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The natural product (+)‐grandifloracin is a potent “anti‐austerity” agent, able to suppress the ability of various pancreatic cancer cell lines to tolerate conditions of nutrient deprivation. Such anti‐austerity agents represent a promising approach to cancer chemotherapy. Here we report the synthesis and biological evaluation of racemic analogues of grandifloracin bearing diverse sidechains, of which two show enhanced potency in comparison with the natural product. Additionally, several unexpected by‐products containing modifications of the grandifloracin core were isolated, identified and similarly evaluated for biological activity., Austerity measures: Grandifloracin is a natural product that is known to exhibit anti‐austerity activity, i. e. it is able to abolish the ability of pancreatic cancer cells to survive under “austere” conditions of nutrient deprivation. Herein we report the synthesis and biological evaluation of analogues of grandifloracin, as well as our findings on rearrangement and fragmentation reactions of the dimeric grandifloracin core. Live imaging, fluorescence microscopy and colony formation experiments with the most active analogue are described.

Precision medicine has increased the demand for stage-specific cancer chemotherapy. Drugs with different properties are needed for different stages of tumor development, which is, inducing rapid destruction in the early stage and facilitating deep penetration in the advanced stage. Herein, we report a novel reduction-activated charge-conversional core-shell nanoparticle (CS NP) formula based on ring-closing metathesis of the thiamine disulfide system (TDS) to deliver the chemotherapeutic agent-gambogic acid (GA). Methods: The shell consisted of hyaluronic acid-all-trans retinoid acid with a disulfide bond as the linker (HA-SS-ATRA). The core was selected from poly (γ-glutamic acid) with different grafting rates of the functional group (Fx%) of TDS. GA/CF100%S NPs, with the strongest reduction-responsive drug release, and GA/CF60%S NPs with the strongest penetration have been finally screened. On this basis, a stage-specific administration strategy against a two-stage hepatocellular carcinoma was proposed. Results: The developed CS NPs have been confirmed as inducing reduction-activated charge conversion from about -25 to +30 mV with up to 95% drug release within 48 h. The administration strategy, GA/CF100%S NPs for the early-stage tumor, and sequential administration of GA/CF60%S NPs followed by GA/CF100%S NPs for the advanced-stage tumor, achieved excellent tumor inhibition rates of 93.86±2.94% and 90.76±6.43%, respectively. Conclusions: Our CS NPs provide a novel platform for charge conversion activated by reduction. The stage-specific administration strategy showed great promise for cancer therapy.

Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, regulates various intracellular responses, such as telomere maintenance, Wnt/β-catenin signaling and cell cycle progression through its interactions with multiple target proteins. Tankyrase contains a long stretch of 24 ankyrin repeats that are further divided into five subdomains, called ANK repeat clusters (ARCs). Each ARC works as an independent ligand-binding unit, which implicates tankyrase as a platform for multiple protein-protein interactions. Furthermore, tankyrase distributes to various intracellular loci, suggesting potential distinct but yet unidentified physiological functions. To explore the novel functions of tankyrase, we performed liquid chromatography-mass spectrometry analysis and identified the BRE-BRCC36-MERIT40 complex, a regulator of homologous recombination, as tankyrase-binding proteins. Among the complex components, MERIT40 was directly associated with tankyrase via a tankyrase-binding consensus motif, as previously reported. In X-ray-irradiated non-small cell lung cancer cells, tankyrase localized to DNA double-stranded break sites in a MERIT40-dependent manner. MERIT40 knockdown increased the cell sensitivity to X-ray, whereas the wild-type, but not the tankyrase-unbound mutant, MERIT40 rescued the phenotype of the knockdown cells. Tankyrase inhibitors, such as G007-LK and XAV939, increased the cellular sensitivity to X-ray irradiation and anticancer drugs that induce DNA double-stranded breaks. These observations suggest that tankyrase plays a role in the DNA damage repair response and implicates a potential therapeutic utility of tankyrase inhibitors in combination treatments with DNA-damaging anticancer drugs.

// Rina Nakakaji 1, 2, * , Masanari Umemura 1, * , Kenji Mitsudo 2 , Jeong-Hwan Kim 1 , Yujiro Hoshino 3 , Itaru Sato 1, 2 , Takatsugu Masuda 4 , Masahiro Yamamoto 5 , Mitomu Kioi 2 , Toshiyuki Koizumi 2 , Takayuki Fujita 1 , Utako Yokoyama 1 , Masaki Iida 2 , Motohiko Sato 6 , Hiroshi Sato 7 , Shoko Murofushi 7 , Sayaka Shibata 8 , Ichio Aoki 8 , Haruki Eguchi 7 , Iwai Tohnai 2 and Yoshihiro Ishikawa 1 1 Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan 2 Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan 3 Department of Environment and Natural Sciences, Yokohama National University Graduate School of Environment and Information Sciences, Yokohama, Japan 4 Tokyo Neutron Science Laboratory, Tokyo University Institute for Solid State Physics, Kashiwa, Japan 5 Department of Chemistry of Functional Molecules, Konan University Faculty of Science and Engineering, Kobe, Japan 6 Department of Physiology, Aichi Medical University, Nagakute, Japan 7 Advanced Applied Science Department, Research Laboratory, IHI Corporation, Yokohama, Japan 8 Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan * These authors contributed equally to this work Correspondence to: Masanari Umemura, email: umemurma@yokohama-cu.ac.jp Yoshihiro Ishikawa, email: yishikaw@med.yokohama-cu.ac.jp Keywords: iron-salen; taxol; oral cancer; paclitaxel; magnetism Received: July 14, 2017 Accepted: February 20, 2018 Epub: February 26, 2018 Published: March 20, 2018 ABSTRACT N,N’-Bis(salicylidene)ethylenediamine iron (Fe(Salen)) is an anti-cancer agent with intrinsic magnetic property. Here, we covalently linked Fe(Salen) to paclitaxel (PTX), a widely used anti-cancer drug, to obtain a magnetized paclitaxel conjugate (M-PTX), which exhibited magnetic characteristics for magnet-guided drug delivery and MRI visualization. M-PTX increased apoptosis and G2/M arrest of cultured human oral cancer cell lines in the same manner as PTX. Furthermore, marked contrast intensity was obtained in magnetic resonance imaging (MRI) of M-PTX. In a mouse oral cancer model, a permanent magnet placed on the body surface adjacent to the tumor resulted in distinct accumulation of M-PTX, and the anti-cancer effect was greater than that of M-PTX without the magnet. We believe that this strategy may improve future cancer chemotherapy by providing conventional anti-cancer drugs with novel functionalities such as magnet-guided drug delivery or MRI-based visualization/quantitation of drug distribution.

