Effects Of Teniposide Combined With Semustine On O~6-methylguanine-DNA Methyltransferase Expression In Patients With Glioma

Effects of teniposide combined with semustine on o6-methylguanine-DNA methyltransferase expression in patients with gliomaBACKGROUND & OBJECTIVEGlioma is a tumor derived from neuroectodermal glial cells, accounting for 35.2% to 61.0% of intracranial tumors, an average of 49.7%. Because the active proliferation is one of the pathological features of glioma tumor cell, it mixed with normal tissue and often attack along the two kinds of classic paths:First, there are two ways which glioma tumor cell migrate along the myelinated nerve fibers, the corpus callosum and the former cross, which is the main migratory path of glioma, so tumors can spread from one side of the brain hemisphere to contralateral hemisphere; Second, the tumor cells invase along the vascular basement membrane, the formation of new blood vessels is the guide structure of diffusion of tumor cells. Tumor cells can produce toxins or soluble substances, so that the surrounding tissue lose the ability to resist the invasion, the higher degree of malignancy, the features more obviously. Because of glioma characteristics of invasion, infiltrative growth, and the boundaries between the surrounding brain tissue and tumor is unclear, so the treatment is extremely difficult. Operation is still difficult to completely remove. Post-operative radiotherapy can improve the treatment of glioma, but because of limits of radiation dose, and there are comparative parts of the tumor are not sensitive to radiation therapy,so the majority of patients is inevitable recurrence. The method of gene therapy have been emergeing in recent years did not enter clinical stages. Therefore, the chemical treatment has become an important component of comprehensive treatment for postoperative glioma, although chemotherapy for brain glioma has been used for several decades, and there have been a number of chemotherapy programs and chemotherapy drugs, but its efficacy is still not satisfactory. How to improve chemotherapy efficacy of glioma become a research hotspot.In recent years, scientists found that 06-methylguanine-DNA methyltransferase (MGMT) can specificly repair alkylated tumor cells that cause tumor resist to drugs, it was one of reason that alkylating chemotherapeutic drugs which widely be used in the current clinical failure to treat glioma. At present, alkylating agent were widely used in clinic, such as:Nimustine (ACNU), Lomustine (CCNU), and new drug temozolomide (TMZ), were unable to obtain satisfactory effect, how to overcome the resistance caused by MGMT has become a breakthrough point. This part of study explored the relationship between MGMT expression in brain and effects of Teniposide (VM-26) combined with Me-CCNU, it aimed at provide a better chemotherapy program which treat glioma, in particular the positive expression of MGMT of glioma.METHODS1. Collection of clinical dataCollection of 47 cases confirmed by pathology which are brain glial cell tumors (WHO classification) with a complete follow-up data in the Zhujiang Hospital of South Medical University from 2000 to 2007; aged from 10 to 60 years, mean 34.9 years old; Karnof sky Performance Scale (KPS)≥60 points; blood examination was normal (WBC)≥4.0×109/L, Plt≥100×109/L), there were no severe liver and kidney impairment; excluding pregnant and lactating women.2. TreatmentAll patients underwent operation, to be removed the tumor as far as possible under the premise of retaining nerve function as far as possible intraoperation. Given to 47 patients with routine postoperative radiotherapy. Chemotherapy:All patients accepted the first course of chemotherapy after the start of radiotherapy for 7-10 days, VM-26 combined with Me-CCNU chemotherapy program, repeated a course with interval of 8 to 12 weeks, administrated 2-7 courses according to the patients tolerated (average 3.7 courses); each patients had been rapidly given 20% mannitol 125 ml 30 minutes in advance before be administered chemotherapy drugs through intravenous infusion.3. ImmunohistochemistryThe organization paraffin section were obtained by surgical specimens. The staining were used immunohistochemistry method of two-step. To determine positive results:MGMT positioning in the nucleus or cytoplasm, show brown. MGMT expression is divided into four ranks:no MGMT positive expression were regard as negative (-); MGMT-positive cells<10% as suspicious (+-); positive cells range from 10% to 30% as positive (+);>30% positive cells as strongly positive (++).4. Observation MethodTracking the patient's overall survival (OS).3-year survival rates were calculated, recorded data and draw the Kaplan-Meier survival curve. Rechecked routine blood test the first week after the start of chemotherapy, then once a time every two weeks, observed and recorded WBC and Plt changes of the two groups of patients.Bone marrow suppression is divided into 0-Ⅳdegrees according to the WHO classification.5. Statistical MethodsThe data were used SPSS 13.0 statistical software to analyze. The relationship of survival time between the two groups used Kaplan-Meier survival curves to indicate, Log-Rank tested 3-year survival rate, mean survival time; the difference was statistically significant when the P≤0.05.RESULTSThe rate of MGMT positive expression was 40.4%.,3-year survival rate was 66.7%, with mean survival time was 67.861±10.094 months of MGMT-negative group; MGMT-positive group was 52.6%, with mean survival time was 47.263± 7.983 months, there were no statistically significant differences (χ2=0.552,P=0.458). 