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

Memorized gray-scale capability was demonstrated in a ferroelectric liquid crystal optically addressed spatial light modulator (OASLM) prepared by using polyimide Langmuir-Blodgett films for the orientation of the liquid crystal.

Ferroelectric Liquid Crystal Spatial Light Modulator with Gray-Scale Capability

Purpose We performed intrarenal bacillus Calmette-Guerin (BCG) instillation for carcinoma in situ (CIS) of the upper urinary tract. Its efficacy and safety are evaluated. Material and methods Eight patients (6 men and 2 women, median age of 63.7 years) diagnosed as upper urinary tract carcinoma in situ were studied. One had bilateral upper urinary tract CIS. Thus, 9 units of upper urinary tract were treated with BCG instillation. Diagnostic criteria of upper urinary tract CIS were: 1. positive voided urinary cytology, 2. negative multiple random biopsy of the bladder and the prostatic urethra, 3. negative radiographic studies, 4. two serial positive cytologies in selective ipsilateral urine sampling. The BCG solution was administered weekly by retrograde ureteral catheterization under local anesthesia and instillation during one hour. Second course instillation was performed when 1st course was not effective. Results Of 9 renal units 7 (78%) had normalization of the urinary cytology at the end of the 1st course BCG therapy. One patient with CIS of the bilateral upper tract had negative cytology of the unilateral unit, and underwent the contralateral nephroureterectomy because of persistent positive urinary cytology and coincidental renal cell carcinoma. One patient did not have negative cytology even after three courses of BCG instillation and is now under observation. During the procedure, high fever and bladder irritative symptom were observed in 6 out of the 8 patients (75%) and 4 (50%), respectively. Conclusions Although longer followup and further experience with intrarenal BCG are required, this treatment is considered to be effective and safe for upper tract CIS.

https://www.jstage.jst.go.jp/article/jpnjurol1989/88/3/88_3_386/_pdf

[Intrarenal bacillus Calmette-Guerin therapy for carcinoma in situ of the upper urinary tract].

Chronic granulomatous disease (CGD) causes impaired hydrogen peroxide (H(2)O(2)) generation. Consequently, neutrophils in patients with CGD fail to kill infecting pathogens. We expected that supplementation with H(2)O(2) would effectively restore the bactericidal function of neutrophils in CGD. Here, we used polyethylene glycol-conjugated D-amino acid oxidase (PEG-DAO) as an H(2)O(2) source. The enzyme DAO generates H(2)O(2) by using D-amino acid and oxygen as substrates. PEG-DAO plus D-amino acid indeed exerted bacteriostatic activity against Staphylococcus aureus via H(2)O(2) in vitro. Furthermore, use of PEG-DAO plus D-amino acids, which increased the amount of intracellular H(2)O(2), restored bactericidal activity of neutrophils treated with diphenylene iodonium, in which nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was defective. This restoration of bactericidal activity was mediated by myeloperoxidase, with concomitant production of H(2)O(2) by PEG-DAO plus D-Ala. We also confirmed that PEG-DAO treatment restored bactericidal activity of congenitally defective neutrophils from patients with CGD. These results indicate that PEG-DAO can supply additional H(2)O(2) for defective NADPH oxidase of neutrophils from patients with CGD, and thus neutrophils regain bactericidal activity.

PEGylated D-amino acid oxidase restores bactericidal activity of neutrophils in chronic granulomatous disease via hypochlorite.

Crystal growth of large size Dy3Al5O12 Garnet single crystals

High-damping materials are widely used in engineering fields. In order to increase the precision of vibration control to different levels, high-damping materials with high-rigidity are required. This study attempts to develop a new high-damping high-rigidity material using ductile ceramics based on the Al2TiO5–MgTi2O5 system, which has many continuous microcracks along the grain boundaries. Ductile ceramics have high internal friction (Q−1 = 0.01–0.037), but very low rigidity (<10 GPa). The rigidity of Al2TiO5–MgTi2O5 ceramics was improved by combining them with a polymer such as acrylic resin. The Young’s modulus and internal friction of the composites of Al2TiO5–MgTi2O5 ceramics and acrylic resin are investigated. They show high-damping capacity (Q−1 = 0.03–0.04) with high rigidity (E = 50–60 GPa), and their properties depend on those of the polymer. Thus, the composites fabricated using the above method can serve as high-damping high-rigidity materials.

Hiroshi Maeda

Papers

Ferroelectric Liquid Crystal Spatial Light Modulator with Gray-Scale Capability

[Intrarenal bacillus Calmette-Guerin therapy for carcinoma in situ of the upper urinary tract].

PEGylated D-amino acid oxidase restores bactericidal activity of neutrophils in chronic granulomatous disease via hypochlorite.

Crystal growth of large size Dy3Al5O12 Garnet single crystals

High-damping and high-rigidity composites of Al2TiO5–MgTi2O5 ceramics and acrylic resin