Adverse Effects Of Anticancer Drugs Research Articles

Cardiotoxicity risk assessment of anti-cancer drugs and future perspectives

Cardiotoxicity is a serious adverse effect of anti-cancer drugs. Anti-cancer drug-induced cardiotoxicity are arrhythmia, cardiac contractile dysfunction, coronary artery disease, and hypertension, which affect to the quality of life in patients with cancer. In particular, cardiac contractile dysfunction is a life-threatening symptom leading to heart failure, suggesting that it is very important to predict the risk of developing the contractile dysfunction by anti-cancer drugs. Recently, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be used to assess the risk of drug-induced arrhythmias. This prompts us to evaluate other cardiotoxic effects such as contractility dysfunction and structural toxicity with hiPSC-CMs. Since anti-cancer drug-induced contractility dysfunction are considered to be induced by chronic exposure, we have developed a method to assess chronic contractility dysfunction by imaging analysis of hiPSC-CMs. BMS-986094, which failed in clinical trials due to the occurrence of heart failure, was used as a positive compound. We found that chronic exposure to BMS-986094 decreased the contraction and relaxation velocity in hiPSC-CMs. Doxorubicin was observed to decrease cytotoxicity and both contraction and relaxation velocities in hiPSC-CMs. We are currently further evaluating other anti-cancer drugs with different mode-of-actions using hiPSC-CMs and assess the predictivity and utility of contractile assessment using hiPSC-CMs by comparing with real-world data. Here, we introduce our novel method to assess the chronic contractility of hiPSC-CMs by imaging analysis and discuss the future perspectives for assessing the anti-cancer drug-induced cardiotoxicity.

Cardioprotective effects of Rhododendron arboreum leaf extract against Doxorubicin-induced cardiotoxicity in Wistar rats by modulating electrocardiographic and cardiac biomarkers

BackgroundCardiotoxicity and related complications are well-known adverse effects of anticancer drugs like doxorubicin (DOX). A medicinal plant called Rhododendron arboreum is used by traditional healers of Sikkim in the treatment of heart ailments and has also been reported for widespread therapeutic effects in many clinical studies. Thus the present study has been designed to evaluate the protective effects of Rhododendron arboreum leaf extract (RALE) against DOX-induced cardiotoxicities.MethodsCommencement of research with the collection of the Rhododendron arboreum leaves and drying it in the shade, the extraction was performed using the Soxhlet method with an ethanolic solvent. The phytoconstituents of the RALE were then quantified and qualitatively evaluated. Doxorubicin-induced cardiotoxicity was carried out using four groups consisting of six animals each. Doxorubicin was administered with a dose of 3 mg/kg injected intraperitoneally (i.p.) on the 1st,7th,14th,21st and 28th day of cumulative dose of 15 mg/kg throughout the experimental period with RALE treatment (250 mg/kg and 100 mg/kg) orally for 28 days. The influence of the treatment was analyzed by quantification of cardiac biomarkers and electrocardiographic method.ResultsThe serum levels of cardiac biomarkers such as Lactate Dehydrogenase (LDH), Creatine kinase-N-acetyltransferase (CK-NAC), Creatine kinase-MB (CK-MB), Aspartate Transaminase (AST), Alanine Transaminase (ALT), which were elevated due to DOX-induced cardiotoxicity were significantly reduced in all RALE (250 mg/kg and 100 mg/kg) treated groups. Similarly, the electrocardiographic changes like prolonged QT interval, widening of QRS complex amplitude, undefined ST segment, arrhythmias and increased heart rate were also restored close to normal in all treated groups compared to the DOX control group.ConclusionFollowing the data observed during the study, results reported that R. arboreum possesses the free radical scavenging property, improved cardiotoxic laboratory parameters and restored reversible cellular injury due to existing of the principle constituent’s impact on proinflammatory mediators.

Pathophysiology and Therapeutic Perspectives for Chemotherapy-induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) develops as a challenging nerve-damaging adverse effect of anticancer drugs used in chemotherapy. The disorder may require a chemotherapy dose reduction and a cessation of administration of chemotherapeutic drugs. Its principal sensory symptoms include, tingling, and numbness in the hands and feet. Severe pain can be encompassed among clinical manifestations. CIPN affects dramatically the patient's quality of life (QoL). Pain and sensory symptoms may occur for months, or even years after the termination of chemotherapeutic drugs. Although many pharmacological and non-pharmacological therapeutic approaches have been tested to overcome these symptoms, there is currently no standardized treatment for CIPN. According to current guidelines, Duloxetine is the only recommended agent for painful neuropathic symptoms. Therefore, finding effective therapies for CIPN is mandatory. The aim of this review was to dissect CIPN, the target and immunotherapy-based approaches to this disorder, as well as to offer new insights for new therapeutic perspectives.

