Side Effects Of Anticancer Therapy Research Articles

THE RELATIONSHIP BETWEEN METABOLIC DISORDERS AND TUMOR PROGRESSION: REVIEW OF PRESENT DATA AND NEW THERAPEUTIC TARGETS

Background. Type 2 diabetes mellitus, obstructive sleep apnea, osteoarthritis and certain types of cancer are known to correlate with obesity. The mechanisms underlying the link between metabolic disorders and cancer remain obscure, yet assuming a potentially important role of reduced insulin sensitivity, altered glucose metabolism in tumor cells (the so-called Warburg effect), changes in the spectrum of secreted adipokines or interaction with their cognitive receptors as well as changes in steroid sex hormone production.Material and methods. A search for articles published in peer-reviewed journals indexed in pubmed, Wos, scopus and Rsci was carried out. More than 150 articles devoted to the study of the relationship between metabolic disorders and tumor progression were analyzed, of which 69 were included in this review.Results. The main strategy of anticancer therapy is to suppress the proliferation of tumor cells and metastasis. However, one should take into consideration a significant role of additional factors that can enhance side effects of anticancer therapy, ensure the resistance of tumor cells to chemotherapy or change cancer cell metabolic profile. New data recently emerging in the literature indicate an important function of proteins such as t-cadherin and urokinase receptor (upar) and their possible involvement in the regulation of tumor cell metabolism, in particular, sensitivity to insulin and adipose tissue hormones. The review encompasses recent data on the involvement of t-cadherin and upar in the regulation of metabolism and proposes a model explaining the relationship between these proteins and metabolic disorders associated with the processes of carcinogenesis and chemoresistance of cancer cells.Conclusion. Understanding of the factors and mechanisms that support obesity and metabolic disorders is relevant both for the development of cancer preventive measures and optimization of therapeutic strategies for combating cancer.

Glycyrrhiza glabra root extract alleviates cyclophosphamide induced mucositis of the tongue in adult male albino rats

ABSTRACTIntroduction: Cyclophosphamide (CPA) is an anti-cancer medication, utilized in chemotherapy. Recently, inflammation of oral mucosa (mucositis) is thought to be one of the most serious side effects of anticancer therapy. Aim of the work: To investigate the role of glycyrrhiza glabra (Licorice) root extract on rat tongue mucositis induced by CPA.Materials and methods: Forty adult male albino rats were classified into four groups, (each included 10 rats): Group I (Control group), Group II (Licorice group): each rat received licorice root extract by an oral daily dose of 200 mg/kg/day for 10 days, Group III (CPA group): each rat received CPA in a single intraperitoneal dose of 300 mg/kg on the second day of experiment and Group IV (Licorice CPA group): each rat received licorice root extract by an oral daily dose of 200 mg/kg/day for ten days, on the second day of experiment, the rats received CPA in a single intraperitoneal dose of 300 mg/kg. At the end of the experiment, the rats were anesthetized, and the tongue was excised for histological, immunohistochemical and ultrastructural analysis. Morphometric and statistical analysis were also done.Results: Licorice root extract reduced the severity of CPA induced oral mucositis by increasing the epithelial thickness, normalization of congested blood vessels in the lamina propria of tongue mucosa, significant amelioration of immunoreactivity to anti-Ki-67, anti-E-cadherin and anti-P53.Conclusion: CPA chemotherapy has a detrimental effect on the oral mucosa resulting in marked morphometric and microscopic changes. Glycyrrhiza glabra extract can protect the oral mucosa from CPA-induced toxicity and reduce the associated injury.

