The first objective of this program is to define single agents and combinations of agents which are highly active in vitro against human gliomas, and which have appropriate properties for use in the polymer release system. Agents to be evaluated include chemotherapeutic drugs, differentiating agents, exotoxins, and anti-glioma antibodies. Agents and combinations which are active in vitro will be evaluated for activity against an established tumor in vivo after release from biodegradable polymers in a flank glioma xenograft system. in this system the agent or combination of agents, incorporated into a polymer disk, will be place in direct apposition to the established glioma xenograft. Those compounds and combinations which are active in vivo will be studied in Program l for neurotoxicity after polymer release in the brain, and for activity against intracranially established rat and human gliomas in a rat model. The second objective of this program is to work with Program 3 to develop approaches to increasing the diffusion distance of agents in the brain, after intracranial release from polymers. Previous work in Program 3 established that macromolecules diffuse much further in the brain than low molecular weight compounds. Therefore, a major component of the work will be the further development, with Program 3, of the concept of agents bound to macromolecules through labile bonds, such that the agents are released over time and space as the macromolecules diffuse through the brain. A third objective is to evaluate the potential of drug containing microspheres for direct implantation in tumors, for release from polymers adjacent to tumors, and for intrathecal administration for the treatment of intrathecal tumor. Finally, this program will provide chemical support to the other programs of this NCDDC by synthesizing radiolabeled agents for diffusion and pharmacokinetic studies.
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