11 cases show grade I bone marrow suppression, there are six cases show stomach discomfort, vomiting, diarrhea, loss of appetite or digestive symptoms, does not appear serious consequences of adverse reactions. ConclusionVM-26 combined Me-CCNU chemotherapy program can effectively overcome drug resistance problems caused by MGMT in glioma,and toxic effects of the program are not severe, so it is an effective chemotherapy program. Section twoEffects of teniposide combined with semustine on o6-methylguanine-DNA methyltransferase expression in patients with greadⅡgliomaBACKGROUND & OBJECTIVELow-grade gliomas (LGGs) is divided into WHOⅠand WHOⅡ, WHOⅠgrade glioma generally do not need adjuvant chemotherapy postoperation. But the WHOⅡgrade glioma is a low-grade malignant gliomas, it has characteristics of high degree of differentiation, slow growth, diffuse infiltration of the the surrounding normal brain structure, so the whole cutting is not easy, and it may be develop to be the high-grade gliomas postoperation, in view of the above characteristics, so a further treatment is necessary postoperation. Radiotherapy in the treatment of LGGs gradually been confirmed, but chemotherapy is still debatable. In 2008 American Society of Clinical Oncology (ASCO) reported Radiation Therapy Oncology Group (RTOG) 9802 clinical trial that 251 cases of low-grade glioma were randomly assigned to radiotherapy alone group or radiotherapy combined with chemotherapy group, results showed that 5-year progression-free survival (PFS) were 46% and 63% (P=0.005),5-year overall survival rate (OS) were 63% and 70%(P=0.13). Multivariate analysis showed that chemotherapy is a positive factor. In recent years, scientists found that O6-methylguanine-DNA methyltransferase (MGMT) can specificly repair alkylated tumor cells that cause tumor resist to drugs, it was one of reason that alkylating chemotherapeutic drugs which widely be used in the current clinic failure to treat glioma. At present, the mainstream view is that the rate of MGMT expression in low-grade gliomas is greater than high-grade gliomas, it may result that sensitivity of alkylating agent is worse to LGGs, finally failure to treatment. Past studies have come to results that chemotherapy for the LGGs have no benefit may also not unrelated to this, so only selecting alkylating agent to treatⅡgrade gliomas is inappropriate. In this study, we used VM-26 combining with Me-CCNU to treat cerebral gradeⅡglioma, explored the relationship between MGMT expression in gradeⅡglioma and effects of Teniposide (VM-26) combined with Me-CCNU, in support of chemotherapy can benefit patients of LGGs and improve it efficacy.METHODS1. Collection of clinical dataCollection of 32 cases confirmed by pathological which were brain glial cell tumors (WHO classification) with a complete follow-up data in the Zhujiang Hospital of South Medical University from 2000 to 2007; aged from 10 to 53years, mean 30.3 years old; Karnof sky Performance Scale (KPS)≥60 points; blood examination was normal (WBC)≥4.0×109/L, Plt≥100×109/L), there were no severe liver and kidney impairment; excluding pregnant and lactating women.2. TreatmentAll patients underwent operation, to be removed the tumor as far as possible under the premise of retaining nerve function as far as possible intraoperation. Given to 32 patients with routine postoperative radiotherapy. Chemotherapy:All patients accepted the first course of chemotherapy after the start of radiotherapy for 7-10 days, VM-26 combined with Me-CCNU chemotherapy program, repeated a course with interval of 8 to 12 weeks, administrated 2-7 courses according to the patients tolerated (average 4courses); each patients had been rapidly given 20% mannitol 125 ml 30 minutes in advance before be administered chemotherapy drugs through intravenous infusion.3. ImmunohistochemistryThe organization paraffin section were obtained by surgical specimens. The staining wers used immunohistochemistry method of two-step. To determine positive results:MGMT positioning in the nucleus or cytoplasm, show brown. MGMT expression is divided into four ranks:no MGMT positive expression regard as negative (-); MGMT-positive cells<10% as suspicious (+-); positive cells range from 10% to 30% as positive (+);≥30% positive cells as strongly positive (++).4. Observation Method Tracking the patient's overall survival (OS).3-year survival rates were calculated, recorded data and draw the Kaplan-Meier survival curve. Rechecked routine blood test the first week after the start of chemotherapy, then once a time every two weeks, observed and recorded WBC and Plt changes of the two groups of patients.Bone marrow suppression is divided into 0-Ⅳdegrees according to the WHO classification. 5. Statistical MethodsThe data were used SPSS 13.0 statistical software to analyze. The relationship of survival time between the two groups used Kaplan-Meier survival curves to indicate, Log-Rank tested 3-year survival rate, mean survival time; the difference was statistically significant when the P<0.05.RESULTSThis study, the rate of MGMT positive expression was 40.6%.,3-year survival rate was 90.9%, with mean survival time was 86.896±9.535 months of MGMT-negative group; MGMT-positive group was69.2%, with mean survival time was 60.538±8.141 months; here were no statistically significant differences (χ2=0.616,P=0.433).11 cases show grade I bone marrow suppression, there are six cases show stomach discomfort, vomiting, diarrhea, loss of appetite or digestive symptoms, does not appear serious consequences of adverse reactions.CONCLUSIONSMe-CCNU combined VM-26 may be a effective program to patients with glioma gradeⅡ, but it should increase the samples size for further study.