Clinical Research On The Treatment Of Metastatic Spinal Tumors Percutaneous Injected With Recombinant Adenovirus P53

[Background]Spinal bone metastases is the most common disease site. According to statistics, the incidence of spinal metastases of primary malignant bone 35-40 times. Abroad each year, according to statistics newly diagnosed malignant tumors,2/3 of cases have occurred in other parts of the transfer. With the treatment of primary malignant tumors of the continuous improvement of patient survival constant desire to extend its influence distant metastasis has become an important survival and quality of life factors. Caused by spinal metastases pathological fracture, spinal cord compression, hypercalcemia, and bone marrow failure and other complications, accelerated the development of the disease, which seriously affect the quality of life of patients with malignant tumors. Despite the recent years, many scholars the pathogenesis of spinal metastases, control methods, have made unremitting efforts, but so far not been that effective radical means. As the complexity of spinal anatomy important to the organizational structure and the surrounding close relationship, are multi-use of radiotherapy, chemotherapy, small operation, but for spinal metastases radical subtotal or complete resection difficult, and the great trauma, concurrent disease, which is why a comprehensive spine treatment of metastatic tumors is very important.p53 gene is most closely related with the cancer tumor suppressor gene, 60% of the tumor for p53 gene abnormalities (including point mutations, allelic loss, rearrangement, insertion, gene fusion, etc.). p53 gene and tumor occurrence, development and clinical efficacy are closely related. Study suggests that, p53 genes in tumor treatment mainly from P53 protein involved in the regulation of cell cycle regulation, DNA repair, cell differentiation, apoptosis and other anti-cancer biological functions. p53 by upregulating P21, mdm2, GADD45 gene in DNA damage such as caused by the G1/S pause play an important role; p53 C-terminal to detect DNA damage in a firm with the combination of DNA damage to p53 and the formation of complex, on the one hand can regulate and activate genes involved in gene repair, the other using their own enzyme activity with the outside, directly involved in the repair gene; P53 and apoptosis by regulating the number of related genes, such as Bax, DR5, IGFs and growth factor signal interference pathway to induce apoptosis; p53 gene conditions affect cells on chemotherapy sensitivity, wild-type p53 gene transfer can increase the radiotherapy and chemotherapy on tumor cells lethal. In addition to directly affect the biological status of cells, p53 can also change the environment for the survival of tumor exert effects. P53 protein can stimulate the endogenous TSP1 gene, positive regulate TSP1 expression, inhibition of tumor angiogenesis; P53 protein may also be conducted through the cells and the regulation of the immune system, play a "bystander effect" killing tumor cells. In a variety of tumors in clinical trials, also confirmed that rAd-p53 anti-cancer effect.Recombinant human p53 adenovirus injection is the world's first listing of generic drugs, by the State Food and Drug Administration approved for clinical treatment of malignant tumors. This study investigated the recombinant human p53 adenovirus (rAd-p53) in the treatment of spinal metastases in effect. The project will minimally invasive surgery and gene medicines percutaneous treatment of spinal metastases combined with traditional radiation therapy, chemotherapy, surgery compared with minimally invasive of the project, side effects, fewer complications, less pain, less cost, efficacy and good advantages also apply to the frail elderly, patients with cardiopulmonary dysfunction. This study will be the clinical treatment of spinal metastases to provide a safe, convenient and efficacious, minimally invasive new treatment method for the comprehensive treatment of metastatic spinal tumors provide a new approach.[Methods]This study selected from lung squamous cell carcinoma cases of spinal metastases,36 cases were confirmed by histopathological spinal metastases, and the existence of p53 mutations tested, including 16 male and 20 female, aged 32 to 73 years The average age of 48.3 years.22 cases of thoracic vertebrae; lumbar 9; cervical 3; sacral vertebrae in 2 cases.6 cases of benign tumors, including giant cell tumor in 4 cases,2 cases of osteochondroma, aged 32 to 73 years, mean age 36.3 years, thoracic,5 cases; lumbar in 1 case. According to the pre-designed randomized group program, the selected cases were randomized into control and experimental groups of 18 patients. The experimental group first percutaneous injection of recombinant human P53 adenovirus (1×1012VP)×4 weeks,2 days after intratumoral injection of routine radiotherapy, radiotherapy dose 50Gy/25f/5-6w. The control group received only the same conventional radiotherapy. Patients and their families signed the informed consent, and reported by the hospital ethics committee approval. Observation of the experimental group and control group patients after treatment for 4 weeks and 8 weeks, pain relief, according to VAS pain visual analogue score (VAS, Visual Analogue Score) for pain assessment, conducted before and after treatment comparison group and treatment groups between the two groups, evaluation of the experimental group and control group patients after treatment for 4 weeks and 8 weeks, the relief of pain; Histopathological study group and control group after 8 weeks treatment of tumor cell necrosis rate; immunohistochemical staining method to measure the P53 protein in cancer tissues; ELISA assay of serum anti-adenovirus antibody specific P53 gene; observed adverse drug reaction, testing liver function, kidney function, blood, injection of recombinant human P53 compared before and after the change of adenovirus, focusing on changes in body temperature observed.[Results] 1. Pain relief:The experimental group and control group were compared line group, the experimental group patients after treatment for 4 weeks and 8 weeks, VAS decreased significantly compared with before treatment (P <0.01), while the control group after treatment in 4 Week VAS less than before treatment and after 8 weeks and no significant treatment differences (P>0.05). Experimental group and control group between the two groups, the experimental group after treatment for 4 weeks and 8 weeks, VAS was significantly lower than the control group (P<0.01).2. Tumor cell necrosis rate:the experimental group after treatment was significantly higher in tumor cell necrosis (P<0.05), the experimental group biopsy histopathologic examination shows fibrosis with lymphocyte infiltration of tumor tissue or obvious necrosis.3. P53 protein in cancer tissue:36 cases of tumor samples,36 samples before treatment showed no expression of p53 protein; treatment and control group sample of 18 cases yet to see the expression of p53 protein in the experimental group,18 cases of samples positive expression of p53 protein occurs.4. Serum anti-p53 adenovirus specific antibodies:36 cases of tumor samples, 36 samples before treatment, serum anti-p53 adenovirus-specific antibodies were negative; treatment,18 cases in control group samples to detect the specific anti- p53 gene adenovirus antibodies, the experimental group sample of 18 cases the first 4 weeks of the injection of serum anti-p53 adenovirus-specific antibodies all were positive, including strong positive 27.8%(5/18), medium positive was 72.2%(13/18).8 weeks injection of serum anti-p53 adenovirus-specific antibodies all were positive, including strong positive 77.8%(14/18), moderate positive 22.2%(4/18).5. Adverse reactions:patients liver function, kidney function, blood in the recombinant human p53 adenovirus injection no significant change before and after. Clinical application of rAd-p53 treatment of spinal metastases is basically safe, adverse reactions were transient and self-limited fever. Patients in the experimental group were 18 cases, mild fever or fever cases (less than 38 OC) 27.8%, moderate fever cases (38.1～39 OC) 72.2%, no cases of high fever (39.1～410C). Most patients start treatment 5-7 h, fever, continued 6-13h.[Conclusion]The results show that recombinant human p53 adenovirus gene therapy can inhibit tumor growth, combined with radiotherapy can make up for lack of a single radiation to improve sensitivity to radiotherapy, effective treatment for spinal metastases; clinical use of safe, adverse reactions were transient and self-limited fever.