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.
| Gerson, S L; Schupp, J; Liu, L et al. (1999) Leukocyte O6-alkylguanine-DNA alkyltransferase from human donors is uniformly sensitive to O6-benzylguanine. Clin Cancer Res 5:521-4 |