Thrombotic microangiopathy (TMA) in adult patients with solid tumors: a challenging complication in the era of emerging anticancer therapies.

Thrombotic microangiopathy (TMA) is a syndrome that encompasses a group of disorders defined by the presence of endothelial damage leading to abnormal activation of coagulation, microangiopathic hemolytic anemia and thrombocytopenia, occlusive (micro)vascular dysfunction, and organ damage. TMA may occur in patients with malignancy as a manifestation of cancer-related coagulopathy itself or tumor-induced TMA (Ti-TMA) as a paraneoplastic uncommon manifestation of Trousseau syndrome. TMA can also be triggered by other overlapping conditions such as infections or more frequently as an adverse effect of anticancer drugs (drug-induced TMA or Di-TMA) due to direct dose-dependent toxicity or a drug-dependent antibody reaction. The clinical spectrum of TMA may vary widely from asymptomatic abnormal laboratory tests to acute severe potentially life-threatening forms due to massive microvascular occlusion. While TMA is a rare condition, its incidence may progressively increase within the context of the great development of anticancer drugs and the emerging scenarios in supportive care in cancer. The objective of the present narrative review is to provide a general perspective of the main causes, the key work-up clues that allow clinicians to diagnose and manage TMA in patients with solid tumors who develop anemia and thrombocytopenia due to frequent overlapping causes.

Formulation and Characterization of Poly (Ethylene Glycol)-Coated Core-Shell Methionine Magnetic Nanoparticles as a Carrier for Naproxen Delivery: Growth Inhibition of Cancer Cells.

Simple SummaryNaproxen was loaded onto a magnetic nanoparticle coated with polyethylene glycol. Magnetic nanoparticles (MNPs) were used in this study to develop a smart naproxen delivery system. One of the most potent COX-1 and COX-2 inhibitors is naproxen, which belongs to the NSAID family of drugs. Although this drug has a short half-life, it has considerable toxicities and side effects on gastrointestinal tissues. The significant potential of our proposed nanocarrier for biomedical applications has been widely recognized; we modified MNPs to attach to this drug via disulfide bonds, promote the selective release of naproxen in inflammatory cells, and prevent adverse effects on the digestive system. It was found that the cytotoxicity of the drug was lowered by this change, which prevented unspecific protein binding.An efficient and selective drug delivery vehicle for cancer cells can remarkably improve therapeutic approaches. In this study, we focused on the synthesis and characterization of magnetic Ni1−xCoxFe2O4 nanoparticles (NPs) coated with two layers of methionine and polyethylene glycol to increase the loading capacity and lower toxicity to serve as an efficient drug carrier. Ni1−xCoxFe2O4@Methionine@PEG NPs were synthesized by a reflux method then characterized by FTIR, XRD, FESEM, TEM, and VSM. Naproxen was used as a model drug and its loading and release in the vehicles were evaluated. The results for loading efficiency showed 1 mg of Ni1−xCoxFe2O4@Methionine@PEG NPs could load 0.51 mg of the naproxen. Interestingly, Ni1−xCoxFe2O4@Methionine@PEG showed a gradual release of the drug, achieving a time-release up to 5 days, and demonstrated that a pH 5 release of the drug was about 20% higher than Ni1−xCoxFe2O4@Methionine NPs, which could enhance the intracellular drug release following endocytosis. At pH 7.4, the release of the drug was slower than Ni1−xCoxFe2O4@Methionine NPs; demonstrating the potential to minimize the adverse effects of anticancer drugs on normal tissues. Moreover, naproxen loaded onto the Ni1−xCoxFe2O4@Methionine@PEG NPs for breast cancer cell lines MDA-MB-231 and MCF-7 showed more significant cell death than the free drug, which was measured by an MTT assay. When comparing both cancer cells, we demonstrated that naproxen loaded onto the Ni1−xCoxFe2O4@Methionine@PEG NPs exhibited greater cell death effects on the MCF-7 cells compared with the MDA-MB-231 cells. The results of the hemolysis test also showed good hemocompatibility. The results indicated that the prepared magnetic nanocarrier could be suitable for controlled anticancer drug delivery.

Cancer Chemotherapy-Induced Sinus Bradycardia: A Narrative Review of a Forgotten Adverse Effect of Cardiotoxicity

Cardiotoxicity is a common adverse effect of anticancer drugs (ACDs), including the so-called targeted drugs, and increases morbidity and mortality in patients with cancer. Attention has focused mainly on ACD-induced heart failure, myocardial ischemia, hypertension, thromboembolism, QT prolongation, and tachyarrhythmias. Yet, although an increasing number of ACDs can produce sinus bradycardia (SB), this proarrhythmic effect remains an underappreciated complication, probably because of its low incidence and severity since most patients are asymptomatic. However, SB merits our interest because its incidence increases with the aging of the population and cancer is an age-related disease and because SB represents a risk factor for QT prolongation. Indeed, several ACDs that produce SB also prolong the QT interval. We reviewed published reports on ACD-induced SB from January 1971 to November 2020 using the PubMed and EMBASE databases. Published reports from clinical trials, case reports, and recent reviews were considered. This review describes the associations between ACDs and SB, their clinical relevance, risk factors, and possible mechanisms of onset and treatment.

