MOLECULAR-BASIS AUGMENTED CHEMOTHERAPY AND CLINICAL APPLICATION IN BRAIN TUMORS

0^6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）活性和MGMT mRNA与肿瘤细胞对氯乙基亚硝基脲（CENU）的耐药性密切相关，因为MGMT通过在半胱氨酸部分接受烷基基团来去除CENU诱导的DNA中的0^6-烷基鸟嘌呤。MGMT的失活是降低肿瘤细胞对CENUs的MGMT相关抗性的合理方式。在本研究中，我们测试了这些0^6-氟苄基鸟嘌呤的体内活性。用0^6-（4-氟苄基）鸟嘌呤+ ACNU和0^6-（3-氟苄基）鸟嘌呤+ ACNU治疗显著减小肿瘤体积并延长生长延迟（p < 0.05）。两种衍生物处理后12 h的增殖指数均显著低于对照组（p < 0.05）。这些结果表明，O^6-（4-和3-氟苄基）鸟嘌呤以及O^6-苄基鸟嘌呤增强ACNU对体内移植瘤生长的作用。 关于我们 肿瘤我们检测了人脑肿瘤中0^6-甲基鸟嘌呤-DNA甲基转移酶的免疫组化表达及其作为CENU敏感性指标的意义。本研究共纳入42例恶性胶质瘤患者。10例胶质瘤（24%）的MGMT阳性细胞水平较低（低于10%），表明对CENU化疗更敏感。而其余胶质瘤则表现出较高的水平，对CENU化疗的敏感性较低。针对耐药肿瘤的另一种化疗策略是根据脑肿瘤的细胞遗传学改变来选择和应用抗癌药物。应用荧光原位杂交（FISH）和微卫星分析对14例少突胶质细胞瘤进行细胞遗传学和洛缺失分析。少突胶质细胞肿瘤中1 p和19 q的联合缺失是其对丙卡巴肼+ ACNU +长春新碱（PCV）化疗敏感的标志，其耐药或敏感性可能受多种机制的影响。用于确定肿瘤是否对抗癌药物敏感或耐药的实际和临床有用的测试。此外，基于分子遗传学的脑肿瘤诊断及其在选择敏感脑肿瘤的临床应用在某些类型的脑肿瘤中也很重要。要实现脑肿瘤的化疗治愈，还需要对脑肿瘤的抗肿瘤药物作用机制和生物学特性进行多学科的研究。少

0^6-Methylguanine-DNA methyltransferase (MGMT) activity and MGMT mRNA are well related with drug resistance of tumor cells to chloroethylnitrosoureas (CENUs), because MGMT removes CENU-induced 0^6-aikylguanines in DNA by accepting the alkyl group at a cysteine moiety. Inactivation of MGMT is a reasonable way to reduce MGMT-related resistance of tumor cells to CENUs. In the present study, we tested the in vivo activity of these 0^6-fluorobenzylguanines. Treatment with O^6- (4-fluorobenzyl) guanine + ACNU and 0^6- (3-fluorobenzyl) guanine + ACNU significantly decreased tumor volume and extended the delay of growth (p < 0.05). Also, these two derivatives showed significantly lower proliferating indices (p < 0.05) 12h after treatment. These results indicate that O^6- (4-and 3-fluorobenzyl) guanines as well as O^6-benzylguanines enhance the effect of ACNU on the growth of tumor xenografts in vivo.MGMT activity and the levels of MGMT mRNA varied widely, even within different types of brain t … More umors. We examined immunohistochemical expression of 0^6-methylguanine-DNA methyltransferase in human brain tumors and its significance as an indicator of CENU sensitivity. A total of 42 patients with malignant gliomas were included in this study. Ten gliomas (24 %) had a low level of MGMT-positive cells (less than 10 %), indicative of more sensitivity to CENU chemotherapy. However, the remaining gliomas showed a high level, and indicated less sensitivity to CENU chemotherapy.Another way of the chemotherapeutic strategies for the resistant tumor is selection and application of anticancer drugs based on the cytogenic and genetic alternations of brain tumors. Cytogenetic and LOH analysis were examined in 14 oligodendroglial tumors using fluorescent in situ hybridization (FISH) and microsatellite analysis. A combined loss of 1p and 19q in oligodendroglial tumors was highly noted and it indicated chemosensitivity to procarbazine + ACNU + vincristine (PCV) therapy.A variety of mechanisms may affect drug resistance or sensitivity. The practically and clinically useful test for determining whether tumors will be sensitive or resistant to anticancer drugs. Also, molecular genetics-based diagnosis of brain tumors and its clinical applications on selection of sensitive brain tumors are also important in some types of brain tumors. Multidisciplinary studies on both side of anticancer drug mechanism and biologic characteristics of brain tumors are further required to accomplish chemotherapeutic cure. Less