Treatment Of Neoplastic Diseases Research Articles

Benzofuran hydrazones as potential scaffold in the development of multifunctional drugs: Synthesis and evaluation of antioxidant, photoprotective and antiproliferative activity

New benzofuranhydrazones 3–12 were easily prepared and assayed for their radical-scavenging ability. Hydrazones 3–12 showed different extent antioxidant activity in DPPH, FRAP and ORAC assays. Good antioxidant activity is related to the number and position of hydroxyl groups on the arylidene moiety. High antioxidant activity is showed by the 2-hydroxy-4-(diethylamino)benzylidene derivative 11. Furthermore, hydrazones 3–12 showed photoprotective capacities with satisfactory in vitro SPF as compared to the commercial PBSA sunscreen filter. The antiproliferative effects of the hydrazones 3–12 was tested on erythroleukemia K562 and Colo-38 melanoma human cells. All the compounds showed growth inhibition in the micromolar to sub micromolar concentration range. If taken together these results points to benzofuran hydrazones as potential multifunctional molecules especially in the treatment of neoplastic diseases being the good antioxidant properties of 5, 7 and 11 correlated to their high antiproliferative activity.

Melatonin Analogue Antiproliferative and Cytotoxic Effects on Human Prostate Cancer Cells.

Melatonin has been indicated as a possible oncostatic agent in different types of cancer, its antiproliferative role being demonstrated in several in vitro and in vivo experimental models of tumors. Specifically, melatonin was proven to inhibit cell growth of both androgen-dependent and independent prostate cancer cells, through various mechanisms. A number of melatonin derivatives have been developed and tested for their role in the prevention and treatment of neoplastic diseases. We recently proved the in vitro and in vivo anticancer activity of UCM 1037, a newly-synthetized melatonin analogue, on melanoma and breast cancer cells. In this study we evaluated UCM 1037 effects on cell proliferation, cell cycle distribution, and cytotoxicity in LNCaP, PC3, DU145, and 22Rv1 prostate cancer cells. We demonstrated significant dose- and time-dependent UCM 1037 antiproliferative effects in androgen-sensitive LNCaP and 22Rv1 cells. Data from flow cytometric studies suggest that UCM 1037 is highly cytotoxic in androgen-sensitive prostate cancer cells, although no substantial increase in the apoptotic cell fraction has been observed. UCM 1037 cytotoxic effects were much less evident in androgen-insensitive PC3 and DU145 cells. Experiments performed to gain insights into the possible mechanism of action of the melatonin derivative revealed that UCM 1037 down-regulates androgen receptor levels and Akt activation in LNCaP and 22Rv1 cells.

Options in Hypersensitivity Reactions to Chemotherapeutics

Chemotherapeutic drugs still represent a gold standard for the treatment of neoplastic disease. They can induce hypersensitivity reactions and are the third leading cause of fatal drug-induced anaphylaxis in the USA. This article has tried to highlight and summarize the most recent scientific progress concerning risk factors, pathogenesis, diagnosis, and treatment of these reactions. Identification of patients at high risk of developing hypersensitivity reactions allows risk stratification to guide clinical decision-making. Therefore, the most recent researches evaluated the possibility to perform risk stratification in case of hypersensitivity reactions to platinum compounds and taxanes. In addition, new data are now available regarding the role of in vitro test for the diagnosis of reactions to platins and the role of drug provocation test in case of hypersensitivity to a number of chemotherapeutics. However, actually, the allergological work-up includes a very careful anamnesis of the patient and the characteristics of reaction, whereas skin tests are useful only for few classes of chemotherapy, namely platinum salts and probably taxanes. Premedication, desensitization and, in some cases, skin tests are able to prevent the majority of hypersensitivity reactions, permitting the administration of the most effective therapy. Clearly, more studies are needed to better understand, diagnose, treat, and prevent these reactions. To reach this aim, a multidisciplinar approach to the cancer patient with potential allergies is needed.