The cyclin-dependent kinase-interacting proteins Cyclin-dependent Kinase Subunit 1 and 2 (CKS1 and 2) are frequently overexpressed in cancer and linked to increased aggressiveness and poor prognoses. We previously showed that CKS protein overexpression overrides the replication stress checkpoint activated by oncoproteins. Since CKS overexpression and oncoprotein activation/overexpression are often observed in the same tumors, we have hypothesized that CKS-mediated checkpoint override could enhance the ability of premalignant cells experiencing oncoprotein-induced replication stress to expand. This tumor advantage, however, could represent a vulnerability to exploit therapeutically. Here, we first show in vitro that CKS protein overexpression selectively sensitizes tumor-derived cell lines to nucleoside analog-mediated toxicity under replication stress conditions. A treatment combination of the nucleoside analog gemcitabine and an agent that induces replication stress (thymidine or methotrexate) resulted in selective targeting of CKS protein-overexpressing tumor-derived cells while protecting proliferative cells with low CKS protein levels from gemcitabine toxicity. We validated this strategy in vivo and observed that Cks2-overexpressing mammary tumors in nude mice were selectively sensitized to gemcitabine under conditions of methotrexate-induced replication stress. These results suggest that high CKS expression might be useful as a biomarker to identify subgroups of cancer patients who might benefit from the described therapeutic approach.

// Jana Simova 1 , Olena Sapega 1 , Terezie Imrichova 2 , Ivan Stepanek 1 , Lenka Kyjacova 2 , Romana Mikyskova 1 , Marie Indrova 1 , Jana Bieblova 1 , Jan Bubenik 3 , Jiri Bartek 2, 4, 5 , Zdenek Hodny 2 , Milan Reinis 1 1 Immunology Unit, Czech Centre for Phenogenomics, BIOCEV and Department of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, v.v.i., Prague 14220, Czech Republic 2 Department of Genome Integrity, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Prague 14220, Czech Republic 3 First Faculty of Medicine, Charles University in Prague, Prague 12000, Czech Republic 4 Danish Cancer Society Research Center, Copenhagen DK-2100, Denmark 5 Department of Medical Biochemistry and Biophysics, Science For Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institute, 17121 Solna, Sweden Correspondence to: Zdenek Hodny, email: hodny@img.cas.cz Milan Reinis, email: reinis@img.cas.cz Keywords: cellular senescence, cancer chemotherapy, docetaxel, IL-12, cell therapy Received: April 18, 2016 Accepted: May 29, 2016 Published: July 19, 2016 ABSTRACT Standard-of-care chemo- or radio-therapy can induce, besides tumor cell death, also tumor cell senescence. While senescence is considered to be a principal barrier against tumorigenesis, senescent cells can survive in the organism for protracted periods of time and they can promote tumor development. Based on this emerging concept, we hypothesized that elimination of such potentially cancer-promoting senescent cells could offer a therapeutic benefit. To assess this possibility, here we first show that tumor growth of proliferating mouse TC-1 HPV-16-associated cancer cells in syngeneic mice becomes accelerated by co-administration of TC-1 or TRAMP-C2 prostate cancer cells made senescent by pre-treatment with the anti-cancer drug docetaxel, or lethally irradiated. Phenotypic analyses of tumor-explanted cells indicated that the observed acceleration of tumor growth was attributable to a protumorigenic environment created by the co-injected senescent and proliferating cancer cells rather than to escape of the docetaxel-treated cells from senescence. Notably, accelerated tumor growth was effectively inhibited by cell immunotherapy using irradiated TC-1 cells engineered to produce interleukin IL-12. Collectively, our data document that immunotherapy, such as the IL-12 treatment, can provide an effective strategy for elimination of the detrimental effects caused by bystander senescent tumor cells in vivo .

WOS: 000422084700006, PubMed ID: 26199568, Aim of the study: Genistein, an isoflavonoid, plays roles in the inhibition of protein tyrosine kinase phosphorylation, induction of apoptosis, and cell differentiation in breast cancer. This study aims to induce cellular stress by exposing genistein to determine alterations of miRNA expression profiles in MCF-7 cells. Material and methods: XTT assay and trypan blue dye exclusion assays were performed to examine the cytotoxic effects of genistein treatment. Expressions of miRNAs were quantified using Real-Time Online RT-PCR. Results: The IC50 dose of genistein was 175 mu M in MCF-7 cell, line and the cytotoxic effect of genistein was detected after 48 hours. miR-23b was found to be up-regulated 56.69 fold following the treatment of genistein. It was found that miR-23b was up-regulated for MCF-7 breast cancer cells after genistein treatment. Conclusions: Up-regulated ex-expres-sion of miR-23b might be a putative biomarker for use in the therapy of breast cancer patients. miR-23b up-regulation might be important in terms of response to genistein., Ege University Medical Faculty Research Project SubcommitteeEge University [2008/TIP/021], This study was supported by Ege University Medical Faculty Research Project Subcommittee (Grant number: 2008/TIP/021).

Spontaneous neoplasm metastasis, a fatalist pathological feature of cancer, is a long-evolving, multi-steps process that can now only be treated or controlled by drugs or immuno-modulators. As we have previously hypothesized, each drug or immuno-modulator might act differently within various stages of a metastasis. Therefore any researches helping to determine these differences will be beneficial for updating therapeutics for metastasis. In this work, we have testified this hypothesis by using a series of well-known anti-metastatic agents – Bisdioxopiperazine compounds.

Spontaneous neoplasm metastasis, a fatalist pathological feature of cancer, is a long-evolving, multi-steps process that can now only be treated or controlled by drugs or immuno-modulators. Probimane (Pro), as a representative of the well-known class of antimetastatic agents âBisdioxopiperazine compounds (Biz)â, is systematically studied for its absorption, distribution and excretion in mice bearing Lewis lung carcinoma by a radioactivity-detective method in this investigation. It is found that the (14)C-Pro concentrations in different normal organs of mice at 2 hrs are very high and dramatically declined at 24 and 48 hrs. However, Pro concentrations in metastatic foci are slightly changed at the same time. Almost no change of Pro concentrations is observed in pulmonary metastatic nodules within 48 hrs. This evidence can be used to explain the characteristics of good metastatic inhibition by Biz compounds. The radioactivity in brain is relatively low because Pro can hardly penetrate into the blood-brain-barrier to eliminate brain tumors. The excretion of (14)C-Pro is observed at the same ratios from both urine and feces and also at constant rates. These data are much useful for better understanding of the general pharmacological characters and possible antimetastatic mechanisms of actions of probimane and other Biz compounds from a new perspective and research angles.

Initially, DNA topoisomerase (topo) inhibitors found clinical applications as antibiotics and cancer chemotherapeutic agents. Recently, we demonstrated that plant flavonoids that inhibit mammalian topo I or topo II might be useful as cancer chemopreventive agents (Constantinou et al., 1995b). Phytochemicals can inhibit DNA topoisomerases in different ways depending on the mode and the type of enzyme, these can be classified as topo I poisons, topo II poisons, topo I antagonists, or topo II antagonists. Correctly classifying topo inhibitors is critical because it provides an important lead as to whether the plant agent can be useful in chemoprevention or in chemotherapy. We outline below a strategy that was designed to identify and classify topo I and II inhibitors. 2 167 171

Excerpt To the Editor:The Chief of Pharmacy eagerly presented me with a copy of a position paper by the American College of Physicians (1). He needed an explanation because his impression from read...

