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

It is scientifically and industrially important to clarify the stabilizing mechanism of proteases in extraordinary environments We used subtilisins ALP I and Sendai as models to study the mechanism Subtilisin ALP I is extremely sensitive to highly alkaline conditions, even though the enzyme is produced by alkalophilic Bacillus, whereas subtilisin Sendai from alkalophilic Bacillus is stable under conditions of high alkalinity We constructed mutant subtilisin ALP I enzymes by mutating the amino acid residues specific for subtilisin ALP I to the residues at the corresponding positions of amino acid sequence alignment of alkaline subtilisin Sendai We observed that the two mutations in the C-terminal region were most effective for improving stability against surfactants and heat as well as high alkalinity We predicted that the mutated residues are located on the surface of the enzyme structures and, on thebasis of three-dimensional modelling, that they are involved in stabilizing the conformation of the C-terminal region As proteolytic enzymes frequently become inactive due to autocatalysis, stability of these enzymes in an extraordinary environment would depend on the conformational stability of the molecular surface concealing scissile peptide bonds It appeared that the stabilization of the molecular surface structure was effective to improve the stability of the proteolytic enzymes

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.1432-1033.2002.03153.x

The molecular surface of proteolytic enzymes has an important role in stability of the enzymatic activity in extraordinary environments.

Cefixime (CFIX) was given orally in a single dose of 100 mg to 7 patients with varying degrees of impaired renal function (Ccr 12.0-56.7 ml/min) and serum concentrations and urinary excretion rates were measured with time for the first 24 hours by the bioassay method to investigate in vivo pharmacokinetics of the drug. The results obtained are summarized as follows. The mean peak serum concentration of CFIX in 3 patients with moderately impaired renal function (group I: Ccr greater than or equal to 30-less than 60 ml/min) was 2.04 micrograms/ml at 6 hours after dosing and gradually declined to 0.10 microgram/ml at 24 hours after dosing. The half-life was 4.15 hours. The mean peak serum concentration of CFIX achieved was 2.27 micrograms/ml at 8 hours after dosing in 4 patients with severely impaired renal function (group II: Ccr greater than or equal to 10-less than 30 ml/min) and the concentration of CFIX was 0.99 microgram/ml even after 24 hours. The half-life was prolonged to 11.05 hours. There was no great difference between groups I and II in the first 24-hour urinary excretion rates. However, the first 4-hour urinary excretion accounted for 2.14% of the administered dose of CFIX in group I but only 0.47% in group II. Urinary concentrations of CFIX peaked at 4-6 hours after dosing in both groups, and thereafter gradually decreased in group I. Whereas, they did not decline much in group II until 24 hours after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of cefixime in patients with impaired renal function

The present invention provides a new copper alloy containing silver from 4 to 32 at. %, which is useful for a magnet conductor, an IC lead frame, etc., having simultaneously a high strength and a high conductivity, manufactured by blending from 4 to 32 at. % silver into copper, casting, rapidly cooling and cold-working wherein the cold-working step includes a hot working treatment at a reduction rate of 40% to 70% at temperatures of from 300° to 500° C.

Method of manufacturing a high strength, high conductivity copper-silver alloy

The toxicity of the bis-succinyl derivative of the protein antibiotic, neocarzinostatin, was compared with the parent compound, neocarzinostatin (NCS), in rats. The derivative was found to be about two to five fold more active than NCS in vivo. The antitumor activity in rats bearing eleven distinct YOSHIDA hepatoma ascitic cell lines was tested under four possible combinations with regard to sites of drug and tumor cell administration. The results indicate that the antitumor spectrum of the derivative had changed slightly. Antitumor activity in mice was also tested with L1210 and P388 lymphatic leukemia, and with B16 melanocarcinoma. When the effect of the derivative was compared with parental NCS at the molecular level with respect to the inhibition of DNA synthesis in vitro, the specific activities of the two were found to be almost identical. These results were interpreted to indicate that the succinyl derivative of NCS was more stable to inactivation and proteolytic break-down in vivo than NCS as observed previously in in vitro studies.

Evaluation of succinyl neocarzinostatin in vivo.

Quantification of reaction fluxes of metabolic networks can help us understand how the integration of different metabolic pathways determines cellular functions. Yet, intracellular fluxes cannot be measured directly but are estimated with metabolic flux analysis (MFA) that relies on the patterns of isotope labeling of metabolites in the network. The application of MFA also requires a stoichiometric model with atom mappings that are currently not available for the majority of large-scale metabolic network models, particularly of plants. While automated approaches, such as Reaction Decoder Toolkit (RDT), can produce atom mappings for individual reactions, tracing the flow of individual atoms of the entire reactions across a metabolic model remains challenging. Here we establish an automated workflow to obtain reliable atom mappings for large-scale metabolic models by refining the outcome of RDT, and apply the workflow to metabolic models of Arabidopsis thaliana. We demonstrate the accuracy of RDT through a comparative analysis with atom mappings from a large database of biochemical reactions, MetaCyc. We further show the utility of our automated workflow by simulating 15 N-isotope enrichment and identifying nitrogen (N)-containing metabolites which show enrichment patterns that are informative for flux estimation in future 15 N-MFA studies of A. thaliana. The automated workflow established in this study can be readily expanded to other species for which metabolic models have been assembled and the resulting atom mappings will facilitate MFA and graph-theoretic structural analyses with large-scale metabolic networks.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/tpj.15903

Hiroshi Maeda

Papers

The molecular surface of proteolytic enzymes has an important role in stability of the enzymatic activity in extraordinary environments.

Pharmacokinetics of cefixime in patients with impaired renal function

Method of manufacturing a high strength, high conductivity copper-silver alloy

Evaluation of succinyl neocarzinostatin in vivo.

An automated workflow that generates atom mappings for large scale metabolic models and its application to Arabidopsis thaliana.