The central hypothesis of this proposal is that there are definable mechanisms for drug sensitivity and resistance in human gliomas and that sensitivity to nitrosoureas and procarbazine is largely determined by the capacity of the tumor cell to repair potentially lethal DNA adducts at the 06-position of guanine. The enzyme that repairs these lesions, 06-alkylgaunine-DNA alkyltransferase (AT), is present in variable amounts in human glioma xenografts, and we are postulating that there is a strong relationship between the level of the enzyme in a glioma and its resistance to these alkylating drugs. We are also proposing that the therapeutic synergy we have observed between the nitrosoureas and the thiopurines is based on enhanced alkylation of the incorporated thiol group in DNA. Finally, we propose to expand the drug evaluation cascade system that we have developed for the identification of new active agents in the treatment of anaplastic glioma. Accordingly, the specific aims of this proposal are: (1) to quantify and modulate the capacity of human glioma xenografts to repair cytotoxic lesions produced by alkylating antineoplastic drugs; (2) to define relationships between the AT level of glial neoplasms and their natural history and response to therapy; (3) to determine the mechanism of therapeutic synergy between alkylating agents and thiopurines observed in human glioma xeongrafts; and (4) to identify new drugs and drug combinations for the treatment of anaplastic gliomas using a refined glioma xenograft model. With these experiments, we expect to define the range of expression of an important phenotypic trait in human gliomas and to define its biologic importance in their treatment sensitivity. We also expect to define the biochemical basis of alkylator- thiopurine interaction and to exploit it to maximum advantage in the treatment of gliomas. Finally, we anticipate identification of additional new active drugs and drug combinations that can be taken to clinical trial in glioma patients.