Extracts of Rumex hymenosepalus have shown antitumor activity against the Sarcoma 180 and Walker 256 test systems of the Cancer Chemotherapy National Service Center, Bethesda, Md. The extracts have been fractionated by means of solvent extraction and paper chromatography into two distinct fractions. The partial characterization of these fractions is described, including the characterization of leucocyanidin as one of the constituents and the identification of benzoic acid as a hydrolysis product of a polyphenolic ester.

Extracts of the bark of Abies concolor have shown antitumor activity against the adenocarcinoma of the duodenum test system of the Cancer Chemotherapy National Service Center. One of the active materials appears to be a complex tannin. The isolation of the active fractions has been reported utilizing solvent extraction, column, paper, and thin-layer chromatography.

This paper presents a new measurement-based control design method for cancer chemotherapy. Cancer chemotherapy aims basically at simultaneously eradicating or significantly reducing the number of cancer cells and maintaining tolerable levels of drug concentration and toxicity. To achieve such aim, drugs are often injected into the patient's body according to a drug schedule specifying the drug dose and delivery time. Several strategies for planning cancer chemotherapy have been developed in the literature, where evolutionary algorithms have been applied to find optimal drug schedules of cancer treatment under constraints on some key treatment parameters such as drug concentration and toxic side effects. In such methods, the amount of drug doses, delivered in the body at each time during the treatment, does not depend on the current drug concentration, toxicity level, and/or number of cancer cells. Successful design of chemotherapy drug scheduling requires the availability of an accurate mathematical model that perfectly predicts the number of cancerous cells and describes effects of treatment. Several models with either complex or simple structures are available in the literature. Complex-structure models are proposed to deeply understand interactions between cancer and normal cells that affect the performance of the cancer chemotherapy. Nevertheless, such complex models are based on a high-order set of differential equations which can be difficult to solve. Simple-structure models, which are often obtained on the basis of some simplifying assumptions, can be viewed only as an approximation of the cancer system. Hence, designing chemotherapy drug schedules on the basis of simplified models may result in unsuccessful cancer treatment. Unlike conventional control strategies for cancer chemotherapy, our attempt in this paper is to address the problem of designing a control system for cancer treatment using a set of frequency-domain data. Hence, a two-degree-of-freedom PID (proportional-integral-derivative) control scheme is proposed to control cancer growth. These PID controllers are designed to simultaneously provide the optimal amount of drug doses to be delivered into the patient's body according to the current drug concentration and toxicity level, and maintain the drug concentration and toxicity levels within their pre-specified ranges. The proposed cancer control technique is validated through a first simulation example. Another example to control biological systems is also presented to show the feasibility of the proposed method. Simulation results obtained have demonstrated the capability of the proposed control scheme to address cancer chemotherapy problems.

Background: Throughout the history of human civilizations, cancer has been a major health problem. Despite the advancements made by modern medical sciences, complete treatment or removal of cancerous cells is still a challenging task. Vinblastine, an alkaloid obtained from Catharanthus roseus (L.) G. Don is one of the prominent antineoplastic agents that is being clinically used. To improve the biological potential and reduce sideeffects of this structurally complex molecule, several related analogues have been reported. The present article reviews recently reported structurally modified vinblastine analogues and its impact on biological activity. Methods: We carried out a comprehensive database search on recently reported vinblastine analogues. Both upper (catharanthine) and lower (vindoline) structural units have been considered. The role of functional group modification on anticancer activities has been discussed. In addition, formulations based on vinblastine being considered by NIH, USA for different types of cancers have also been discussed. Results: Around fifty papers were included in the review, including computational and experimental ones. These papers were analysed to discuss the mechanism of action of the parent vinblastine molecule and their analogues. The importance of each functionalities on its anticancer activity have been discussed. This reviewed identified the potential sites of vinblastine core where modification led to improved anticancer activity. Furthermore, several new formulations have also been discussed which are under different phases of clinical trial. Conclusion: The present article highlights the importance of vinblastine in cancer chemotherapy. Literature survey confirms that it is now possible to synthesize new molecules with activity in picomolar range. Not only the periphery of the molecule, the core structure of this magical molecule can be modified to achieve next generation antineoplastic agents.

In this paper, a design method for optimal cancer chemotherapy schedules via genetic algorithm (GA) is presented. The design targets the key objective of chemotherapy to minimize the size of cancer tumor after a predefined time with keeping toxic side effects in limit. This is a difficult target to achieve using conventional clinical methods due to poor therapeutic indices of existing anti-cancer drugs. Moreover, there are clinical limitations in treatment administration to maintain continuous treatment. Besides, carefully decided rest periods are recommended to for patient’s comfort. Three intermittent drug scheduling schemes are presented in this paper where GA is used to optimize the dose quantities and timings by satisfying several treatment constraints. All three schemes are found to be effective in total elimination of cancer tumor after an agreed treatment length. The number of cancer cells is found zero at the end of the treatment for all three cases with tolerable toxicity. Finally, two of the schemes, “Fixed interval variable dose (FIVD) and “Periodic dose” that are periodic in characteristic have been emphasized due to their additional simplicity in administration along with friendliness to patients. responses to the designed treatment schedules. Therefore the proposed design method is capable of planning effective, simple, patient friendly and acceptable chemotherapy schedules.

The present paper centers on mammalian metallothionein 1 and 2 in relationship to cell and tissue injury beginning with its reaction with Cd²⁺ and then considering its role in the toxicology and chemotherapy of both metals and non-metal electrophiles and oxidants. Intertwined is a consideration of MTs role in tumor cell Zn²⁺ metabolism. The paper updates and expands on our recent review by Petering et al. (Met Ions Life Sci 5:353-398, 2009).

Tumors in humans are believed to be caused by a sequence of genetic abnormality. Understanding these sequences is important for improving cancer treatments. Biologists have uncovered some of the most basic mechanisms by which normal stem cells develop into cancerous tumors. These biological theories can then be transformed into mathematical models. In this paper, we review the mathematical models applied to the optimal design of cancer chemotherapy. However, chemotherapy is a complex treatment mode that requires balancing the benefits of treating tumors with the adverse toxic side effects caused by the anti-cancer drugs. Some methods of computational optimization have proven useful in helping to strike the right balance. The purpose of this paper is to discuss the limitations of the existing theoretical research and provide several directions to improve research in optimizing chemotherapy treatment planning using real protocol treatments defined by the oncologist.