Individual and mixed effects of anticancer drugs on freshwater rotifers: A multigenerational approach

Human population growth has led to an increased release of chemical contaminants into aquatic environments. Emerging chemical contaminants (ECCs) are of increasing concern because they can affect non-target organisms in aquatic ecosystems. The application of anticancer drugs is increasing because of enhanced cancer rates and use of chemotherapy. We assessed the impacts of two widely used anticancer drugs known for their distinct modes of action, namely 5-fluorouracil (5-FU) and doxorubicin (DOX), on the freshwater rotifer Brachionus calyciflorus across generations. Rotifer mortality (24 h) and population growth (48 h) were assessed to determine initial lethal and sub-lethal effects. Exposure of rotifers to 5-FU (up to 200 mg L−1) did not cause mortality, while DOX caused mortality at high concentrations (EC50 = 15.6 mg L−1). Effects of 5-FU on population growth rate was higher than DOX (5-FU EC50 =10.49 µg L−1, DOX EC50 = 8.78 mg L−1). The effects of the drugs in binary mixture on population growth rates were dose dependent; significant antagonistic effects were found when 5-FU was present in the mixture at high concentrations. Finally, a transgenerational assay for five generations revealed that rotifers were able to recover their population growth rate after fourth generation when exposed to 5-FU; however, population became non-viable after the second generation of exposure to DOX. At the cellular level, accumulation of reactive oxygen species and plasma membrane damage were observed at EC10 and increased at EC50 for both drugs. After exposure of rotifers to 5-FU across generations, there were signs of oxidative stress recovery, as shown by a decrease in ROS accumulation and plasma membrane damage. Our results showed for the first time that the adverse effects of anticancer drugs on freshwater rotifer populations are drug and dose dependent and can persist or be attenuated along generations.

Sex-dependent liver cancer xenograft models for predicting clinical data in the evaluation of anticancer drugs

BackgroundThe incidence and mortality of liver cancer show a great difference between the sexes. We established sex-dependent liver cancer xenograft models and investigated whether such sex-dependent models could be used to simultaneously evaluate the therapeutic and adverse effects of anticancer drugs for drug screening.ResultsIn the in-vitro test, the cytotoxicity of anticancer drugs (cisplatin, 5-fluorouracil, and doxorubicin) was compared between male- and female-derived liver cancer cell lines. Cisplatin and 5-fluorouracil exhibited cytotoxicity without sex-difference, but doxorubicin showed dose-dependently significant cytotoxicity only in male-derived cells. Our results showed a strong correlation between preclinical and clinical data with the use of sex-dependent liver cancer xenograft models. Moreover, the male-derived Hep3B-derived xenograft model was more sensitive than the female-derived SNU-387-derived xenograft model against doxorubicin treatment. Doxorubicin showed more severe cardiotoxicity in the male xenograft model than in the female model. We investigated the occurrence frequency of doxorubicin-related cardiotoxicity using data obtained from the Korea Institute of Drug Safety & Risk Management Database, but no significant difference was observed between the sexes.ConclusionsOur results suggest that sex-dependent xenograft models are useful tools for evaluating the therapeutic and adverse effects of anticancer drugs, because sex is an important consideration in drug development.

Vincristine exposure impairs skin keratinocytes, ionocytes, and lateral-line hair cells in developing zebrafish embryos

Environmental contamination by anticancer pharmaceuticals has been widely reported. These drugs are not readily biodegradable, and their parent compounds and/or metabolites have been detected in surface waters and groundwater throughout the world. Adverse effects of anticancer drugs occur frequently in cancer patients, and a large body of clinical knowledge has accumulated. However, the effects of these drugs on aquatic organisms have not been thoroughly studied. This study aimed to investigate the effects of acute exposure to a common anticancer drug, vincristine (VCR), on zebrafish embryonic development and skin function. After 96 h of VCR exposure (0, 1, 10, 15, and 25 mg/L), significant teratogenic effects were observed, including growth retardation, pericardial edema, spine, tail, and yolk sac malformations (VCR ≥ 15 mg/L), a decreased heart rate, and ocular malformations (VCR ≥ 10 mg/L). The value of the half lethal concentration for zebrafish embryos was 20.6 mg/L. At ≥10 mg/L VCR, systemic ion contents and acid secretion in the skin over the yolk-sac decreased, and these findings were associated with decreases in skin ionocytes (H+-ATPase-rich cells and Na+-K+-ATPase-rich cells). Also, the microridge-structure of skin keratinocytes was significantly damaged. The number of lateral line hair cells was reduced when VCR was ≥10 mg/L, and functional impairment was detected when VCR was as low as 1 mg/L. Results of this in vivo study in zebrafish embryos indicate that acute exposure to VCR can lead to developmental defects, impairment of skin functions, and even fish death.

