Investigative Treatment Division
The main goal of the research in this Division is to innovate and formulate a new strategy for cancer diagnosis and treatment on the basis of a better understanding of the biology of cancer tissues and the interaction between the cancer and host tissues. Improvement of the preexistent modalities for cancer diagnosis and treatment is also within the scope of the research activity.
Drug Delivery Systems in Cancer Chemotherapy
One of the objectives of developing drug delivery systems (DDSs) in cancer chemotherapy is to find methods by which anticancer agents selectively target solid tumors. The 2 main concepts for this constitute selective tumor targeting and active and passive targeting. The former involves monoclonal antibodies or ligands to tumor-related receptors, which can target the tumor by utilizing specific binding abilities between the antibody and the antigen or between the ligand and its receptor. The latter system can be achieved by the so-called “EPR effect,” i.e., enhanced permeability and retention effect. The EPR effect was named according to the pathophysiological characteristics of solid tumors: (a) hypervasculature, (b) incomplete vascular architecture, (c) several vascular permeability factors that stimulate extravasation within the tumor, and (d) little drainage of macromolecules and particulates. Macromolecular anticancer agents such as liposomal or micellar drugs have long plasma half-lives because they are too large to pass through the normal vessel walls unless they are trapped by the reticuloendothelial system in various organs. Such macromolecular agents can diffuse out of the tumor blood vessels, reach the solid tumor tissue effectively, and be retained for a long period of time due to the EPR effect (86). It was revealed that paclitaxel (PTX)-incorporated micelle nanoparticle NK105 could extend its antitumor activity in vivo and reduce the neurotoxicity of the parent drug. A phase I study on NK105 was conducted in patients with advanced solid tumors. The plasma AUC of NK105 at 150 mg/m2 was approximately 15-fold higher than that of the conventional PTX formulation. NK105 was well tolerated, and the recommended dose for the phase II study was determined to be 150 mg/m2 every 3 weeks. The phase II study is currently in progress in patients (87). SN-38, a biologically active metabolite of CPT-11, has potent antitumor activity but has not been used clinically because it is water insoluble. For delivery by iv injection, our Division has successfully developed NK012, a SN-38-releasing micellar system.
It was shown that the therapeutic effect of NK102/5FU was significantly superior to that of CPT-11/5FU (88).
A Noninvasive Diagnostic Test for Colorectal Cancer
Colon cancer is known to be almost 100% curable by operation if detected early Thus, colorectal cancer is included in an early cancer screening schema, and many examination methods have been developed. Recently, a new method has been developed, by which exfoliated colorectal cancer cells can be effectively isolated from naturally voided feces. The cell recovery method and apparatus of our invention can simplify the cell recovery process and allow cancer cells in the stool to be recovered stably and efficiently, thereby providing a high accuracy of determination (89,90).
Pharmacogenomic Research
Dihydropyrimidine dehydrogenase (DPD) is an
inactivating and rate-limiting enzyme for 5-fluorouracil (5-FU), and its deficiency is associated with a risk for developing a severe or fatal toxicity to 5-FU. In order to determine the genetic variations of DPYD-encoding DPD in the Japanese population, the putative promoter region, all exons, and the flanking introns of DPYD were sequenced from 341 subjects, including cancer patients treated with 5-FU. The SNPs and haplotype distributions in the Japanese population were quite different from those reported previously among Caucasians (27).
● Y. Matsumura ●
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