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ABSTRACT: Despite great advances in cell and molecular biology, pharmacology and medicine, there is to date no antitumor drug available which can specifically kill tumor cells in the human body without damaging normal tissue, because it has not been possible to find a truly cancer specific molecule to target. Low molecular weight (MW) anticancer drugs extravasate easily from normal vessels in the body causing drug adverse effects. Conversely, high MW anti-tumor agents including antibodies against cancer cell antigens, accumulate selectively in tumors because of their leaky vasculature. However, most human solid tumors possess abundant intercellular connective tissue, hindering diffusion of such macromolecules. That is why immunoconjugate therapy for stroma rich common solid cancer has not yet proved successful in clinics. In this review, I describe a successful new strategy that overcomes the above contradictory drawbacks by conjugating a small MW cyototoxic drug with an antibody against particular components of tumor stroma. Stroma-targeting immunconjugates bound to the stroma to create a scaffold, from which sustained release of cytotoxic agent occurred and subsequently diffused throughout the tumor tissue to damage both tumor cells and tumor vessels. Cancer-stroma targeting (CAST) therapy was thus validated as a new modality of oncological therapy, especially for refractory, stromal-rich cancers.
Advanced drug delivery reviews 12/2011; 64(8):710-9. · 11.96 Impact Factor
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ABSTRACT: Polymeric micelles are ideally suited to exploit the EPR effect, and they have been used for the delivery of a range of anticancer drugs in preclinical and clinical studies. NK012 is an SN-38-loaded polymeric micelle constructed in an aqueous milieu by the self-assembly of an amphiphilic block copolymer, PEG-PGlu(SN-38). The antitumor activity was evaluated in several orthotopic tumor models including glioma, renal cancer, stomach cancer, and pancreatic cancer. Two independent phase I clinical trials were conducted in Japan and the USA. In the preclinical studies, it was demonstrated that NK012 exerted significantly more potent antitumor activity with no intestinal toxicity against various orthotopic human tumor xenografts than CPT-11. In clinical trials, predominant toxicity was neutropenia. Non-hematologic toxicity, especially diarrhea, was mostly Grade 1 or 2 during study treatments. Total 8 partial responses were obtained. According to data of preclinical studies, NK012 showing enhanced distribution with prolonged SN-38 release may be ideal for cancer treatment because the antitumor activity of SN-38 is time dependent. Clinical studies showed that NK012 was well tolerated and had antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing in patients with colorectal cancer in Japan and in patients with triple negative breast cancer and small cell lung cancer in the USA.
Advanced drug delivery reviews 03/2011; 63(3):184-92. · 11.96 Impact Factor
Advanced drug delivery reviews 05/2010; 63(3):129-30. · 11.96 Impact Factor