Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Inflammation and cancer

Nanotechnology has the potential to revolutionize cancer diagnosis and therapy. Advances in protein engineering and materials science have contributed to novel nanoscale targeting approaches that may bring new hope to cancer patients. Several therapeutic nanocarriers have been approved for clinical use. However, to date, there are only a few clinically approved nanocarriers that incorporate molecules to selectively bind and target cancer cells. This review examines some of the approved formulations and discusses the challenges in translating basic research to the clinic. We detail the arsenal of nanocarriers and molecules available for selective tumour targeting, and emphasize the challenges in cancer treatment.

Nanocarriers as an emerging platform for cancer therapy

We previously found that a polymer conjugated to the anticancer protein neocarzinostatin, named smancs, accumulated more in tumor tissues than did neocarzinostatin. To determine the general mechanism of this tumoritropic accumulation of smancs and other proteins, we used radioactive (51Cr-labeled) proteins of various molecular sizes (Mr 12,000 to 160,000) and other properties. In addition, we used dye-complexed serum albumin to visualize the accumulation in tumors of tumor-bearing mice. Many proteins progressively accumulated in the tumor tissues of these mice, and a ratio of the protein concentration in the tumor to that in the blood of 5 was obtained within 19 to 72 h. A large protein like immunoglobulin G required a longer time to reach this value of 5. The protein concentration ratio in the tumor to that in the blood of neither 1 nor 5 was achieved with neocarzinostatin, a representative of a small protein (Mr 12,000) in all time. We speculate that the tumoritropic accumulation of these proteins resulted because of the hypervasculature, an enhanced permeability to even macromolecules, and little recovery through either blood vessels or lymphatic vessels. This accumulation of macromolecules in the tumor was also found after i.v. injection of an albumin-dye complex (Mr 69,000), as well as after injection into normal and tumor tissues. The complex was retained only by tumor tissue for prolonged periods. There was little lymphatic recovery of macromolecules from tumor tissue. The present finding is of potential value in macromolecular tumor therapeutics and diagnosis.

https://cancerres.aacrjournals.org/content/canres/46/12_Part_1/6387.full.pdf

A New Concept for Macromolecular Therapeutics in Cancer Chemotherapy: Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs

Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review.

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

/pdf/nitric-oxide-and-peroxynitrite-in-health-and-disease-3uuuqgfdcz.pdf

Nitric Oxide and Peroxynitrite in Health and Disease

http://www.jstage.jst.go.jp/article/cpb1958/37/7/37_7_1764/_pdf

Practical Synthesis of Optically Pure 1- and 3-Substituted Dihydroorotic Acids

Metallurgical studies and optimization of sintering condition to obtain the maximum volume fraction of the high Tc phase (∼110 K) have been made for the Bi‐Sr‐Ca‐Cu‐O system. In the differential thermal analysis, double peaks of endothermic reaction at ∼870 and ∼910 °C were observed during the increase of temperature, and a weight loss accompanied each endothermic reaction. Optimum calcining and sintering conditions to obtain a large volume fraction of the high Tc phase were 820 °C×14 h+840 °C×6 h and 875 °C×100 to 200 h in air, respectively. As for the variation of Cu concentration, nominal composition of Bi1Sr1Ca1Cu2Ox gave the maximum volume fraction of the high Tc phase. (For these specimens, sintering time was varied up to 20 days.) Post annealing at 400 °C for 20 h in an oxygen atmosphere after the sintering at 875 °C for 100 to 470 h in air had little effect on the improvement of volume fraction of the high Tc phase. As for the specimen to which Pb is added, however, the post annealing at 400 °C fo...

Metallurgical studies and optimization of sintering for the Bi-Sr-Ca-Cu-O superconductors

We investigated the ability of rice-shochu postdistillation residue (RSDR) to stimulate the activity of macrophages. RSDR significantly stimulated mouse macrophage activity and induced significant IL-12 production in vitro. In syngeneic C38 solid tumor model in mice, a diet containing 1.0% RSDR caused a significant suppression of tumor growth and prolonged the life span of the tumor-bearing mice. Further, using this model, mice fed for 21 days with RSDR showed significantly increased levels of serum IL-12 and IFN-γ compared with controls. Moreover, the splenic NK cell activity of mice fed with RSDR was significantly elevated compared with that of mice on a normal diet and thereby suppressed C38 tumor growth. We also investigated the tumor growth suppressing effect of RSDR using a tumor model of B16-F10 melanoma cells. Dietary preconditioning with RSDR significantly suppressed B16-F10 tumor growth. Moreover, RSDR significantly increased the production of IL-12 either before or after B16-F10 tumor implantat...

Immunostimulation-mediated antitumor activity by preconditioning with rice-shochu distillation residue against implanted tumor in mice.

Fluorescence polarization technique was applied for the assay of angiotensin I (Al) in human plasma. In this assay system, fluorescein labeled Al (F-Al), which retained the original antigenicity, and antibody to Al was allowed to interact in a cuvette in the instruments yielding an increase in the fluorescence polarization (P) value. Non-labeled Al in the sample blocked the binding of F-Al to the antibody resulting lower P value. Log of antigen concentration and P value was found to exhibit reverse linear proportionality between 0.05 ng to 2 ng/ml of antigen (Al) concentration. The present method was compared with standard radio-immunoassay method and the result showed that data were compatible with each other. The calculation of P value is automated and three cavity filter and optics of the instrument gave reliable results. The method is fast (<2 min), sensitive (<10 picomole/ml) and simple (no separation step before readout of the results).

Assay of angiotensin I by fluorescence polarization method.

A polymer type antitumor agent comprising a polymer micelle complex structure formed as a result of intermolecular boding or interaction between a low-molecular antitumor agent, such as an anthracycline antitumor agent (e.g., pirarubicin, doxorubicin, epirubicin, daunorubicin or aclarubicin), cisplatin or an alkaloid antitumor agent (e.g., taxol), and a styrene/maleic acid copolymer (SMA). This polymer type antitumor agent exerts excellent effects, namely, enhancing the selective accumulation of drug on tumor region so as to increase an antitumor efficacy while avoiding the accumulation on normal organs and tissues so as to reduce side effects thereof. This polymer type antitumor agent can be obtained through a process comprising dissolving SMA and an antitumor agent in a water base solvent, effecting a pH adjustment in the presence of soluble carbodiimide, amino acid or polyamine so as to form a micelle complex structure and separating and recovering the polymer component.

Hiroshi Maeda

Papers

Practical Synthesis of Optically Pure 1- and 3-Substituted Dihydroorotic Acids

Metallurgical studies and optimization of sintering for the Bi-Sr-Ca-Cu-O superconductors

Immunostimulation-mediated antitumor activity by preconditioning with rice-shochu distillation residue against implanted tumor in mice.

Assay of angiotensin I by fluorescence polarization method.

Antitumor agent and process for producing the same