REGIONAL THERAPY WITH AGT INHIBITORS AND BCNU

中枢神经系统(CNS)肿瘤发生在大脑或 从神经外原发部位转移的是高度恶性的肿瘤 对所有常规疗法都无效。同样，患有 几乎任何肿瘤引起的肿瘤性脑膜炎，如黑色素瘤、肉瘤、 或者乳腺癌表现不佳，软脑膜后的平均存活率 以月为单位的价差。据观察，O6的消耗- 烷基鸟嘌呤-DNA烷基转移酶。(AGT)含烷基鸟嘌呤或甲基化 药物使细胞对2-羟色胺的细胞毒作用敏感 氯乙基亚硝脲为以下研究提供了理论基础 人髓母细胞瘤中亚硝脲活性的增强 和多形性胶质母细胞瘤裸鼠移植瘤生长SQ O6-苄基鸟嘌呤(BG)介导AGT耗竭。不幸的是，BG的使用 伴随着BCNU诱导的全身毒性增强， 因此有必要大幅减少剂量，以最大限度地减少这些影响。地区性 动脉插管或动脉插管治疗软脑膜肿瘤的中枢神经系统实质 鞘内给药分别提供了潜在的好处 加强对靶肿瘤的传递，同时最大限度地减少传递和 因此对全身器官有毒性。初步工作是在 这项药物发现奖助金的第一个资助期已经证实了这一点 动脉内注射BG可显著增强活性 系统性BCNU治疗人脑胶质瘤移植瘤的实验研究 在无性系大鼠身上。观察到一种细菌的物理化学性质 药物，特别是它的脂类对水的溶解度，显著 影响动脉或鞘内给药后的药物传递， 为旨在加强选择性给药的研究提供理论基础 AGT抑制剂对脑实质或软脑膜肿瘤部位的作用 适当改变这些试剂的物理化学性质。 这项提案的具体目的是：1)界定毒性和 鞘内注射水溶性AGT抑制剂联合鞘内注射或 全身性BCNU治疗人脑胶质瘤细胞系D456 MG和 人髓母细胞瘤细胞系D341MED在蛛网膜下腔的生长 无性系裸鼠空间；2)确定其毒性和活性 动脉内脂溶AGT抑制剂联合全身性BCNU治疗 人脑胶质瘤细胞系D456-MG和人脑胶质瘤细胞的治疗 人髓母细胞瘤细胞系D341MED在小鼠蛛网膜下腔生长 裸鼠；2)确定其毒性和活性。 动脉内脂溶AGT抑制剂联合全身性BCNU治疗 人脑胶质瘤细胞系D456-MG和人脑胶质瘤细胞的治疗 髓母细胞瘤细胞系D341MED生长I.C.在裸鼠体内。

Central nervous system (CNS) neoplasms which either arise in th brain or metastasize from an extraneural primary site, are highly malignant tumors refractory to all conventional therapy. Similarly, patients with neoplastic meningitis from virtually any tumor such as melanoma, sarcoma, or breast carcinoma do poorly, with mean survival following leptomeningeal spread measured in months. The observation that depletion of O6- alkylguanine-DNA alkyltransferase. (AGT) with alkylguanines or methylating agents sensitizes cells to the cytotoxic action of 2- chloroethylnitrosoureas provided the rationale for studies which demonstrated enhancement of nitrosourea activity in human medulloblastoma and glioblastoma multiforme xenografts growing SQ in athymic nude mice by O6-benzylguanine (BG) mediated depletion of AGT. Unfortunately, use of BG is accompanied by enhancement of BCNU induced systemic toxicity, necessitating a large dose reduction to minimize these effects. Regional therapy of CNS parenchymal of leptomengeal neoplasms with intraarterial or intrathecal administration respectively, offers the potential benefit of enhancing delivery to the target neoplasm while minimizing delivery and hence toxicity to systemic organs. Initial work accomplished during the first funding period of this Drug Discovery Grant has confirmed this promise with intraarterial delivery of BG markedly enhancing the activity of systemic BCNU in the treatment of intracranial human glioma xenografts in athymic rats. The observation that the physiochemical properties of a drug, particularly its degree of lipid-vs water-solubility, dramatically influence drug delivery following arterial or intrathecal administration, provides rationale for studies designed to enhance the selective delivery to brain parenchymal or leptomeningeal tumor sites of AGT inhibitors by appropriate alteration of the physiochemical properties of these agents. The specific aims of this proposal are: 1) to define the toxicity and activity of intrathecal water soluble AGT inhibitors plus intrathecal or systemic BCNU in the treatment of the human glioma cell line D456 MG and the human medulloblastoma cell line D341 MED growing in the subarachnoid space of athymic nude rats; 2) to define the toxicity and activity of intraarterial lipid soluble AGT inhibitors plus systemic BCNU in the treatment of the human glioma cell line D456 MG and the human medulloblastoma cell line D341 MED growing in the subarachnoid space of athymic nude rats; 2) to define the toxicity and activity of intraarterial lipid soluble AGT inhibitors plus systemic BCNU in the treatment of the human glioma cell line D456 MG and the human medulloblastoma cell line D341 MED growing i.c. in athymic nude rats.