Hepatoprotective Effect of the Aqueous Extract of Camellia sinensis Against Methotrexate-induced Liver Damage in Rats

Methotrexate (MTX) is a folate antagonist widely used in the treatment of neoplastic diseases; its biotransformation in the liver produced active metabolites that promote hepatotoxicity. The present study was designed to evaluate the hepatoprotective effect of aqueous extract of Camellia sinensis (Green tea) against MTX-induced liver damage in rats. A model of liver injury in rats was induced by intraperitoneal injection of 20mg/kg MTX as a single dose followed by saline and 1.25% and 2.5% aqueous extract of green tea (GTE) were orally administered 7 days prior and 5 days after MTX-intoxication as a sole source of drinking water. After killing the animals, blood samples were obtained for evaluation of serum levels of alanine and aspartate aminotransferases (ALT and AST) and alkaline phosphatase (ALP) activities, while liver tissue homogenate was prepared to evaluate tissue levels of glutathione (GSH) and malondialdehyde (MDA). Additionally, liver tissue sections were prepared and stained with hematoxylin and eiosin for histological evaluation. The results showed that administration of green tea extract (GTE) significantly decreased the elevated levels of ALT, AST and ALP activities in the serum compared to MTX-treated group. Treatment of animals with GTE 7 days before and 5 days after MTX also elevates GSH levels and decreases MDA levels significantly compared to MTX-treated group, this was associated with improving histological features that already impaired due to exposure to MTX. In conclusion, treatment of rats with GTE protects hepatic tissue against MTX-induced liver damage in dose dependent manner.
 Key words: Green tea, Hepatotoxicity

Gastrointestinal and Hepatic Complications of Immune Checkpoint Inhibitors.

Gastrointestinal complications are very common in patients undergoing cancer treatment. Some of these complications can be life threatening and require prompt and appropriate diagnosis and treatment. The purpose of this review is to address luminal gastrointestinal and hepatic complications associated with a new class of anticancer drugs, immune checkpoint inhibitors (CPIs), and focuses on the identification, evaluation, and management of the complications associated with this class of drugs. It is now recognized that immune checkpoint inhibitors are frequently associated with luminal GI side effects such as diarrhea and enterocolitis and hepatic complications such as hepatitis. While colitis associated with CPIs, to some extent, mimics that found in idiopathic inflammatory bowel disease, the complex interplay of genes, the environment, the immune system, and the microbiome make it difficult to fully differentiate these conditions clinically. CPI-induced hepatitis is most often associated with a pattern of hepatocellular injury with panlobular hepatitis. A variety of biomarkers have been proposed to predict an adverse response to CPIs and are under investigation. It has been proposed that alterations in the microbiome may impact the risk of developing colitis, and these studies are reviewed. In contrast to idiopathic chronic inflammatory bowel disease, CPI-induced colitis is often reversible if rapidly treated in accordance with the immune-mediated adverse reaction management guidelines. Treatment algorithms have been suggested but are, to some extent, empiric and based on algorithms for the treatment of idiopathic inflammatory bowel disorders. CPIs may be associated with significant GI complications which impact their successful use in the treatment of neoplastic diseases. Much of what we currently know about the mechanisms and treatment of these complications is empiric and extrapolated from experience with idiopathic inflammatory bowel disease and other immune disorders. Current research focuses on understanding genetic predisposition and the role of the microbiome and identifying predictive risk markers for developing complications.

Abstract 2722: Reviving kinesin-5 inhibitors: Evidence for a powerful combinatorial strategy

