Improving drug penetration in tumors by targeting tumor vascularization

Clinical oncologists have not been paying enough attention to the fact that poor tumor penetration represents a major impediment to the efficiency of cancer chemotherapeutics. The cytokine tumor necrosis factor (TNF) was the first treatment shown to affect tumor vessel destruction and improve vascular permeability of drugs in a clinical setting. TNF produces an early increase of vessel permeability followed by a dual targeting: TNF induces apoptosis of intratumoral angiogenic endothelial cells and melphalan during the apoptosis of tumor cells. Given the systemic toxicity, TNF has to be administered by regional therapy. However, experimental data indicate that a systemic approach will be possible, thanks to TNF targeting. Three fusion proteins with TNF were shown to target tumors: anti-EDB fibronectin/TNF, Asn-Gly-Arg-TNF, and anti-gp240/TNF. Current approaches to blocking angiogenesis include strategies that target vascular endothelium growth factor (VEGF)-A. However, little attention has been paid to possible drawbacks, which may include vessel destruction and reduced penetration by chemotherapeutic agents administered simultaneously or subsequently. An antiangiogenic treatment is optimal when it is given at a critical dose and at a critical time. Current protocols seem not to take these prerequisites into consideration. Other new approaches to increased tumor vessel permeability include histamine and combretastatin analog. The current paradigm of antitumor strategy based on the synergism of empirical drug combinations is obsolete. Instead, the design of protocols based on new pharmacodynamic concepts should provide better efficiency of cancer treatment as exemplified in the use of TNF and anti-VEGF antibod