Although taxol and many anti-cancer agents are highly lipophilic, they typically do not cross the blood-brain barrier (BBB), due to active efflux by P-glycoprotein. The BBB of patients with malignant brain tumors is often not totally intact and allows chemotherapeutic agents to enter the tumor tissue. However, the amount of drug that reaches the tumor depends on the extent of disruption of the BBB, which varies considerably. Drug concentrations in the brain tissue usually drop with increasing distance from the tumor, and thus the drug concentration is fairly low in the peripheral pars of the tumor, where tumor cells infiltrate the brain. In these areas, where tumor proliferation is most rapid, the BBB is relatively intact. Relapse of patients after surgery is believed to occur from residual tumor cells that have escaped surgery and have infiltrated the """"""""normal"""""""" brain tissue, protected by the BBB. Novel approaches for effective delivery of anti-cancer agents, that are substrates of P-glycoprotein through the BBB would be high desirable and would provide clinicians with additional anti-cancer agents for the treatment of brain tumors in their efforts to increase survival rates of brain tumor patients. Taxol is a representative example of an anti-tumor agent that is a substrate for P-glycoprotein mediated efflux from the BBB. Preliminary results suggest that it is possible to develop taxon analogues that retain cytotoxicity and have the ability to cross the BBB. Based on this observation, the design, synthesis, and biological evaluation of taxon analogues is under study. It is the hypothesis that taxol analogues an be prepared that elude the MDR transporter by altering and/or deleting functional groups that are recognition elements for the transporter. In another approach to overcome P-glycoprotein efflux, it is hypothesized. that analogues in which taxol is covalently linked to known vectors with carriers in the endothelial cells of the BBB will be delivered to the brain with the aid of these transport systems. The designed taxol analogues will be tested for their tubulin assembly properties and their cytotoxic properties against several brain tumor cell lines. They will also be evaluate din vitro for their affinity for the P-glycoprotein in bovine brain micro-vessel endothelial cells (BMEC),a nd for their transcellular permeability properties in diffusion experiments across BMEC monolayers. In vivo studies with an in situ rat perfusion model will be used to assess their in vivo protein to cross the BBB.
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