Gout is a common cause of acute arthritis. An ageing population, increasing obesity, and lifestyle changes will render it more common.1 Here I outline the epidemiology of gout, appraise the evidence base for its management, and suggest ways of managing idiopathic gout. Management of hyperuricaemia due to inborn errors of metabolism (for example, Lesch-Nyhan syndrome) and its prevention during cancer chemotherapy are not discussed here. The material for this review draws heavily on my chapter on gout in Clinical Evidence and from my work on a recent systematic review of studies on the prevention and treatment of recurrent gout. To ensure that no relevant randomised controlled trials published since the systematic review had been overlooked, I ran a previous search strategy in PubMed and the Cochrane database of systematic reviews. I identified other relevant studies from my personal database of papers on gout, did forward and backward citation tracking from other key papers, and carried out new targeted searches of multiple electronic databases. The clinical syndrome of gout arises from deposition of urate crystals in joints, where they cause an inflammatory response, and in soft tissues, where they do not. The classic symptom of gout affecting the big toe, podagra, literally a “foot catch,” has been recognised since antiquity. Crystal deposition occurs when serum becomes saturated with urate, the final breakdown product of purine metabolism. Most patients with idiopathic gout have a genetically reduced renal excretion of urate. This alone does not usually lead to hyperuricaemia. Many other factors affect serum urate concentration (box 1). Typically, gout produces an acute monoarthritis of rapid onset, often waking patients from sleep. The most commonly affected joints are the great toe, foot, ankle, knee, wrist, finger, and elbow, possibly because urate is more likely to crystallise in cooler parts of the body. …

In spite of recent diagnostic and therapeutic advances, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains very poor. As most patients are not amenable to curative intent treatments, optimized palliative management is highly needed. One key question is to what extent promising results produced by randomized controlled trials (RCTs) correspond to clinically meaningful outcomes in patients treated outside the strict frames of a clinical trial. To answer such questions, real-world evidence is necessary. The present paper reviews and discusses the current literature on first- and second-line palliative chemotherapy in PDAC. Notably, a growing number of studies report that the outcomes of the two predominant first-line multidrug regimens, i.e. gemcitabine plus nab-paclitaxel (GnP) and folfirinox (FFX), is similar in RCTs and real-life populations. Outcomes of second-line therapy following failure of first-line regimens are still dismal, and considerable uncertainty of the optimal management remains. Additional RCTs and real-world evidence studies focusing on the optimal treatment sequence, such as FFX followed by GnP or vice versa, are urgently needed. Finally, the review highlights the need for prognostic and predictive biomarkers to inform clinical decision making and enable personalized management in advanced PDAC.

Aim Since there are no established guidelines for the treatment of gynecological cancer in the elderly, medical treatment policy is currently decided by discussion with patients and their families based on doctors' experiences, referring to data from nonelderly patients and healthy elderly patients. The aim of this review was to clarify the current position of chemotherapy for elderly gynecological cancer patients and discuss the problems to be addressed in the future. Methods Little evidence has been accumulated for anticancer drug treatment in elderly individuals with gynecological cancer. This review presents outlines and representative papers on general cancer chemotherapy for the elderly, and problems that need to be solved in gynecological cancer fields in the future are identified. Results In 2018, the American Society of Clinical Oncology (ASCO) published guidelines for "Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Chemotherapy: ASCO Guideline for Geriatric Oncology Summary". This guideline emphasizes that, when administering chemotherapy to patients over 65 years of age, vulnerabilities should be identified using geriatric assessment (GA). However, there have been no reports of clinical studies using GA in patients with cervical or uterine cancers, and only a few clinical studies using GA have been reported in patients with ovarian cancer. Conclusions Scoring systems suitable for elderly Japanese patients remain lacking. A Japanese gynecological GA needs to be developed in cooperation with other disciplines.

Due to the increase in knowledge about cancer pathways, there is a growing interest in finding novel potential drugs. Quinazoline is one of the most widespread scaffolds amongst bioactive compounds. A number of patents and papers appear in the literature regarding the discovery and development of novel promising quinazoline compounds for cancer chemotherapy. Although there is a progressive decrease in the number of patents filed, there is an increasing number of biochemical targets for quinazoline compounds.This paper provides a comprehensive review of the quinazolines patented in 2007 - 2010 as potential anticancer agents. Information from articles published in international peer-reviewed journals was also included, to give a more exhaustive overview.From about 1995 to 2006, the anticancer quinazolines panorama has been dominated by the 4-anilinoquinazolines as tyrosine kinase inhibitors. The extensive researches conducted in this period could have caused the progressive reduction in the ability to file novel patents as shown in the 2007 - 2010 period. However, the growing knowledge of cancer-related pathways has recently highlighted some novel potential targets for therapy, with quinazolines receiving increasing attention. This is well demonstrated by the number of different targets of the patents considered in this review. The structural heterogeneity in the patented compounds makes it difficult to derive general pharmacophores and make comparisons among claimed compounds. On the other hand, the identification of multi-target compounds seems a reliable goal. Thus, it is reasonable that quinazoline compounds will be studied and developed for multi-target therapies.

This paper presents an investigation into the development of a multi-objective optimal chemotherapy control model to reduce the number of cancer cells after a number of fixed treatment cycles with minimum side effects. A phase specific drug scheduling method using a close-loop control method with multi-objective techniques is proposed in this paper. Genetic Algorithm (GA) and particle swarm optimisation algorithm (PSO) are used to optimise the control solution for trading-off between the cell killing and toxic side effects. A close-loop control method, namely Integral-Proportional-Derivative (I-PD) is designed to control the drug to be infused into the patient's body and multi-objective GA (MOGA) and multi-objective PSO (MOPSO) are used to find suitable parameters of the controller. The proposed algorithm is implemented, tested and verified through a set of experiments. Performances of the proposed methods demonstrated that both the MOGA and MOPSO approach can offer very efficient drug scheduling that trade-off between cell killing and toxic side effects and satisfy associated design goals. It is also noted that the MOGA based method offers better performance as compared to MOPSO and can reduce the number of proliferating and quiescent cells up to 72.2% and 60.4% respectively. Future research needs to evaluate the proposed scheduling with clinical data and experiments.