Abstract Mitosis serves as a powerful opportunity for therapeutic intervention in the treatment of neoplastic diseases like cancer. Anti-mitotic pharmacological agents tame the proliferative capacity of tumor cells by interfering with proper function of the mitotic spindle. Several next generation anti-mitotics target kinesins involved in assembling the mitotic spindle. Of these mitotic kinesins, the kinesin-5 Eg5 (also known as KSP) is perhaps the most compelling because of its primacy during spindle assembly in animal cells. Indeed, Eg5-inhibitors (K5Is) induce a potent and lethal mitotic arrest in cell culture and murine xenografts; however, K5Is failed to induce tumor regression during Phase II trials. This devastating clinical performance has halted further development of K5I monotherapies and motivated investigation into the underlying reason(s) for K5I inefficacy. We previously showed that tumor cells in culture are capable of acquiring K5I resistance by employing parallel spindle assembly pathways. By studying a limited number of K5I-resistant cell lines, we showed that resistance involved the kinesin-12 Kif15; however, the generality of this finding was unclear. In this study we capitalize on the latest methodologies in targeted genome editing to study mechanisms of K5I resistance on a broader cell population level. We find that cells require Kif15 in all cases of K5I resistance, and that rescue is sensitive to the timing and extent of Kif15 expression. We propose that K5Is steer cells into an evolutionary bottleneck that requires Kif15, and that adaptive changes occur during passage through the bottleneck that enable populations to recover and diversify. These findings prompt a search for pharmacological inhibitors of Kif15 to test in combination with K5Is as an anti-mitotic chemotherapeutic regimen. Citation Format: Emma G. Sturgill, Ryoma Ohi. Reviving kinesin-5 inhibitors: Evidence for a powerful combinatorial strategy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2722.

Multidisciplinary approach to introducing new technologies and reconstructive surgeries in diagnosis and treatment of neoplastic diseases of the female reproductive organs

Multidisciplinary approach that comprises the passing the examination in the exam room with the Pap test, questionnaires, ultrasound or digital mammography screening (MS) according to the age is a promising way of solving the problems with the visual localization of cancer, in particular with the reproductive organs. A minimally invasive removal technology that helped to determine the nature of tumor pathologies and remove those potentially dangerous hotbeds at the same time, was an important component of this secondary prevention system. Organ preserving and reconstructive surgeries (to our knowledge to 38,8% of patients with breast cancer and 95% of patients with vulvar cancer and vulvar dysplasia) have a positive effect not only on women’s life quality, but also become a good motivation for regular women’s screening in the region. Nothing is more convincing than the vivid example and “word of mouth”. A multidisciplinary approach to solving problem with the help of different specialists helped to reduce mortality rates for breast cancer by 30,03 ± 2,1% compared with 2009 (after the introduction of reconstructive surgery) and vulvar cancer by 83,3 ± 5,7% in comparison with 2005 (after the introduction of reconstructive surgery) at the continuing trend of increasing incidence rate. Cytological screening for dysplasia and early forms of cervical cancer needs a serious adjustment in accordance with the WHO recommendations and per capita accounting used in Russia.

Arsenic - Poison or medicine?

Arsenic (As) is commonly known as a poison. Only a few people know that As has also been widely used in medicine. In the past years As and its compounds were used as a medicine for the treatment of such diseases as diabetes, psoriasis, syphilis, skin ulcers and joint diseases. Nowadays As is also used especially in the treatment of patients with acute promyelocytic leukemia. The International Agency for Research on Cancer (IARC) has recognized arsenic as an element with carcinogenic effect evidenced by epidemiological studies, but as previously mentioned it is also used in the treatment of neoplastic diseases. This underlines the specificity of the arsenic effects. Arsenic occurs widely in the natural environment, for example, it is present in soil and water, which contributes to its migration to food products. Long exposure to this element may lead to liver damages and also to changes in myocardium. Bearing in mind that such serious health problems can occur, monitoring of the As presence in the environmental media plays a very important role. In addition, the occupational risk of As exposure in the workplace should be identified and checked. Also the standards for As presence in food should be established. This paper presents a review of the 2015 publications based on the Medical database like PubMed and Polish Medical Bibliography. It includes the most important information about arsenic in both forms, poison and medicine.

Oxidative Stress and Response to Thymidylate Synthase-Targeted Antimetabolites.