Beneficial Effects of Polysaccharides on the Epithelial Barrier Function in Intestinal Mucositis

Intestinal mucositis is a clinically relevant side effect of anticancer therapies. It is experienced by 60–100% of patients undergoing treatment with high doses of chemotherapy, radiation therapy, and bone marrow transplantation. Intestinal mucositis can manifest as pain, weight loss, inflammation, diarrhea, rectal bleeding, and infection; affecting normal nutritional intake and intestinal function. It often impacts adherence to anticancer therapy as it frequently limits patient’s ability to tolerate treatment, causing schedule delays, interruptions, or premature discontinuation. In some cases, local and systemic secondary infections are observed, increasing the costs toward medical care and hospitalization. Several strategies for managing mucositis are available which do not always halt this condition. In this context, new therapeutic strategies are under investigation to prevent or treat intestinal mucositis. Polysaccharides from natural resources have recently become promising molecules against intestinal damage due to their ability to promote mucosal healing and their anti-inflammatory actions. These effects are associated with the protection of intestinal mucosa and regulation of microbiota and immune system. This review aims to discuss the recent advances of polysaccharides from natural resources as potential therapies for intestinal mucositis. The source, species, doses, treatment schedules, and mechanisms of action of polysaccharides will be discussed in detail.

Pain Relieving and Neuroprotective Effects of Non-opioid Compound, DDD-028, in the Rat Model of Paclitaxel-Induced Neuropathy

Chemotherapy-induced neuropathy (CIN) is a major dose-limiting side effect of anticancer therapy that can compel therapy discontinuation. Inadequate analgesic efficacy of current pharmacological approaches requires the identification of innovative therapeutics and, hence, the purpose of this study is to conduct a preclinical evaluation of the efficacy of DDD-028, a versatile pentacyclic pyridoindole derivative, against paclitaxel-induced neuropathic pain. In two separate experiments, DDD-028 was administered per os acutely (1–25 mg kg−1) or repeatedly (10 mg kg−1) in paclitaxel-treated rats. The response to mechanical noxious stimulus (paw pressure) as well as to non-noxious mechanical (von Frey) and thermal (cold plate) stimuli was investigated. Acute administration of DDD-028 induced a dose-dependent anti-neuropathic pain effect in all tests performed. Further, repeated daily treatment for 18 consecutive days (starting the first day of paclitaxel administration) significantly reduced the development of pain over time without the development of tolerance to the anti-hyperalgesic effect. Ex vivo analysis showed that DDD-028 was able to reduce oxidative damage of dorsal root ganglia as evidenced by the increase in the level of carbonylated proteins and the decrease in catalase activity. In the lumbar spinal cord, periaqueductal gray matter, thalamus, and somatosensory cortex 1, DDD-28 significantly prevented the activation of microglia and astrocytes. The pharmacodynamic study revealed that the pain-relieving effects of DDD-028 were fully blocked by both the non-selective nicotinic receptor (nAChR) antagonist mecamylamine and by the selective α7 nAChR antagonist methyllycaconitine. In conclusion, DDD-028 was active in reducing paclitaxel-induced neuropathic pain after single or repeated administrations without tolerance development and displaying a double symptomatic and neuroprotective profile. DDD-028 could represent a valuable candidate for the treatment of CIN.

Proteolytic Enzyme Therapy in Complementary Oncology: A Systematic Review.

Bromelain, papain and chymotrypsin are proteolytic enzymes. They can be found in fruits such as pineapple or papaya, but also in the human body, namely in the pancreas. Besides their enzymatic function, they are said to reduce side-effects and even to improve the outcome of cancer therapies. We, therefore, aimed to critically examine and systematically review existing evidence on the role that these enzymes might play in cancer treatment. In May 2019, a systematic literature search was conducted by using five electronic databases (Embase, Cochrane, PsychInfo, CINAHL and Medline) to find studies concerning the use, effectiveness and potential harm of enzyme therapy on cancer patients. Out of 13,046 search results, 15 studies with 3,008 patients were included in this systematic review. Patients treated with enzymes were diagnosed with various entities of gastrointestinal, gynecologic, head and neck and lung cancer as well as hematological malignancies. The therapy concepts included mainly oral intake of enzymes in addition to conventional therapies. Investigated outcomes were side-effects of anticancer therapy, quality of life, as well as anticancer effects and survival rates. In summary, due to conflicting results and moderate quality of the included studies, the evidence is insufficient to attribute positive effects to enzymes in terms of better tolerability of the various antineoplastic therapies or even improvement in treatment efficacy. In most cases, enzyme therapy was well tolerated; side-effects were mainly gastrointestinal complaints such as diarrhea or meteorism. On the basis of existing evidence, there is no clear therapeutic benefit of enzymes neither as supportive therapy nor as part of antineoplastic therapy.

