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

Background: The ratio of free PSAin total PSA(fit) has been reported to improve the diagnostic accuracy of prostate cancer in the groupwith slightly elevated serum PSA values. In Japanese cases, the clinical significance of fit is still controversial. Methods: The diagnostic significance of fit in serum for prostate cancer was evaluated in a cooperative study. A total of 77 cases with prostate cancer and 224 with non-prostate cancer showing less than 20 ng/ml of total PSAwere evaluated. Results: Serum total and free PSA values were not affected by storage at 25°C for 2 days. The determination of fit was useful in the cases with a serum total PSA of 5.1-10 ng/ml; the specificity was 60% with a sensitivity of 90% at an fit of 0.148. The positive predictive value for diagnosis of prostate cancer also increased to 54%from 34% of that in total PSA alone. In the range of 4.1-10 ng/ml, the cut-off value of fit was 0.155 for obtaining relatively high specificity; sensitivity was 85% and specificity was 56.5%. Conclusions: Thus, thedetermination offit wasconsidered to beaneffective tool fordiscriminating the non-prostate cancer cases from those of prostate cancer.

Significance of Free to Total PSA Ratio in Men with Slightly Elevated Serum PSA Levels: A Cooperative Study

Synthetic studies of tedanolide. 4. stereoselective and efficient synthesis of the c13-c23 part

With the aim of preparing a single, high-Tc phase in the Bi-Sr-Ca-Cu-O system, optimization of the composition and heat treatment have been studied. It was found that the temperature range at which the high-Tc phase forms, was very narrow (865–880°C) and a process of furnace-cooling was required to reduce a residual resistance due to the low-Tc phase. The high-Tc phase in this oxide system can easily form from a limited starting composition around Bi1Sr1Ca1Cu2Ox. Tc values for the high-Tc phase do not change much from the initial composition or the heat treatment, while that for the low-Tc phase moves considerably from about 88 K down to below 20 K. Existence of new superconducting phases in the Sr-Ca-Cu-O system is mentioned.

https://iopscience.iop.org/article/10.1143/JJAP.27.L548/pdf

Effects of Synthesis Conditions on the Properties of a Superconducting Bi–Sr–Ca–Cu–O System

The role of NO and superoxide (O(2)(-)) in tissue injury during cardiac allograft rejection was investigated by using a rat ex vivo organ perfusion system. Excessive NO production and inducible NO synthase (iNOS) expression were observed in cardiac allografts at 5 days after cardiac transplantation, but not in cardiac isografts, as identified by electron spin resonance spectroscopy and Northern blotting. Cardiac isografts or allografts obtained on Day 5 after transplantation were perfused with Krebs bicarbonate buffer with or without various antidotes for NO or O(2)-, including N(omega)-monomethyl-L-arginine (L-NMMA; 1 mM), 2-phenyl-4,4,5, 5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO; 100 microM), 4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP; a xanthine oxidase inhibitor; 100 microM), and superoxide dismutase (SOD; 100 units/ml). Treatment of the cardiac allografts with PTIO showed most remarkable improvement of the cardiac injury as revealed by significant reduction in aspartate transaminase, lactate dehydrogenase, and creatine phosphokinase concentrations in the perfusate. Similar but less potent protective effect on the allograft injury was observed by treatment with L-NMMA, AHPP, and SOD. Immunohistochemical analyses for iNOS and nitrotyrosine indicated that iNOS is mainly expressed by macrophages infiltrating the allograft tissues, and nitrotyrosine formation was demonstrated not only in macrophages but also in cardiac myocytes of the allografts, providing indirect evidence for the generation of peroxynitrite during allograft rejection. Our results suggest that tissue injury in rat cardiac allografts during acute rejection is mediated by both NO and O(2)(-), possibly through peroxynitrite formation.

Role of nitric oxide and superoxide in acute cardiac allograft rejection in rats.

A sharp resistive superconducting transition above 100 K has been achieved for Bi-Sr-Ca-Cu-O superconductors. The resistance at 100 K was estimated to be less than 10-6 Ω cm in a zero magnetic field.

Hiroshi Maeda

Papers

Significance of Free to Total PSA Ratio in Men with Slightly Elevated Serum PSA Levels: A Cooperative Study

Synthetic studies of tedanolide. 4. stereoselective and efficient synthesis of the c13-c23 part

Effects of Synthesis Conditions on the Properties of a Superconducting Bi–Sr–Ca–Cu–O System

Role of nitric oxide and superoxide in acute cardiac allograft rejection in rats.

Preparation of High- T c Bi–Sr–Ca–Cu–O Superconductors