Thymidylate synthase (TYMS; EC 2.1.1.15) catalyzes the reductive methylation of 2'-deoxyuridine-5'-monophosphate (dUMP) by N(5),N(10)-methyhlenetetrahydrofolate, forming dTMP for the maintenance of DNA replication and repair. Inhibitors of TYMS have been widely used in the treatment of neoplastic disease. A number of fluoropyrimidine and folate analogs have been developed that lead to inhibition of the enzyme, resulting in dTMP deficiency and cell death. In the current study, we have examined the role of oxidative stress in response to TYMS inhibitors. We observed that intracellular reactive oxygen species (ROS) concentrations are induced by these inhibitors and promote apoptosis. Activation of the enzyme NADPH oxidase (NOX), which catalyzes one-electron reduction of O2 to generate superoxide (O2 (●-)), is a significant source of increased ROS levels in drug-treated cells. However, gene expression profiling revealed a number of other redox-related genes that may contribute to ROS generation. TYMS inhibitors also induce a protective response, including activation of the transcription factor nuclear factor E2-related factor 2 (NRF2), a critical mediator of defense against oxidative and electrophilic stress. Our results show that exposure to TYMS inhibitors induces oxidative stress that leads to cell death, while simultaneously generating a protective response that may underlie resistance against such death.

Bioresponsive antisense DNA gold nanobeacons as a hybrid in vivo theranostics platform for the inhibition of cancer cells and metastasis.

Gold nanobeacons can be used as a powerful tool for cancer theranostics. Here, we proposed a nanomaterial platform based on gold nanobeacons to detect, target and inhibit the expression of a mutant Kras gene in an in vivo murine gastric cancer model. The conjugation of fluorescently-labeled antisense DNA hairpin oligonucleotides to the surface of gold nanoparticles enables using their localized surface plasmon resonance properties to directly track the delivery to the primary gastric tumor and to lung metastatic sites. The fluorescently labeled nanobeacons reports on the interaction with the target as the fluorescent Cy3 signal is quenched by the gold nanoparticle and only emit light following conjugation to the Kras target owing to reorganization and opening of the nanobeacons, thus increasing the distance between the dye and the quencher. The systemic administration of the anti-Kras nanobeacons resulted in approximately 60% tumor size reduction and a 90% reduction in tumor vascularization. More important, the inhibition of the Kras gene expression in gastric tumors prevents the occurrence of metastasis to lung (80% reduction), increasing mice survival in more than 85%. Our developed platform can be easily adjusted to hybridize with any specific target and provide facile diagnosis and treatment for neoplastic diseases.

Effect of pentoxifillyine in the expression of apoptotic genes in leukemic cells of pediatric patients with acute lymphoblastic leukemia during steroid window phase

Effect of pentoxifillyine in the expression of apoptotic genes in leukemic cells of pediatric patients with acute lymphoblastic leukemia during steroid window phase

Photodynamic Therapy Relieves Colitis and Prevents Colitis-associated Carcinogenesis in Mice

Inflammatory bowel diseases are incurable illnesses of the gastrointestinal tract, which substantially enhance the risk of developing colorectal carcinogenesis. Conventional photodynamic therapy is a clinically approved therapeutic modality used in the treatment of neoplastic diseases. Recent preclinical and clinical studies have shown that photodynamic therapy with low doses of photosensitizer and/or light improves inflammatory conditions, including colitis. This study aims therefore at investigating the therapeutic potential of low-dose photodynamic therapy (LDPDT) with a liposomal formulation of meta-tetra(hydroxyphenyl)chlorin (namely Foslip) in the prevention of colitis-associated cancer in mice. LDPDT efficacy was evaluated by endoscopic, macroscopic, and histological analysis. Myeloperoxidase levels were quantified by enzyme linked immunosorbent assay and cytokines expression by quantitative RT-PCR analysis. The integrity of the intestinal barrier was evaluated by immunostaining, and bacterial composition of the fecal microbiota was determined by 454 pyrosequencing of V3-V4 region of bacterial 16S rRNA genes. LDPDT reduced intestinal tumor growth by decreasing the expression of a wide range of inflammatory mediators and by lowering neutrophil influx. LDPDT treatment prevents onset of a dysbiotic microbiota in the colitis-associated cancer model. LDPDT with Foslip could be considered as a novel treatment modality to prevent colorectal carcinogenesis in patients with inflammatory bowel disease.