A Fibrinogen Alpha Fragment Mitigates Chemotherapy-Induced MLL Rearrangements.

Rearrangements in the Mixed Lineage Leukemia breakpoint cluster region (MLLbcr) are frequently involved in therapy-induced leukemia, a severe side effect of anti-cancer therapies. Previous work unraveled Endonuclease G as the critical nuclease causing initial breakage in the MLLbcr in response to different types of chemotherapeutic treatment. To identify peptides protecting against therapy-induced leukemia, we screened a hemofiltrate-derived peptide library by use of an enhanced green fluorescent protein (EGFP)-based chromosomal reporter of MLLbcr rearrangements. Chromatographic purification of one active fraction and subsequent mass spectrometry allowed to isolate a C-terminal 27-mer of fibrinogen α encompassing amino acids 603 to 629. The chemically synthesized peptide, termed Fα27, inhibited MLLbcr rearrangements in immortalized hematopoietic cells following treatment with the cytostatics etoposide or doxorubicin. We also provide evidence for protection of primary human hematopoietic stem and progenitor cells from therapy-induced MLLbcr breakage. Of note, fibrinogen has been described to activate toll-like receptor 4 (TLR4). Dissecting the Fα27 mode-of action revealed association of the peptide with TLR4 in an antagonistic fashion affecting downstream NFκB signaling and pro-inflammatory cytokine production. In conclusion, we identified a hemofiltrate-derived peptide inhibitor of the genome destabilizing events causing secondary leukemia in patients undergoing chemotherapy.

Flavonolignans: One Step Further in the Broad-Spectrum Approach of Cancer

The small chemical class of flavonolignans encompasses unique hybrid molecules with versatile biological activities. Their anticancer effects have received considerable attention, and a large body of supporting evidence has accumulated. Moreover, their ability to interact with proteins involved in drug resistance, and to enhance the effects of conventional chemotherapeutics in decreasing cell viability make them influential partners in addressing cancer. The review provides an outline of the various ways in which flavonolignans advance the combat against cancer. While the main focus falls on flavonolignans from milk thistle, attention is drawn to the yet, underexplored potential of less known flavonolignan subgroups derived from isoflavonoids and aurones. Proceeding from the presentation of natural flavonolignan subtypes and their occurrence, the present work reviews these compounds with regard to their molecular targets in cancer, anti-angiogenetic effects, synergistic efficacy in conjunction with anticancer agents, reversal of drug resistance, and importance in overcoming the side effects of anticancer therapy. Recent advances in the endeavor to improve flavonolignan bioavailability in cancer are also presented. Significant progress has been achieved in detailing the molecular mechanisms of silybin and its congeners in experimental models of cancer. The availability of novel formulations with improved bioavailability, and data from phase I clinical trials in cancer patients provide an encouraging basis for more extensive trials aimed at evaluating the benefits of Silybum flavonolignans in cancer management. On the other hand, further research on the antitumor efficacy of iso-flavonolignans and other subtypes of flavonolignans should be pursued.

Possible Susceptibility Genes for Intervention against Chemotherapy-Induced Cardiotoxicity.

Recent therapeutic advances have significantly improved the short- and long-term survival rates in patients with heart disease and cancer. Survival in cancer patients may, however, be accompanied by disadvantages, namely, increased rates of cardiovascular events. Chemotherapy-related cardiac dysfunction is an important side effect of anticancer therapy. While advances in cancer treatment have increased patient survival, treatments are associated with cardiovascular complications, including heart failure (HF), arrhythmias, cardiac ischemia, valve disease, pericarditis, and fibrosis of the pericardium and myocardium. The molecular mechanisms of cardiotoxicity caused by cancer treatment have not yet been elucidated, and they may be both varied and complex. By identifying the functional genetic variations responsible for this toxicity, we may be able to improve our understanding of the potential mechanisms and pathways of treatment, paving the way for the development of new therapies to target these toxicities. Data from studies on genetic defects and pharmacological interventions have suggested that many molecules, primarily those regulating oxidative stress, inflammation, autophagy, apoptosis, and metabolism, contribute to the pathogenesis of cardiotoxicity induced by cancer treatment. Here, we review the progress of genetic research in illuminating the molecular mechanisms of cancer treatment-mediated cardiotoxicity and provide insights for the research and development of new therapies to treat or even prevent cardiotoxicity in patients undergoing cancer treatment. The current evidence is not clear about the role of pharmacogenomic screening of susceptible genes. Further studies need to done in chemotherapy-induced cardiotoxicity.

