COMMENTARY Tumor Vasculature Targeted Therapies GETTING THE PLAYERS ORGANIZED Grietje Molema,*†‡ Dirk K. F. Meijer† and Lou F. M. H. de Leij* *DEPARTMENT OF CLINICAL IMMUNOLOGY AND †DEPARTMENT OF PHARMACOKINETICS AND DRUG DELIVERY, GRONINGEN UTRECHT INSTITUTE FOR DRUG EXPLORATION (GUIDE), GRONINGEN, THE NETHERLANDS ABSTRACT. Based on their location and central role in solid tumor growth, tumor vascular endothelial cells may present an attractive target for the delivery of therapeutic drugs or cells. The potency of blocking the tumor blood supply in eradicating solid tumors was demonstrated recently in a mouse model of tumor vasculature targeting (Huang et al., Science 275: 547–550, 1997). For clinical application of such strategies, tumor endothelium specific target epitopes need to be identified. Recent studies on angiogenesis have identified angiogenesis-related molecules as potential target epitopes. Among these are vascular endothelial growth factor (VEGF)/VEGF-receptor complex, v integrins, and Tie receptor tyrosine kinases. Besides blockade of their signalling cascades leading to inhibition of angiogenesis, these epitopes may also be instrumental in tumor vessel specific delivery of therapeutics. Data on the efficacy of therapeutic modalities aimed at these, mostly heterogeneously distributed tumor endothelial epitopes are scarce, and sophisticated experimentation is required to rationalize the development of new therapeutic strategies. Importantly, only detailed evaluations in cancer patients will provide the blueprint for the development of clinically effective tumor vascular targeted therapies. BIOCHEM PHARMACOL 55;12:1939 –1945, 1998. © 1998 Elsevier Science Inc. KEY WORDS. tumor; vasculature; targeting; target epitopes; animal; human The treatment of solid tumors using chemotherapeutic agents is a difficult task due to a number of factors: limited accessibility of tumor tissue, occurrence of multidrug resis- tance, major/intolerable toxicity of the anti-cancer drugs and heterogeneity of tumor tissue. To circumvent toxicity and/or to increase the effectiveness of anti-neoplastic ther- apy, approaches have been developed that aim at selec- tively delivering the pharmacologically active compound to the tumor or attempt to target enzymes that can activate prodrugs at the tumor site (for reviews see Refs. 1–5). The success of these so called “drug-targeting” strategies lies in the selectivity of the interaction between the carrier mol- ecule and its target epitope. Furthermore, as with any other therapy, accessibility of the target tissue for the carrier-drug conjugates or prodrug-activating modality is of fundamental importance. By now, it has become increasingly clear that this last feature in particular impedes the effectiveness of drug- targeting strategies in vivo. Using immunotoxins (conju- gates of antibodies/antibody fragments and plant or bacte- rial toxins) for example, encouraging responses have been observed in patients with hematological malignancies. Treatment of solid tumors, however, has not been success- ful due to (among other factors) poor penetration of the conjugates in solid tumor masses [6]. It is widely accepted, therefore, that treatment with immunotoxins should con- centrate on patients with minimal residual disease. Yet, the quest for effective procedures for the treatment of solid tumor masses continues. TUMOR VASCULAR ENDOTHELIUM AS A TARGET The vasculature in solid tumor tissue is highly disordered, with numerous vascular shunts, irregular vascular diame- ters, wide interendothelial junctions, large numbers of fenestrae and transendothelial channels, and discontinuous or absent basement membranes [7, 8]. Although overall vascular permeability of tumor blood vessels is increased as compared with normal tissue vessels, not all tumor blood vessels are leaky. In addition, the tumor blood vessel walls and high interstitial fluid pressure within the tumor tissue form a major barrier for the transport of tumor cell-directed therapeutic modalities [1, 9]. Based on their location, the cells lining the tumor blood vessel wall present a much more attractive site for specific delivery of therapeutics than tumor cells, as they are more easily accessible from the blood. Furthermore, tumor endothelial cells themselves may be a lucrative target for therapeutic intervention since most tumor cells rely for their growth and survival on an intact blood supply. While tumor cells are genetically unstable, rapidly mutating, and able to develop multidrug ‡ Corresponding author: Grietje Molema, Ph.D., Department of Clinical Immunology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Tel. 31-50-3613733/3633287; FAX 31-50- 3121576; E-mail: g.molema@med.rug.nl. Biochemical Pharmacology, Vol. 55, pp. 1939 –1945, 1998. ISSN 0006-2952/98/$19.00 + 0.00 © 1998 Elsevier Science Inc. All rights reserved. PII S0006-2952(98)00011-2