El linfoma difuso de células grandes (LDCGB) es la neoplasia linfoide agresiva más frecuente en el mundo occidental. Sin embargo, es una entidad nosológica heterogénea de difícil caracterización por técnicas convencionales. Por otro lado, desde los años ochenta sabemos que es una enfermedad con potencial curativo. La introducción de la inmunoquimioterapia con rituximab (IQTR) ha supuesto el mayor avance en el tratamiento de este tipo de linfoma, incrementando las tasas de remisión y de forma más importante la supervivencia de los pacientes. No obstante, un 25-30% de los pacientes serán refractarios al tratamiento o recaerán. En este grupo de pacientes es prioritaria la identificación de factores pronósticos clínicos y biológicos que permitan caracterizar grupos de riesgo y establecer posibles dianas terapéuticas. Esta tesis doctoral ha permitido profundizar un poco más en la caracterización biológica, clínica y pronostica del LDCGB. El primer trabajo ha contribuido a estudiar los LDCGB de origen primario extraganglionar como una variante particular con características diferentes de las formas ganglionares. Así estos pacientes presentan con mayor frecuencia características pronosticas favorables al diagnóstico (estadio temprano, niveles séricos bajos de LDH, e IPI de bajo riesgo), así como en la evolución (tasa de RC, SLP y SG superior). La segunda contribución del primer trabajo yace en cuestionar el papel de la inmunoquimioterapia en el tratamiento de los LDCGB extraganglionares. En esta entidad, quizás por las características iniciales de buen pronóstico, no observamos un incremento significativo de la supervivencia en aquellos pacientes tratados con IQTR. Ello podría suponer una ausencia de beneficio en estos pacientes, o simplemente que el número de pacientes para las diferentes localizaciones extraganglionares no es suficiente para detectar las diferencias que existen. En el segundo trabajo hemos estudiado la reproducibilidad de la caracterización molecular del LDCGB mediante técnicas de inmunohistoquímica. En la actualidad, los estudios de expresión genotípica (GEP) han permitido dividir al LDCGB en dos subgrupos centrogerminal (CGB) y activado (ABC) con impacto en el pronóstico, teniendo este último una menor supervivencia. Sin embargo, estas técnicas no son aplicables a la práctica clínica habitual dada su complejidad y elevado coste. Por ello, se han realizado intentos de remedar esta información utilizando diferentes algoritmos inmunohistoquímicos (Hans, Colomo, Muris, Choi y Tally) basados en la información extraída de los GEP. Estos algoritmos han establecido dos grupos inmunofenotípicos centrogerminal (CGB) y no-CGB. Sin embargo, nuestros resultados cuestionan el valor de los estudios de inmunohistoquímica como remedo de los perfiles de expresión genotípica. Aunque se encontró una correlación significativa entre los GEP y los diferentes algoritmos inmunohistoquímicos los valores predictivo negativo y positivo fueron relativamente bajos para los cinco algoritmos utilizados. De hecho, 30-50% de los LDCGB de origen CGB y 15-25% de los ABC fueron incorrectamente localizados por la inmunohistoquímica. Además, en términos de supervivencia global ninguno de los 5 algoritmos fue capaz de definir grupos con impacto en el pronóstico., Diffuse large B-cell lymphoma (DLBCL), although considered a single category in the WHO classification, most likely includes different clinicopathologic entities difficult to separate with the standard techniques. From the clinical standpoint, the introduction of the immunochemoterapy in the treatment of DLBCL has dramatically improved the outcome of these patients with respect to chemotherapy alone. However, a significant proportion of these patients (20-30%) is refractory or eventually relapses. Nowadays, the identification of factors, either biological or clinical, that could recognize poor risk patients is a priority. Different prognostic factors for response and survival have been described in DLBCL, but in the rituximab era, the role of the biological prognostic factors is yet to be determined. In this sense, the first paper studies the main characteristics of the DLBCL extranodal primary origin. These patients more frequently show favorable prognostic features at diagnosis (early stage, low serum LDH and IPI low risk), as well as in evolution. Moreover, this paper questions the role of the immunochemotherapy in the extranodal DLBCL treatment. We observed lack of benefit in these patients, or simply the number of patients for different extranodal sites is not sufficient to detect differences. In the second paper we studied the reproducibility of the DLBCL molecular characterization by means of immunohistochemical studies. Currently, gene expression profiling studies (GEP) have allowed to separated the DLBCL in two subgroups, germinal centre (GCB) and activated (ABC) with the latter having a poorer outcome. However, molecular techniques are not applicable to the routine clinical practice because of its complexity and high cost. Therefore, attempts have been made to mimic this information using different algorithms immunohistochemical (Hans, Colomo, Muris, Choi and Tally) based on information extracted from the GEP. Nevertheless, in the present study none of the five immunohistochemical algorithms were able to accurately predict the GEP subtype or to separate molecular groups with prognostic value. In summary, this study allows to characterize the DLBCL-EN as a variant of good prognosis with a limited benefit of the immunochemotherapy. On the other hand, the DLBCL stratification based on immunohistochemical algorithms (GCB and non-GCB) should be viewed very cautiously.

Over 40 papers have so far been published dealing with the synthesis of podophyllotoxin and its isomers. The attention devoted to this relatively small group of compounds stems from the use of derivatives of 4′-demethylepipodophyllotoxin in cancer chemotherapy. At first glance it would appear that a wide variety of synthetic methods have been employed. However, closer scrutiny reveals that three, or at most four, common themes can be distinguished. The syntheses can therefore be classified, depending upon whether they involve either a γ-oxo ester or a dihydroxy acid as a key intermediate, or whether they involve a tandem conjugate addition or a Diels-Alder reaction as a key step. Since there is much ongoing activity in this area and a steady stream of papers being published, it is clear that no totally satisfactory solution has so far been found and that ingenuity has not been exhausted. The quest for improved therapeutic activity is an important stimulus for further work, and the need to produce compounds in enantiomerically pure form means that there is continued and indeed increasing interest in this area. 1. Introduction 2. The Oxo Ester Route 3. The Dihydroxy Ester Route 4. The Tandem Conjugate Addition Route 5. Use of the Diels-Alder Reaction 6. Synthesis of 2-Azapodophyllotoxins 7. Modifications of Podophyllotoxin Itself

Over 40 papers have so far been published dealing with the synthesis of podophyllotoxin and its isomers. The attention devoted to this relatively small group of compounds stems from the use of derivatives of 4′-demethylepipodophyllotoxin in cancer chemotherapy. At first glance it would appear that a wide variety of synthetic methods have been employed. However, closer scrutiny reveals that three, or at most four, common themes can be distinguished. The syntheses can therefore be classified, depending upon whether they involve either a γ-oxo ester or a dihydroxy acid as a key intermediate, or whether they involve a tandem conjugate addition or a Diels-Alder reaction as a key step. Since there is much ongoing activity in this area and a steady stream of papers being published, it is clear that no totally satisfactory solution has so far been found and that ingenuity has not been exhausted. The quest for improved therapeutic activity is an important stimulus for further work, and the need to produce compounds in enantiomerically pure form means that there is continued and indeed increasing interest in this area. 1. Introduction 2. The Oxo Ester Route 3. The Dihydroxy Ester Route 4. The Tandem Conjugate Addition Route 5. Use of the Diels-Alder Reaction 6. Synthesis of 2-Azapodophyllotoxins 7. Modifications of Podophyllotoxin Itself

For patients receiving chemotherapy, drugs represent the largest cost. Clinical chemotherapy Pathways have become a critical strategy to identify unnecessary drug costs and to implement mechanisms to deliver lower cost alternatives without sacrificing outcomes or quality of care. This paper describes the steps of development of a functioning pathways program beginning in an environment of full-risk capitation, including drugs. The next steps involved quantitating the potential impact of such a program and then collaborating with a payer to test the concept. When these studies showed promise, the practices adopting pathways used them as a backbone for drug management in the Oncology Care Model. These experiences very likely represent steps in a continuum towards placing more of the drug delivery costs at risk. The potential for again considering capitated payments is discussed.

Mesna is an organosulfur compound used as an adjuvant in cancer chemotherapy and is available in injection formulation in commercial pharmaceutical market. Analytical method for quantitative estimation of Mesna by synthesis of its Cobalt (II) and Vanadium (V) complexes has been described in this research paper. Mesna form red brown colored 1:2 complex with Cobalt (II) with absorbance maximum at 488.5 nm, Beer’s law range of 0.65x102µg/ml to 10.5x102 µg/ml at neutral pH and 55 °C temperature with stability constant 3.045.With Vanadium(V) Mesna forms orange coloured 1:1 complex with absorbance maximum 405 nm, Beer’s law range 0.6 µg/ml to 3.6 µg/ml at acidic pH and 35 °C temperature with stability constant 4.343.