Sex and Gender Influences on Cancer Immunotherapy Response

The global burden of cancer is growing and a wide disparity in the incidence, malignancy and mortality of different types of cancer between each sex has been demonstrated. The sex specificity of cancer appears to be a relevant issue in the management of the disease, and studies investigating the role of sex and gender are becoming extremely urgent. Sex hormones are presumably the leading actors of sex differences in cancer, especially estrogens. They modulate gene expression, alter molecules and generate disparities in effectiveness and side effects of anticancer therapies. Recently immunotherapy aims to improve anticancer treatment strategies reducing off-target effects of chemotherapy and direct cancer cells killing. It is recognized as a fruitful strategy to treat and possible to cure cancer. Immunotherapeutic agents are used to activate or boost the activation of the immune system to fight cancer cells through physiological mechanisms often evaded in the offensive march of the disease. These therapeutic strategies have allowed new successes, but also have serious adverse effects including non-specific inflammation and autoimmunity. Sex and gender issues are of primary importance in this field, due to their recognized role in inflammation, immunity and cancer, and the clarification and understanding of these aspects is a necessary step to increase the responses and to diminish the adverse effects of immunotherapy. This review describes the available knowledge on the role of sex and gender in cancer immunotherapy, and will offer insights to stimulate the attention and practice of clinicians and researchers in a gender perspective of new cancer treatment strategies.

Learning from My Experience: Outpatient Care for Cancer Multigene Genomic Testing

We established an outpatient service in November 2017 to provide cancer gene profiling test services to cancer patients. To date, we have seen approximately 100 patients. Our staff includes genetic counselors and nurses specialized in genetic medicine. Our experience highlights the importance of healthcare professionals having in-depth knowledge of cancer therapeutic drugs and/or investigational drugs based on cancer genome medicine. Recently, poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for treating breast cancer patients with germline BRCA mutation; thus, in-depth knowledge of genetics and skills for genetic counseling are often considered indispensable in working with cancer patients. However, because the prompt treatment of clear and present cancer is the top priority in clinical settings, providing genetic information at that time, including that of unaffected family members, is of low priority for most patients who are dealing with the severe side effects of anti-cancer therapies. Pharmacists have an essential role to play in cancer therapeutics, talking with patients in order to assess their condition and to clarify the status of their treatment with anticancer agents. Genetic pharmacists should therefore work closely with genetics nurses and genetic counselors in the clinical practice of cancer genomic medicine. In this symposium, I would like to describe our experience caring for patients through our outpatient service, and to discuss the ideal framework for multidisciplinary cooperation to promote cancer genomic medicine.

Abstract B24: The macrophage-drug conjugate (MDC) as a “Trojan horse” approach in cancer therapy

