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

A flattened V3Si multifilamentary conductor was prepared by cold-rolling a wire-composite, and then changes in morphology and configuration of the superconductor — normal metal (S-N) interface and grain boundaries were induced. Correlation between microstructure and the angular dependence of Jc with respect to the transverse field direction indicates clearly the existence of two kinds of pinning centers. The S-N interface acts as a dominant pinning center for parallel fields and becomes important in low magnetic fields, in particular for composites with fine V filaments. The element pinning force of the S-N interface was estimated from Fp vs (V3Si layer thickness)-1 relationship.

Superconducting Properties of V3Si Multifilamentary Conductor

In vitro studies of elimination of arbekacin (HBK), a new aminoglycoside antibiotic, from blood by means of hemodialysis or adsorption with charcoal, and pharmacokinetic studies in patients with renal dysfunction were examined. HBK was well eliminated by hollow fiber type artificial kidney (HFAK) with a half-life of 0.13 hr. HBK was also well eliminated by an adsorption tube containing charcoal with even shorter half-life of 0.03 hr. As to pharmacokinetics of HBK in patients with renal dysfunction, blood levels became higher with a greater reduction in 24 hr endogenous creatinine clearance (Ccr). A decreasing tendency was also seen in urinary recovery rate. These results indicated that hemodialysis and adsorption with charcoal are useful for elimination of HBK from blood. It is recommendable in patients with renal dysfunction to take some measures such as prolongation of administration interval of HBK according to the extent of decrease in Ccr.

[Clinical study of aminoglycosides on renal dysfunction--pharmacokinetics of arbekacin and its elimination effects by hemodialysis and adsorption with charcoal].

An oily composition of aclarubicin or aclarubicin hydrochloride comprising aclarubicin or aclarubicin hydrochloride; at least one fatty acid selected from saturated medium chain fatty acids, unsaturated medium chain fatty acids and unsaturated long chain fatty acids; and at least one fats and oils selected from iodized oils and vegetable oils.

Oily composition of aclarubicin or hydrochloride thereof

PURPOSE:To obtain single crystal of rare earth element having improved defects such as dislocation, vacancy, etc., by immersing seed crystal in melt of a specific garnet composition raw material mixture, and pulling it up in a nitrogen gas atmosphere to grow crystal. CONSTITUTION:A composition raw material mixture shown by the formula is melted under heating, seed crystal is immersed in it, and it is pulled up in a nitrogen gas atmosphere to grow crystal. In the formula, M is rare earth element; X is in 0.01<=X<=0.6; 0.01<=Y<=0.3. When value of X is <0.01, effect is hardly shown for improvement in thermal conductivity. When X exceeds 0.6, GdAlO3 phase of perovskite structure is crystallized in the garnet structure, and thermal conductivity is lowered. When Y is smaller than 0.01, effect is small, and when it exceeds 0.3, defects caused by dislocation, vacancy, etc. abruptly increase, and cracks occur. In growing crystal, pulling method is preferable with respect to easy preparation of large-scale crystal.

Single crystal of rare earth element garnet and production thereof

An imidazoline derivative represented by general formula (1), wherein R1 represents a water- or fat-soluble substituent, in particular, carboxyl or carbomethoxy, or a pharmaceutically acceptable salt group thereof. A process for producing the same. A blood pressure retentive containing as the active ingredient the above imidazoline derivative or another imidazoline derivative wherein R1 in formula (1) represents hydrogen. The above imidazoline derivative is a novel substance, and both this compound and the imidazoline derivative wherein R1 represents hydrogen are useful as the blood pressure retentive for treating hypotensive shock by removing excessive NO which is the substantial ingredient of a vascular smooth muscle relaxant (EDRF).

Hiroshi Maeda

Papers

Superconducting Properties of V3Si Multifilamentary Conductor

[Clinical study of aminoglycosides on renal dysfunction--pharmacokinetics of arbekacin and its elimination effects by hemodialysis and adsorption with charcoal].

Oily composition of aclarubicin or hydrochloride thereof

Single crystal of rare earth element garnet and production thereof

Imidazoline derivative, production thereof, and blood pressure retentive