An Overview of Cancer Rehabilitation and Exercise in the Literature: Promoting Increased Referrals to Improve Oncology Outcomes

Medical management for malignant neoplastic diseases includes surgery, chemotherapy, radiation, and hormonal and biological therapies. Each of these antineoplastic interventions has unique impacts on physiological, musculoskeletal and functional performance. Cancer rehabilitation is the area of physical medicine responsible for addressing impairments associated with cancer treatment and survivorship, advanced disease and end of life. Although it is expected that more than one-half of persons being treated for cancer will suffer moderate pain and physical and functional decline, and that most will describe fatigue, referrals to rehabilitation are traditionally low. Evidence suggests that referrals to rehabilitation before, during and after treatment for neoplastic disease may improve physiological and functional performance, quality of life and survival outcomes. Oncology practitioners are encouraged to refer patients undergoing cancer treatment to a rehabilitation professional at the peridiagnosis period. (J Patient-Centered Res Rev. 2014;1:137-141.)

Diagnosis of Chemotherapy-Induced Cardiotoxicity

Cardiotoxicity is a rising issue connected to use of chemotherapy and radiotherapy in the treatment of neoplastic diseases. Early diagnosis during follow-up is of paramount importance, and careful surveillance is recommended. Evaluation of left ventricular ejection fraction by echocardiography and nuclear medicine techniques is widely used in clinical practice; however, their sensitivity in detecting early cardiac damage is low. New instruments like speckle-tracking imaging, cardiac magnetic resonance and cardiac circulating biomarkers are available to clinicians to best evaluate the onset and progression of cardiotoxic effects, improving the therapeutic management and final outcome for the patient.

Spinal Neoplastic Instability: Biomechanics and Current Management Options

Often the spine is afflicted from primary or metastatic neoplastic disease, which can lead to instability. Instability can cause deformity, pain, and spinal cord compression and is an indication for surgery. Although overt instability is uniformly agreed upon, it is sometimes difficult for specialists to agree on subtle degrees of instability due to lack of objective criteria. In this article, treatment options and the spine instability neoplastic system are discussed and the neoplastic instability literature is reviewed. The Spinal Instability Neoplastic Score helps specialists determine whether instability is present and when surgery may be indicated. However, other parameters such as spinal cord compression and extent of disease dictate whether surgery is the most appropriate option. A wide range of fusion techniques exists, each one tailored to the location of the lesion and goals for surgery. To optimize results, expert knowledge on the techniques and patient selection is of importance. Furthermore, a multidisciplinary approach is required because treatment of neoplastic disease is multimodal.

A Comparison of B16 Melanoma Cells and 3T3 Fibroblasts Concerning Cell Viability and ROS Production in the Presence of Melatonin, Tested Over a Wide Range of Concentrations

Melatonin is a pleiotropic molecule with many cellular and systemic actions, including chronobiotic effects. Beneficial effects are widely documented concerning the treatment of neoplastic diseases in vivo as well as reductions in viability of cultured cells from melanoma, one of the most aggressive cancers in humans. However, studies of its effects on non-tumor cells in vitro have not focused on viability, except for experiments aiming to protect against oxidotoxicity or other toxicological insults. Furthermore, there is no agreement on the range of effective melatonin concentrations in vitro, and the mechanisms that reduce cell viability have remained unclear. Tumor cell-specific increases in the production of reactive oxygen and nitrogen species (ROS/RNS) may provide a possible explanation. Our aim was to analyze the potential inhibition of tumor (B16 melanoma 4A5) and non-tumor cell (3T3 Swiss albino) viability using a wide range of melatonin concentrations (10−11–10−2 M), and to determine whether intracellular ROS enhancement was involved in this process. In the absence of fetal bovine serum (FBS), low melatonin concentrations (10−9–10−5 M) reduced the proliferation of melanoma cells with no effect in fibroblasts, whereas, in the presence of FBS, they had no effect or even increased the proliferation of both fibroblast and melanoma cells. Melatonin concentrations in the upper millimolar range increased ROS levels and reduced the viability of both cell types, but more markedly so in non-tumor cells. Thus, low melatonin concentrations reduce proliferation in this specific melanoma cell line, whereas high concentrations affect the viability of both tumor (B16 4A5 melanoma) and non-tumor (3T3 fibroblasts) cells. Increased ROS levels in both lines indicate a role for ROS production in the reduction of cell viability at high—but not low—melatonin concentrations, although the mechanism of action still remains to be elucidated.

