In Response: We are aware of the article published by Sanders (Strickland) et al. as its findings are complementary to our own. It was published after our article was in press so we were unable to cite it in our article, but we are very happy to acknowledge it here (1). Dr. Sanders is correct to point out that expression of PV-1 is not limited to brain tumors but is present in many normal human tissues with fenestrated endothelium. We are well aware of this, mention it in our article, and indeed we used normal human lung tissue as a positive control for PV-1 expression in our laboratory. What is unique to brain tumors is that PV-1 expression is entirely absent in normal brain capillaries, raising the possibility that expression of PV-1 in the brain microvasculature could be a selective target for brain tumor angiogenesis and/or cerebral edema.
In their letter, Drs. Sanders and Koeppen argue that the systemic expression of PV-1 precludes considering it as a target for antiangiogenic therapies. Whereas we share their concerns, we respectively disagree that it should be discarded out of hand. As we argue in our article and will reiterate here, a variety of technologies, including biodegradable polymer matrices and convection-enhanced delivery, have been perfected to deliver drugs and macromolecules to the central nervous system (reviewed by the senior author in ref. 2). Biodegradable Gliadel wafers are Food and Drug Administration approved to deliver 1,3-bis(2-chloroethyl)-1-nitrosourea interstitially to patients with glioblastoma multiforme. The wafers deliver active drug to the tumor site but systemic levels of 1,3-bis(2-chloroethyl)-1-nitrosourea are undetectable and none of the usual dose limiting toxicities associated with systemic 1,3-bis(2-chloroethyl)-1-nitrosourea administration are present. Several macromolecular toxin conjugates are also in phase III clinical trials against glioblastoma administered as an intratumoral infusion with convection-enhanced delivery. These compounds target the transferrin receptor and the epidermal growth factor receptor, both of which are highly expressed in a variety of normal tissues. The selective nature in which the drug-toxin conjugates are infused into the tumor limits systemic toxicity. The availability and development of these technologies in our laboratory makes us more confident about selectively targeting PV-1 in brain tumors.
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