Abstract Unsatisfactory response of tumors to chemotherapy is mainly related to impaired diffusion of the anticancer drug because of decreased drug uptake due to poor vasculature. Moreover, the drug is not able to penetrate the most hypoxic sites. Cells from these “untreated” sites are responsible for relapse and metastasis. However, these avascular regions attract macrophages that migrate even to areas far away from blood vessels. Therefore, they might constitute a unique delivery system of drug-containing particles to these parts of the tumor mass. A promising example of such particles that could be used is ferritins, whose caged architecture allows for efficient drug encapsulation and whose uptake from macrophage cells has been well demonstrated. Macrophages are also able to specifically and actively transfer these taken-up ferritins (loaded with the anticancer drugs) to cancer cells. This is the new mechanism discovered by our team and named TRAIN (TRAnsfer of Iron-binding proteiN). Thus, there is a possibility to use macrophages to deliver ferritin-encapsulated compounds directly to the tumor cells (MDC technology—Macrophage-Drug Conjugate). This is a completely new and modern approach to anticancer therapy and drug delivery. As such, we expect to be able to precisely administer drugs to the tumor site (even to the hypoxic regions), decreasing side effects of anticancer therapy. Acknowledgments: This research is founded by the European Research Council, Starting Grant McHAP: 715048. The dissemination of the project is founded by the KNOW (Leading National Research Centre), Scientific Consortium “Healthy Animal-Safe Food,” decision of Ministry of Science and Higher Education No. 05-1/KNOW2/2015. Citation Format: Bartłomiej Taciak, Maciej Białasek, Paulina Kucharzewska-Siembieda, Łukasz Kiraga, Aleksandra Szulc, Emilia Górka, Małgorzata Kubiak, Zofia Pilch, Katarzyna Tonecka, Zuzanna Sas, Agata Braniewska, Łukasz Cheda, Zbigniew Rogulski, Michał Godlewski, Alberto Boffi, Tomasz Rygiel, Magdalena Król. The macrophage-drug conjugate (MDC) as a “Trojan horse” approach in cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B24.

Photo-Onycholysis : A Particular Chemotherapy-Induced Complication

Onycholysis or photo-onycholysis is a partial or total separation of the nail from the nail-bed secondary to chemotherapy, either alone or associated to ultraviolet phototherapy. It’is not a common side effect of anticancer therapy, even rarer with Paclitaxel. We report here one case.

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

The E3 ubiquitin ligase Murine double minute 2 (MDM2) is the main negative regulator of the tumor protein p53 (TP53). Extensive studies over more than two decades have confirmed MDM2 oncogenic role through mechanisms both TP53-dependent and TP53-independent oncogenic function. These studies have contributed to designate MDM2 as a therapeutic target of choice for cancer treatment and the number of patents for MDM2 antagonists has increased immensely over the last years. However, the question of the physiological functions of MDM2 has not been fully resolved yet, particularly when expressed and regulated physiologically in healthy tissue. Cardiovascular complications are almost an inescapable side-effect of anti-cancer therapies. While several MDM2 antagonists are entering phase I, II and even III of clinical trials, this review proposes to bring awareness on the physiological role of MDM2 in the cardiovascular system.

Selenium nanoparticles act as an intestinal p53 inhibitor mitigating chemotherapy-induced diarrhea in mice

Selenium, at high-dose levels approaching its toxicity, protects tissues from dose-limiting toxicities of many cancer chemotherapeutics without compromising their therapeutic effects on tumors, there by allowing the delivery of higher chemotherapeutic doses to achieve increased cure rate. In this regard, selenium nanoparticles (SeNPs), which show the lowest toxicity among extensively investigated selenium compounds including methylselenocysteine and selenomethionine, are more promising for application. The key issue remains to be resolved is whether low-toxicity SeNPs possess a selective protective mechanism. p53 or p53-regulated thrombospondin-1 has each been confirmed to be an appropriate target for therapeutic suppression to reduce side effects of anticancer therapy. The present study demonstrated that SeNPs transiently suppressed the expression of many intestinal p53-associated genes in healthy mice. SeNPs did not interfere with tumor-suppressive effect of nedaplatin, a cisplatin analogue; however, effectively reduced nedaplatin-evoked diarrhea. Nedaplatin-induced diarrhea was associated with activation of intestinal p53 and high expression of intestinal thrombospondin-1. The preventive effect of SeNPs on nedaplatin-induced diarrhea was correlated with a powerful concomitant suppression of p53 and thrombospondin-1. Moreover, the high-dose SeNPs used in the present study did not suppress growth nor caused liver and kidney injuries as well as alterations of hematological parameters in healthy mice. Overall, the present study reveals that chemotherapeutic selectivity conferred by SeNPs involves a dual suppression of two well-documented targets, the p53 and thrombospondin-1, providing mechanistic and pharmacologic insights on low-toxicity SeNPs as a potential chemoprotectant for mitigating chemotherapy-induced diarrhea.

Effect of L-Leucine Therapy on Hematopoietic Function in Elderly Myelodysplastic Syndrome Patients.

