We will use the athymic mouse-human glioma system to evaluate new forms of therapy for anaplastic human brain tumors. An extensively characterized human glioma tumor line, D-54 MG, will be used to evaluate antineoplastic agents of potential interest for brain tumor chemotherapy. These agents will include currently available drugs that have not been tested against human gliomas, analogs of available agents that have theoretical advantages for treating intracerebral tumors, and drugs in the preclinical stages of development. Drugs that are active against subcutaneous D-54 MG in athymic mice will be tested against intracerebral D-54 MG, against other human glioma lines growing in athymic mice, and in combination with other active antineoplastic drugs. We will refine the efficacy of diaziquone (AZQ) in the D-54 MG/ athymic mouse system by evaluating alternative drug schedules and by using AZQ in combination wilth other active agents. In addition, mechanisms of tumor resistance to AZQ will be explored by determining intratumor levels of AZQ in sensitive and resistant tumor lines, by determining the in vitro chemosensitivity to AZQ of a series of human glioma lines in a soft agar clonogenic assay, and by characterizing a derived AZQ-resistant subline of D-54 MG. A continuing goal of this project is to explore the resemblance between the heterotransplanted human glioma and the tumor from which it was derived. Most patients from whom these tumor lines will be derived will be treated with either AZQ or carmustine (BCNU) in a phase III clinical study at this institution. The transplanted tumor will be treated in mice with the same agent that the patient receives. The growth delay in mice will be compared to time to treatment failure in patients. Finally, compounds capable of producing morphologic and biochemical evidence of differentiation in other tumor lines, such as retinoids, phorbol esters, and cyclic-AMP, will be used against D-54 MG both in vitro and in athymic mice. Induction of differentiation is usually associated with reduced cell proliferation, and this approach offers the prospect of non-cytotoxic chemotherapy for human neoplasms.
