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A rapid survey of the literature shows that little fundamental progress in cancer chemotherapy has been achieved over the last 20 years. This unfortunate state of affairs may reflect the complexity of the tumor environment and our failure to target both cancer cells and their associated stroma. Although the idea of the cancer cell as a “seed” that can only develop if it is supported by a good “soil” (the stroma with connective tissue and angiogenic vessels) is an old one (see recent retrospective by Fidler [1]), traditional therapies failed to consider that the stroma produces various growth factors that differ from tissue to tissue. Even some of the newer anticancer strategies, which do indeed target the mediators of tumor angiogenesis, still fail to account for the fact that anticancer agents must pass through the soil before they can destroy the seed. Thus, for a long time, 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. Meanwhile, work in animal models has shown that low permeability of the tumor vasculature and high interstitial fluid pressure (IFP) represent substantial barriers to drug delivery (2).

Clinical use of TNF revisited: improving penetration of anti-cancer agents by increasing vascular permeability