El treball realitzat en aquesta tesi doctoral constitueix un estudi farmacogenòmic de la resistència al metotrexat (MTX) en cèl·lules de càncer humà, mitjançant experiments amb microarrays per tal de comparar l'expressió gènica diferencial entre cèl·lules sensibles i resistents al MTX.En un primer estudi, vam utilizar com a model la línia cel·lular HT29 de càncer de colon, i vam identificar AKR1C1 com un gen sobreexpressat a les cèl·lules resistents al quimioteràpic. Vam analizar la regulació transcripcional d'aquest gen, mitjançada principalment per Sp1, vam determinar la seva relació amb el cicle cel·lular i amb l'apoptosi i vam establir un paper per AKR1C1 en la resistència al MTX.En un estudi posterior amb microarrays representatius del genoma humà complet, vam identificar un conjunt de gens sobreexpressats i amplificats a les cèl·lules HT29 resistents, amb una localització cromosòmica propera al gen dihidrofolat reductasa.L'anàlisi detallada dels gens diferencialment expressats CAV1, E-Cadherina, PKCi ENO2, ens va permetre determinar per a tots ells un paper en la resistència al MTX, essent els dos primers dianes potencials per al disseny d'una teràpia coadjuvant amb MTX.També vam estudiar la resposta gènica associada a la resistència al MTX en altres línies cel·lulars, representatives de càncer de colon, càncer de mama, càncer de pàncrees, leucèmia eritroblàstica i osteosacoma. Vam realitzar experiments de microarrays per a totes elles i vam obtenir llistes de gens diferencialment expressats. A partir d'aquestes dades, vam construir xarxes d'associació biològica de gens comuns diferencialment expressats en càncer de colon, en càncer de mama o entre les altres tres línies cel·lulars estudiades. Així, vam identificar gens que representaven un node de la xarxa (DKK1), o una xarxa sencera (formada per alguns membres de la família gènica UGT1A) o un gen comú deregulat en càncer de pàncrees, leucèmia eritroblàstica i osteosarcoma (EEF1A1). Validacions funcionals d'aquests gens van mostrar una sensibilització de les cèl·lules vers el MTX., This thesis represents a pharmacogenomic study on methotrexate (MTX) resistance in human cancer cells. Whole human genome microarrays allowed us to compare the gene expression patterns between cell lines sensitive or resistant to MTX.In a first approach, we used HT29 colon cancer cells as a model, and we identified AKR1C1 as a gene overexpressed in the resistant cells. We analyzed its transcriptional regulation, mainly mediated by Sp1, we determined its relationship with cell cycle and with apoptosis, and established a role for AKR1C1 on MTX resistance.In a second study, we identified a set of genes, located flanking the "dhfr locus", which were overexpressed and amplified in the resistant HT29 cells. Detailed analyses on CAV1, E-Cadherin, PKCand ENO2, four differentially expressed genes, allowed us to establish a role for all of them in MTX resistance, and to hypothesize that CAV1 and E-Cadherin may constitute potential targets for coadjuvant therapy.We also studied the gene expression profiles of MTX resistance in other cell lines, representative of colon cancer, breast cancer, pancreatic cancer, erythroblastic leukemia and osteosarcoma. We performed microarray experiments for all of them and obtained lists of genes differentially expressed. We generated biological association networks with genes in common between both colon cancer cell lines, between both breast cancer cell lines or among the other three cell lines studied. We identified a highly interconnected node in a network (DKK1), a network formed by some members of UGT1A family, and a gene deregulated in pancreatic cancer, erythroblastic leukemia and osteosarcoma (EEF1A1). Functional validations of these three genes showed a sensitization toward MTX.

Cancer is one of the major diseases that seriously threaten the human life. Increasing interest in cancer treatment strategies for chemotherapy treatment planning and optimal drug administration has created new applications for mathematical modeling. In this paper, we develop a finite-horizon Markov decision process (MDP) model for cancer chemotherapy treatment planning that could advise selection of the optimal policy for the chemotherapy regimen according to the patient’s condition. The proposed model uses a finite action space of optimal cancer chemotherapy regimens for gastric and gastroesophageal cancers resulted from the proposed optimization model and a finite state space of patients’ toxicity levels. Results show that the proposed approach yields the optimal sequence of gastric and gastroesophageal cancer chemotherapy treatment regimens for a period of chemotherapy treatment which makes possible designing clinical trials for sequential treatments.

Early detection and characterization of circulating tumor DNA (ctDNA) can reveal mint of comprehensive biological insights from indicating the presence of tumor, identifying mutational changes of malignant cells, and allowing precision or targeted therapy together with monitoring disease progression, treatment resistance, and relapse of the disease. Apart from these, one of the greatest axiomatic implications of ctDNA detection is that it provides a new shed of light as noninvasive liquid biopsy as a replaceable procedure of surgical tumor biopsy. Despite the tremendous potential of ctDNA in cancer research, there remains a paucity of quantitative study on ctDNA detection and analysis. The majority of previously published microfluidic-based studies have focused on circulating tumor cell (CTC) detection and have failed to address the potential of ctDNA. The studies on microfluidic ctDNA detection are not consistent might be due to the complexity of ctDNA isolation as they present in low concentration in blood plasma. Researchers need to leverage the ability of microfluidic system for ctDNA analysis so that the significant enigma about cancer can be resolved effectively. This study, therefore, highlights the importance of ctDNA as cancer biomarker for liquid biopsy and provides an overview of the current laboratory as well as microfluidic techniques for ctDNA detection. This paper also attempts to show the emergence of new strands of microfluidic ctDNA detection and analysis for personalized cancer chemotherapy.

Hospital preparations are frequently prepared in Japanese hospitals when ready-made formulations to meet patients' needs are unavailable. Although the quality of hospital preparations have to be ensured for efficacy and safety, such quality evaluation tends to be insufficient mainly due to lack of manpower and experimental environments in hospitals. In this paper, we investigated the applicability of quantitative (q)NMR spectroscopy to the quality control of diclofenac gargles as examples of hospital preparations, as it has various merits for the quantitative analysis of mixtures in solutions. Diclofenac gargles are composed of diclofenac, tranexamic acid, and lidocaine, and are used for the pain relief of stomatitis induced by cancer chemotherapy. Aliquots of the gargles, which were prepared five times, were mixed with dimethylsulfone as an internal standard, followed by qNMR measurements. Water signal suppression was achieved using a pulse program, water suppression enhanced through T1 effects, because the pulse program was superior to other ones such as presaturation and one-dimensional nuclear Overhauser effect spectroscopy in terms of quantitativeness. Concentrations of the three medicinal ingredients were simultaneously determined based on the signals selected by considering the spectral separation and the quantitativeness. Consequently, the gargles were found to be prepared with constant quality, and were stable at room temperature for at least four weeks. qNMR is considered to be potentially useful for the quality control of various hospital preparations because of minimal sample pretreatments, lack of need of calibration curves, and its comprehensive detection abilities.