Patients with myelodysplastic syndrome (MDS) often require blood transfusion and anticancer therapy; however, elderly patients are intolerant to the associated side effects of anticancer therapy. Because L-leucine can be used to treat Diamond-Blackfan anemia, which is caused by defects in ribosomal protein (RP) genes, resulting in increased in vivo hemoglobin synthesis, it is possible that some MDS patients who have aberrations in their RP genes could also be effectively treated with L-leucine. In the present study, we investigated the effects of L-leucine on hematopoietic function (reticulocyte count), red blood cell count, and hemoglobin level in MDS patients. We administered L-leucine (1.8 g, twice daily, 3 d/week) with oral vitamin B6 supplements to a final cohort of eight MDS patients for 15 (interquartile range: 11-18) weeks. We assessed the patients at 10 ± 2 weeks after therapy initiation. Only the absolute reticulocyte count was affected, improving in 6/8 (75%) patients. The median absolute reticulocyte count was 3.5 × 104 (range: 2.7-6.4 × 104) cells/µL, an increase of 0.5 × 104 (range: 0.2-0.7 × 104) cells/µL. At 10 weeks, there was only one case of an improved hemoglobin level. Non-hematological adverse events of grade 3 were observed one raised triglycerides. These data suggest that L-leucine has little effect on MDS. However, it may contribute to the recovery of hematopoietic function, futher study be desired.

Animal models of mucositis: critical tools for advancing pathobiological understanding and identifying therapeutic targets.

Mucositis remains a prevalent, yet poorly managed side effect of anticancer therapies. Mucositis affecting both the oral cavity and gastrointestinal tract predispose to infection and require extensive supportive management, contributing to the growing economic burden associated with cancer care. Animal models remain a critical aspect of mucositis research, providing novel insights into its pathogenesis and revealing therapeutic targets. The current review aims to provide a comprehensive overview of the current animal models used in mucositis research. A wide variety of animal models of mucositis exist highlighting the highly heterogenous landscape of supportive oncology and the unique cytotoxic mechanisms of different anticancer agents. Golden Syrian hamsters remain the gold-standard species for investigation of oral mucositis induced by single dose and fractionated radiation as well as chemoradiation. There is no universally accepted gold-standard model for the study of gastrointestinal mucositis, with rats, mice, pigs and dogs all offering unique perspectives on its pathobiology. Animal models are a critical aspect of mucositis research, providing unprecedent insight into the pathobiology of mucositis. Introduction of tumour-bearing models, cyclic dosing scheduled, concomitant agents and genetically modified animals have been integral in refining our understanding of mucositis.

Nutritional Support Improves Outcome in Patients with Lung Cancer Cachexia Receiving Chemotherapy

Background: Malnutrition is a frequent complication in patients with advanced staged lung cancer and can negatively affect the outcome of treatments. Lack of knowledge about nutrition, complications of disease and side effects of anticancer therapies can also lead to inadequate nutrient intake and subsequent malnutrition. Nutritional status is a strong predictor of quality of life in cancer patients.
 Objective: To get the effect of the nutritional intervention on outcome of dietary intake, body composition, nutritional status, functional capacity and quality of life in patients with lung cancer cachexia receiving chemotherapy.
 Patients and Methods: This 6 months study included the lung cancer patients who were interviewed with clinical assessment. Nutritional score of each patient was recorded. Individualized management plan with nutritional intervention was given and nutritional counseling was done by a nutritionist every week. Chemotherapy ± radiotherapy was given. Every patient was followed up at 1st, 2nd, 3rd and 6th week and was assessed regarding symptoms, clinical findings, nutritional score and radiological status.
 Results: Total 628 lung cancer patients with 523 (83%) males and 105 (17%) females (Male: female 4.98:1) were enrolled. Mean age was 56.88 years. Two thirds of them were illiterate. Around 90% came from poor and below average socioeconomic group. More than 95% male and >66% female were tobacco users in different forms. On assessing nutritional score, almost all were with high risk score (95%). About 80% presented with WHO performance status at 2 and 3. About 61% patients got treatment after hospitalization. Following nutritional intervention along with supportive, symptomatic, treatment of comorbid diseases and anti-cancer treatment, the result showed that mean nutritional score at 1st and 2nd week were 8.24 and 6.63 (high risk), at 3rd and 6th week were 5.46 and 4.34 (Intermediate risk). There was a significant effect for time (p<.001). Symptomatic improvement occurred in 60% of the patients.
 Conclusion: Nutritional intervention improves nutritional score if the other treatment like supportive, symptomatic, comorbid condition and anticancer treatment could be applied adequately.
 J Bangladesh Coll Phys Surg 2019; 37(2): 66-71

