets. PF4 have two important biologic activities including negative regulator of hematopoieses and angiogenesis. It can reversibly inhibit the proliferation of the normal hemopoietic stem/progenitor cells, decrease their sensitivity to the damage of radiotherapy and chemotherapy, and it has not influence on the tumor cells. Therefor, PF4 can be a radioprotector of hematopoietic system. PF4 can inhibit tumor growth through the machanism of anti-angiogenesis in addition. The tumor patients who received radiotherapy and chemotherapy in combination with PF4 could decrease hematopoietic damage and inhibit the growth of tumors through inhibiting angiogenesis. In this study, we emphasize to research hematopoietic protective effect of and compare with WR-2721, in order to search a kind of new radioprotector.AIM: To compare the hematopoietic protective effects of WR-2721 or PF4 from total body irradiation in mice. METHODS: BALB/c male micewere randomly divided into control group, exposure group, protection group with WR-2721 and protection group with PF4. The last three groups were irradiated with 7.0Gy 60Co # rays. The number of their bone marrow nucleated cells was counted; the forming ability of CFU- GM, the change of cell cycle and cellular necrosis or apoptosis was mensurated by flow-cytometry. The bone marrow histopathology was also observed. RESULTS: WR-2721 and PF4 could increase the number of bone marrow nucleated cells, decrease the hematopoietic cellular necrosis and apoptosis, and improve the forming ability of CFU-GM. The effects of PF4 was stronger than WR-2721. CONCLUSION: Administered before total body irradiation in mice, WR-2721 and PF4 could decrease the radiation damage of the bone marrow, be protective agents of the bone marrow while radiotherapy. The hematopoietic protective effect of PF4 was better.