It is well-known that chemotherapy is the most significant method on curing the most death-causing disease like cancer. These days, the use of controller-based approach for finding the optimal rate of drug injection throughout the treatment has increased a lot. Under these circumstances, this paper establishes a novel robust controller that influences the drug dosage along with parameter estimation. A new nonlinear error function-based extended Kalman filter (EKF) with improved scaling factor (NEF-EKF-ISF) is introduced in this research work. In fact, in the traditional schemes, the error is computed using the conventional difference function and it is deployed for the updating process of EKF. In our previous work, it has been converted to the nonlinear error function. Here, the updating process is based on the prior error function, though scaled to a nonlinear environment. In addition, a scaling factor is introduced here, which considers the historical error improvement, for the updating process. Finally, the performance of the proposed controller is evaluated over other traditional approaches, which implies the appropriate impact of drug dosage injection on normal, immune and tumor cells. Moreover, it is observed that the proposed NEF-EKF-ISF has the ability to evaluate the tumor cells with a better accuracy rate.

Azo molecules possess the characteristic azo bond (-N=N-) and are considered fascinating motifs in organic chemistry. Since the last century, these brightly colored compounds have been widely employed as dyes across several industries in applications for printing, food, paper, cosmetics, lasers, electronics, optics, material sciences, etc. The discovery of Prontosil, an antibacterial drug, propelled azo compounds into the limelight in the field of medicinal chemistry. Subsequent discoveries including Phenazopyridine, Basalazide, and Sulfasalazine enabled azo compounds to occupy a significant role in the drug market. Furthermore, azo compounds have been employed as antibacterial, antimalarial, antifungal, antioxidant, as well as antiviral agents. The metabolic degradation of many azo dyes can induce liver problems if ingested, posing a safety concern and limiting their application as azo dyes in medicinal chemistry. However, azo dyes remain particularly significant for applications in cancer chemotherapy. Recently, a paradigm shift has been observed in the use of azo dyes: from medicinal chemistry to biomedical sciences. The latter benefits from azo dye application are related to imaging, drug delivery, photo-pharmacology and photo switching. Herein, we have compiled and discussed recent works on azo dye compounds obtained so far, focusing on their medicinal importance and future prospects.

Poor drug distribution and inefficient drug concentrations within the tumor intracellular environment still limit the therapeutic efficacy of drugs for cancer chemotherapy. Local drug delivery (physical targeting) combined with receptor-mediated drug delivery (chemical targeting) and assistance by a novel shape design is a promising strategy to treat the infiltrating tumor (even those that persist post surgery). In this paper, we prepared dye and methotrexate (MTX) functionalized nanobacilli (MPEG–PLA–MTX–Cy5.5 NB) by a self-assembly technique combined with extrusion through a SPG membrane for intratumoral administration, in which the bacillus-shaped MPEG–PLA–MTX–Cy5.5 NB were armed with a dual-acting MTX that can specifically and efficiently enhance their cellular uptake, while avoiding their dispersion from tumor sites. After intratumoral administration to a H22 xenograft mouse model, the MPEG–PLA–MTX–Cy5.5 NB delivered the drug more effectively to the tumor compared to the MPEG–PLA–Cy5.5 nanospheres (MPEG–PLA–Cy5.5 NSs) and MPEG–PLA–MTX–Cy5.5 nanospheres (MPEG–PLA–MTX–Cy5.5 NSs). Compared to the free MTX and MPEG–PLA–MTX–Cy5.5 NSs, the controlled-release MPEG–PLA–MTX–Cy5.5 NB also significantly inhibited the tumor growth and improved therapeutic efficacy. The platforms are highly convergent, flexible and simplified systems that may serve as guides in the further design of nanoparticles with a revolutionary new shape and function for clinical applications.

As complementary and alternative medicine (CAM) becomes more popular, it is being used in cancer patients to aid in recovery or to treat symptoms associated with the current chemotherapy. Numerous papers exist that discuss patients using CAM with cancer chemotherapy and their outcomes—both positive and negative. However, in the case of the negative outcomes, the reason for the dangers or interactions with drugs are not made clear. Indeed, many chemotherapy regimens are rendered less effective by the well-meaning but uninformed patient or their family members and friends. Similarly, reports of positive outcomes with CAM and chemotherapy provide a strong basis for further research, but do not identify specific mechanisms of action. These small clinical studies and in vitro studies identify a necessary area for further research and provide a much needed, although often rejected, alternative look at whole treatment plans. Careful review of the available information and evaluation of the nature of the CAM effects are necessary to combat the misunderstanding and sometimes unwarranted claims over CAM use. This mini review will explore some of the commonly used CAM agents and their mechanisms of interactions with other treatments. Suggestions as to which agents can be safe and when to use them will be an integral part of this review.

In this paper, a kind of pH-responsive mesoporous silica targeted drug delivery system (DOX-loaded N-CQDs/HA gated pSiO2/MPEG-Glu) was designed and synthesised. In this system, active mesoporous silica (pSiO2) worked as a carrier material, methoxy polyethene glycol amine (MPEG) and L-glutamic acid (Glu) can be coupled and grafted to the surface of the pSiO2 drug carrier to improve the stability of the drug delivery system, nitrogen-doped carbon quantum dots (N-CQDs) and hyaluronic acid (HA) can inhibit the rapid release of drug. Ultraviolet (UV-Vis) spectrum showed that the drug-loading rate of DOX is 8.9%, the drug release in vitro study suggested that the prepared silica drug delivery system had significant pH-responsive and targeted DOX release, the drug release rate is 55.7% at pH = 5.0, which was much higher than the release of pH = 7.4; CLSM and MTT showed that the drug delivery system can enter into cancer cells through endocytosis and the DOX can act on cell nucleus, exhibiting a targeted therapy on cancer cells.

The problem with optimizing cancer chemotherapy has often been formulated as optimal control models, which can be intractable. Such difficulty is compounded by the facts that chemotherapeutic drugs with different mechanisms of action are often used together and that dose adjustments are often warranted according to therapeutic responses in clinical practice. Against this background, this paper addresses the problem of combination chemotherapy with dose adjustment. We first construct a mathematical model of the problem by introducing two cell-cycle phase-specific chemotherapeutic drugs into a mono-chemotherapy model. Next, we design a memetic algorithm (MA) allowing dose adjustments to solve the problem. Finally, we compare the proposed MA with existing algorithms, investigate the efficacies of different treatment strategies, and identify the characteristics of the problem related to the quality of the solutions.

The increasing threat of cancer to human life and the improvement in survival rate of this disease due to effective treatment has promoted research in various related fields. This research has shaped clinical trials and emphasized the necessity to properly schedule cancer chemotherapy to ensure effective and safe treatment. Most of the control methodologies proposed for cancer chemotherapy scheduling treatment are model-based. In this paper, a reinforcement learning (RL)-based, model-free method is proposed for the closed-loop control of cancer chemotherapy drug dosing. Specifically, the Q-learning algorithm is used to develop an optimal controller for cancer chemotherapy drug dosing. Numerical examples are presented using simulated patients to illustrate the performance of the proposed RL-based controller.