In vitro and in vivo evaluation of possible pro-survival activities of PGE2, EGF, TPO and FLT3L on human hematopoiesis

Myelosuppression is a major and frequently dose-limiting side effect of anticancer therapy and is responsible for most treatment-related morbidity and mortality. In addition, repeated cycles of DNA damage and cell death of hematopoietic stem and progenitor cells, followed by compensatory proliferation and selection pressure, lead to genomic instability and pave the way for therapy-related myelodysplastic syndromes and secondary acute myeloid leukemia. Protection of hematopoietic stem and progenitor cells from chemo- and radiotherapy in patients with solid tumors would reduce both immediate complications and long-term sequelae. Epidermal growth factor (EGF) and prostaglandin E2 (PGE2) were reported to prevent chemo- or radiotherapy-induced myelosuppression in mice. We tested both molecules for potentially protective effects on human CD34+ cells in vitro and established a xenograft mouse model to analyze stress resistance and regeneration of human hematopoiesis in vivo. EGF was neither able to protect human stem and progenitor cells in vitro nor to promote hematopoietic regeneration following sublethal irradiation in vivo. PGE2 significantly reduced in vitro apoptotic susceptibility of human CD34+ cells to taxol and etoposide. This could, however, be ascribed to reduced proliferation rather than to a change in apoptosis signaling and BCL-2 protein regulation. Accordingly, 16,16-dimethyl-PGE2 (dmPGE2) did not accelerate regeneration of the human hematopoietic system in vivo. Repeated treatment of sublethally irradiated xenograft mice with known antiapoptotic substances, such as human FLT3L and thrombopoietin (TPO), which suppress transcription of the proapoptotic BCL-2 proteins BIM and BMF, also only marginally promoted human hematopoietic regeneration in vivo.

Insights Into the Relationship Between Gut Microbiota and Colorectal Cancer

There is growing evidence to suggest that gut microbiota plays an important role in colorectal carcinogenesis. Western diet is associated with gut microbial dysbiosis, which leads to inflammation, oxidative stress, and genotoxic effects, all common risk factors for colorectal cancer. Fusobacterium nucleatum, Helicobacter pylori, Bacteroides fragilis, Escherichia coli, and Streptococcus bovis are the main bacterial species associated with colorectal carcinogenesis. Gut microbiota transforms both diet- (meat, processed meat products, fat) and host (bile acids)-derived precursors into carcinogens and further interferes with anti-cancer drug metabolism, chemotherapy efficacy, and drug-induced toxicity. Nutritional interventions, as well as the administration of beneficial bacteria (probiotics), dietary fiber (including prebiotics) supplements, and synbiotics (probiotic + prebiotic), may reduce the risk of colorectal cancer and side effects of anti-cancer therapy. Current evidence suggests gut microbiota may predispose or protect against colorectal cancer. Restoring gut microbial dysbiosis is an emerging nutritional and clinical target in oncology.

CARDIOVASCULAR COMPLICATIONS IN ONCOLOGICAL PATIENTS AT STAGE OF CHEMORADIOTHERAPY: ACTUAL POSITION OF THE PROBLEM

There is presented the review of domestic and foreign publications on cardiovascular complications in cancer patients at the stage of chemoradiation therapy. Cardiovascular сomplications due to cardiotoxicity are among the most severe side effects of anticancer therapy despite improved prognosis and survival of cancer patients. Modern treatment of cancer patients at the stage of chemotherapy and radiotherapy requires a multidisciplinary approach involving cardiologists and physicians of related specialties