Selective Enhancer of Tumor Vascular Permeability for Optimization of Cancer Chemotherapy

Abstract

With the development of tumor biology, molecular biology, and combinatorial chemistry, many therapeutic agents have been developed for tumors. However, the clinical application of antitumor agents such as cytokines, antibodies and chemotherapeutic drugs has failed because of poor accumulation in the tumor tissue.1,2) Heterogeneous tumor perfusion, vascular permeability, and increased interstitial pressure restricted the penetration of therapeutic agents into tumor tissue from circulation. 1,2)It has been suggested that tumor necrosis factor-alpha (TNF-a) can overcome these problems. TNF-a was identified as a cytokine that specifically injures tumors and has been highlighted as a potent anti-tumor agent.3) Furthermore, TNF-a destroyed the tumor vasculature selectively and enhanced the tumor vascular permeability. 4) Regional isolated limb perfusion using TNF-a in combination with melphalan or doxorubicin showed greater therapeutic effects on softtissue sarcoma or melanoma than chemotherapeutic drugs alone.5) It is believed that the synergistic effect between TNF-a and chemotherapeutic drugs results from TNF-a-induced destruction of tumor vasculature and enhancement of tumor vasculature permeability. However, because of its high instability and pleiotropic action in vivo, attempts to use TNF-a as a systemic anticancer agent and an enhancer of tumor vascular permeability in humans, failed due to severe systemic side effects such as fever and decreased blood pressure as seen in case of an endotoxin-like shock, before therapeutic doses could be administered. 6)To overcome these drawbacks and apply TNF-a as a systemic administrator, we have attempted to conjugate TNF-a with polyethylene glycol (PEG) and other water-soluble polymeric modifiers. [7][8][9][10] We showed that the antitumor effects of PEG-TNF-a, obtained by PEGylation with a molecular weight of 5000, was enhanced to 100 times that of unmodified TNF-a, without increasing their toxic side effects. 7,8) In this study, we examined the usefulness of PEG-TNF-a as a selective enhancer of tumor vascular permeability. We showed that PEG-TNF-a enhanced the permeability of tumor vasculature without having any effect on the permeability of normal tissue. We considered that PEG-TNF-a would be used with chemotherapeutic drugs for tumor therapy. MATERIALS AND METHODS Preparation of125 I-Labeled Polymers Radiolabeled polymeric modifiers were prepared by the chloramine-T method. PEGs (average molecular weight: 12000, 50000, 70000, 500000) (purchased from Wako Pure Chemical Industries, Ltd., Osaka, Japan) dissolved in 1,4-dioxan were reacted with N,NЈ-carbonyldiimidazole for 6 h at room temperature. After dialysis in water, the activated polymers were reacted with a 2-fold molar excess of thyramine hydrochloride for 48 h at 4°C. These reaction mixtures were also dialyzed in water and lyophilized. The polymer-thyramine conjugates, dissolved in a 0.4 M sodium phosphate buffer (2.5 mg/ml) and Na 125 I (100 mCi/ml), were mixed in a microcentrifuge tube on ice. The labeling reac...

A novel chemotherapeutic sensitivity-testing system based on collagen gel droplet embedded 3D–culture methods for hepatocellular carcinoma

“…Applications of CD-DST in chemotherapeutic sensitivity examination have been demonstrated in human cancers, e.g., lung cancer, gastric cancer, breast cancer, or colorectal cancer [ 11 – 16 ]. However, reports focused on potential applications and efficacy of CD-DST in HCC remain rare [ 17 , 18 ]. This work aims to identify potential applications of CD-DST in HCC.…”