Multidrug resistance (MDR) is one of the major obstacles confronted in cancer chemotherapy; this obstacle is mainly due to the overexpression of P-glycoprotein (P-gp). Co-administration of anticancer drugs and P-gp inhibitors is a promising approach to overcome MDR. WYX-5, a novel P-gp inhibitor, shows a notable reversal effect with low cytotoxicity in vitro. In this paper, the reversal mechanism and safety of the MDR modulator WYX-5 were explored in vitro, and evaluated for its pharmacokinetics and effects on adriamycin (ADM) metabolism in vivo. The results suggest that WYX-5 is a potent P-gp inhibitor with EC50 in nanomole range (EC50 = 204.3 ± 20.2 nmol·L−1), relative safety (therapeutic index = 446.4), which performs as a substrate of P-gp and retrains its function. Further, WYX-5 (5 mg·kg−1) had relatively ideal pharmacokinetic properties (T1/2 = 6.448 h, F = 96.05%) without interactions with ADM metabolism in vivo. In conclusion, WYX-5 may be a promising candidate for MDR cancer combined-chemotherapy research.

Introduction. The goal of the paper is to show that some problems formulated in the dynamics of atmospheric flight are very similar to the problems formulated in the biomechanics of motion and medicine. Three problems were compared: minimumheat transfer from the boundary layer to the ballistic missile skin, minimum-time ski descent, and the minimisation of the negative cumulated effect of the drug in cancer chemotherapy. Material and methods. All these problems are solved using the same method originally developed for aerospace systems - the method of Miele (the extremisation method of linear integrals via Green’s theorem). Results. It is shown that the problems arising in different branches of knowledge are very similar in problem formulations, mathematical models, and solution methods used. Conclusions. There are no barriers between different disciplines.

Network robustness stands for the capability of networks in resisting failures or attacks. Many robustness measures have been proposed to evaluate the robustness of various types of networks, such as small-world and scale-free networks. However, the robustness of biological networks is different for their special structures related to the unique functionality. Cancer signaling networks which show the information transformation of cancers in molecular level always appear with robust complex structures which mean information exchange in the networks do not depend on skimp pathways in which resulting the low rate of cure, high rate of recurrence and especially, the short time in survivability caused by constantly destruction of cancer. So a network metric that shows significant changes when one node is removed, and further to correlate that metric with survival probabilities for patients who underwent cancer chemotherapy is meaningful. Therefore, in this paper, the relationship between 14 typical cancer signaling networks robustness and those cancers patient survivability are studied. Several widely used robustness measures are included, and we find that the natural connectivity, in which the redundant circles are satisfied with the need of information exchange of cancer signaling networks, is negatively correlated to cancer patient survivability. Furthermore, the top three affected nodes measured by natural connectivity are obtained and the analysis on these nodes degree, closeness centrality and betweenness centrality are followed. The result shows that the node found are important so we believe that natural connectivity will be a great help to cancer treatment.

Natural products were always the key elements in ancient history that are promising to treat various diseases including cancer and prevent any health disorders. They have seen a breakthrough since they were used in cancer chemotherapy and prevention with selective phytochemicals. Fruits and vegetables contain nutrient constituents that are bioactive in disease states. Extensive in vitro and in vivo research data is available to prove their efficacy. While few compounds have successfully transitioned to the clinical trials, few of them are still facing problems due to their poor bioavailability and lack of targeting. The lack of efficacy in human studies can be attributed to the complexity of the biological system and complexity of food. In recent years, identification of molecular targets made it necessary to develop efficient formulations for delivery. Nano formulations such emulsions, nanoparticles and nano vesicles are few of the advancements that showed promising faith in natural product chemotherapy. This paper reviews few of the techniques employed for natural compound delivery which can be applied to various compounds.

Efficient delivery of anticancer drugs to increase the intracellular drug concentration in targeted tissues is urgently needed in cancer chemotherapy, since clinical drugs usually have serious side effects on normal tissues. In this paper, we developed a new method to fabricate multi-functional porous magnetic nano-cargos by grafting PEG/folate onto the surface and storing doxorubicin in the pores of magnetic supraparticles for accurate delivery of anticancer drugs. The anticancer drug doxorubicin was fixed into the porous magnetic cores with acid-sensitive linkers, which can be broken in acidic intracellular environments or organelles; the superficial PEG chains on the magnetic cores not only enhanced the dispersion stability of the nano-cargos but also immobilized folate modified α-cyclodextrin by inclusion complexation, and the α-cyclodextrin derivatives could be flexibly replaced as needed. Remarkable proliferation inhibition of cancer cells and minor side effects on normal cells were achieved due to the controlled drug release manner of the nano-drug system, indicating that this kind of nano-cargo has great potential in cancer chemotherapy for personalized and accurate treatment.

Retinoids show great potential in various kinds of cancer chemotherapy due to its ability to induce signals for cell differentiation or death, as well as inhibit cancer stem cell proliferation. This paper summarized the recent progress of retinoids induced cancer stem cell differentiation and apoptosis in cancer therapy field, with the highlighted novel retinoid named WYC-209 in our lab, which could inhibit the tumor stem cell and malignant melanoma tumors with high efficacy and little toxicity.

In this paper, we apply the q-homotopy analysis transform method to the mathematical model of the cancer chemotherapy effect in the sense of Caputo fractional. We find some new approximate numerical results for different values of parameters of alpha. Then, we present novel simulations for all cases of results conducted by considering the values of parameters of alpha in terms of two- and three-dimensional figures along with tables including critical numerical values.

The aim of this paper is to analyze the sequence of actions in the health system associated with a particular disease. In order to do that, using Electronic Health Records, we define a general methodology that allows us to: (I) identify the actions in the health system associated with a disease; (ii) identify those patients with a complete treatment for the disease; (iii) and discover common treatment pathways followed by the patients with a specific diagnosis. The methodology takes into account the characteristics of the EHRs, such as record heterogeneity and missing information. As an example, we use the proposed methodology to analyze breast cancer disease. For this diagnosis, 5 groups of treatments, which fit in with medical practice guidelines and expert knowledge, were obtained., Artificial Intelligence in BCAM number EXP. 2019/00432, PID2019-104966GB-I00, TIN2016-78365-R, IT1244-19.

One of the important areas of concentration in medical sciences is the development of the treatment regimens in chronic diseases like cancer. This paper provides insights on how to design new clinical trials for gastric and gastroesophageal cancers which can discover the optimal and cost-effective chemotherapy treatment regimens. First, we extract data from the previously published clinical trials for the mentioned cancers to develop statistical models being capable of predicting trial outcomes. Then, using the statistical models, we present a multi-objective multi-drug model for cancer chemotherapy treatment planning. The proposed model yields a wide range of solutions establishing a reasonable tradeoff between patient's survival and treatment costs while satisfying some prevailing limitations on toxicities and the feasibility of treatment regimens. Results show that the proposed approach needs much less time and cost than the trial-and-error manipulation of cancer treatment. It also takes the advantage of saving and improving the quality of patients’ lives by suggesting the new drug regimens which improve the survival time of patients and have reasonable treatment costs compared to the current practice trials.