Pharmacological aspects of targeting cancer gene therapy to endothelial cells

Targeting cancer gene therapy to endothelial cells seems to be a rational a pproach, because (a) a clear correlation exists between proliferation of tu mor vessels and tumor growth and malignancy, (b) differences of cell membra ne structures between tumor endothelial cells and normal endothelial cells exist which could be used for targeting of vectors and (c) tumor endothelia l cells are accessible to vector vehicles in spite of the peculiarities of the transvascular and interstitial blood flow in tumors. Based on the knowl edge on the pharmacokinetics of macromolecules it can be concluded that vec tors targeting tumor endothelial cells should own a long blood residence ti me after intravascular application. This precondition seems to be fulfilled best by vectors exhibiting a slight anionic charge. A long blood residence time would allow the formation of a high amount of complexes between tumor endothelial cells and vector particles. Such high amount of complexes shou ld enable a high transfection rate of tumor endothelial cells. In view of t heir pharmacokinetic behavior nonviral vectors seem to be more suitable for in vivo targeting tumor endothelial cells than viral vectors. Specific bin ding of nonviral vectors to tumor endothelial cells should be enhanced by m ultifunctional ligands and the transduction efficiency should be improved b y cationic carriers. Effector genes should encode proteins potent enough to induce reactions which eliminate the tumor tissue. To be effective to that degree such proteins should induce self-amplificating antitumor reactions. Examples for proteins which have the potential to induce such self-amplifi cating tumor reactions are proteins endowed with antiangiogenic and antipro liferative activity, enzymes which convert prodrugs into drugs and possibly also proteins which induce embolization of tumor vessels. The pharmacologi cal data for such examples are discussed in detail. (C) 2001 Elsevier Scien ce Ireland Ltd. All rights reserved.