The MRTF Induced the Migration of Colon Cancer HT-29 Cell

Tumor is a kind of disease with higher morbidity and mortality, which is currently a serious threat to human health, and to strengthen the prevention and treatment of neoplastic diseases has important economic and social benefits. The migration behavior of tumor cell is a key link in the process of tumor metastasis. In this study, the related cellular and molecular mechanisms of MRTF and AQP1 inducing the migration of colon cancer cells HT-29 were revealed in the respect of Gene transcription regulation. This heralded that MRTF and AQP1 could probably be a new target on treating the tumor cell migration.

Vincristine-induced vocal cord paralysis in a patient with acute lymphoblastic leukemia

Dear Editor, Vincristine is a vinca alkaloid derived from the periwinkle plant, Catharanthus rosea. It is widely used in the treatment of neoplastic diseases and is a potent agent in the armory for the treatment of acute lymphoblastic leukemia. Its doselimiting toxicity is neuropathy, which may include peripheral (motor/sensory), autonomic, cranial nerve neuropathies, or encephalopathy. Peripheral (paraesthesia, neuritic pain) and autonomic (constipation, urinary retention) neuropathies are well described. Cranial neuropathies are less frequently described however and can be associated with more morbidity. Cortical blindness, athetosis, ataxia and parkinsonian-like symptoms have been described and

C(5) modified uracil derivatives showing antiproliferative and erythroid differentiation inducing activities on human chronic myelogenous leukemia K562 cells

The K562 cell line has been proposed as a useful experimental system to identify anti-tumor compounds acting by inducing terminal erythroid differentiation. K562 cells exhibit a low proportion of hemoglobin-synthesizing cells under standard cell growth conditions, but are able to undergo terminal erythroid differentiation when treated with a variety of anti-tumor compounds. In this paper we report a screening study on a set of different modified C(5) uracil derivatives for the evaluation of their antiproliferative effect in connection with erythroid differentiation pathways, and for defining a new class of drug candidates for the treatment of chronic myelogenous leukemia. Activity of the derivatives tested can be classified in two effect: an antiproliferative effect linked to a high level of erythroid differentiation activity and an antiproliferative effect without activation of gamma globin genes The highest antiproliferative effect and erythroid induction was shown by compound 9, a thymine derivative bearing a n-octyl chain on nitrogen N(1), whereas thymine did not show any effect, suggesting the importance of the linear alkyl chain in position N(1). To our knowledge this compound should be considered among the most efficient inducers of erythroid differentiation of K562 cells. This work is the starting point for the quest of more effective and specific drugs for the induction of terminal erythroid differentiation, for leading new insights in the treatment of neoplastic diseases with molecules acting by inducing differentiation rather than by simply exerting cytotoxic effects.

Telomerase-specific oncolytic virotherapy for human gastrointestinal cancer

Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Human telomerase is highly active in more than 85% of primary cancers, regardless of their tissue origins, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (OBP-301), in which the hTERT promoter element drives the expression of E1 genes. Since only tumor cells that express telomerase activity are able to activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with gastrointestinal tumors. In this article we show that intratumoral injection of OBP-301 mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes, which may help optimize treatment of human gastrointestinal malignancies.