Short-term adverse effects of anticancer drugs in patients with type 2 diabetes

The short-term adverse effects of anticancer drugs (AD) in patients with type 2 diabetes (T2D) are poorly studied and their management still represents an important challenge for clinicians. We carried out a retrospective single-center study in 168 patients with T2D and cancer, evaluating both the short-term effects of first-line AD on glycemic control and chronic diabetes complications. Average glycated hemoglobin significantly increased after AD compared to values before treatment (7.5 vs. 7.1%, p < 0.005). In 46.4% of patients, diabetes therapy had to be potentiated, in most cases (82.1%) by shifting to insulin. The use of alkylating agents and high-dose glucocorticoids predicted the need to potentiate diabetes therapy. After AD transaminase values significantly increased, whereas the estimated glomerular filtration rate decreased (in 12.5% <60 mL/min). Kinase inhibitors significantly increased the risk of microalbuminuria onset or progression. The present study provides a real-life information on the effects of different AD on the management of patients with T2D affected by several types of cancer.

Drug discovery of anticancer drugs targeting methylenetetrahydrofolate dehydrogenase 2

Many anticancer drugs have serious adverse effects; therefore, it is necessary to target features specific to cancer cells to minimize the effects on healthy cells. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) was reported to be specifically enhanced in cancer. We confirmed the validity of MTHFD2 as a drug discovery target using clinical data. In addition, we performed in silico screening to design an anticancer drug specifically targeting MTHFD2. Analysis of the clinical data indicated that MTHFD2 was enhanced in most cancers compared with normal tissues, and affected the prognosis in cancer patients. Candidate compounds for MTHFD2 inhibitors were identified using in silico drug discovery techniques, and the important interactions for MTHFD2 binding were determined. In addition, these candidate compounds decreased levels of MTHFD2 metabolites in cancer cells. The findings of the present study may help to develop anticancer drugs targeting MTHFD2, with a view to minimizing the adverse effects of anticancer drugs.

Cutaneous Adverse Reactions of Chemotherapy in Cancer Patients: A Clinicoepidemiological Study.

Background:The diagnosis of cutaneous adversities in the cancer patient is especially difficult, given the complexity of their illness and combination protocols used for the treatment. The present study was undertaken to know the spectrum of cutaneous adversities in patients undergoing chemotherapy and the drug(s) most commonly associated with it.Materials and Methods:A total of 1000 patients with malignancies under chemotherapy in the oncology ward and outpatient department were screened in this observational study from January 2013 to February 2015. Relevant investigations for diagnosis of malignancies under chemotherapy and dermatological disorders were carried out.Results:Three hundred and eighty-four patients presented with cutaneous adversities of chemotherapy. The most common was anagen effluvium (78.6%), followed by xerosis (4.4%), thrombophlebitis (3.1%), generalised pruritus (2.9%), melanonychia (2.9%), hand-foot syndrome (2.6%), extravasation reactions (1.8%), flagellate dermatosis (1.3%), prurigo nodularis (0.8%), exfoliation (0.5%), ichthyosis (0.5%), papulopustular rash (0.3%), bullous photodermatitis (0.3%), and Sweet's syndrome (0.3%). Chemotherapeutic drugs were mostly given in combinations. Most common drugs to cause anagen effluvium were alkylating agents in combinations, hand-foot syndrome by taxanes (docetaxel), flagellate dermatoses by antitumour antibiotics (bleomycin), and exfoliation by antimetabolites (methotrexate). The limitation of this study was to imply a specific drug as the causation of the cutaneous adversities since the chemotherapy mostly consisted of combination protocols. Therefore, we have tried to associate the drug combination itself.Conclusion:Chemotherapeutic drugs produce a range of cutaneous adversities, certain specific adversities pertaining to drugs, and their combinations have been implicated which should be looked for and managed accordingly. Knowledge of the adverse effects of anticancer drugs will help reduce the psychological trauma and improve the quality of life.

Effects of Anticancer Drugs in Reproductive Parameters of Juvenile Male Animals and Role of Protective Agents

Nowadays, the advances in knowledge about oncologic treatment have led to an increase in survival rate for cancer patients and, consequently, a growing concern about the adverse effects of treatment in medium and long term, in order to ensure the future quality of life. For male patients in reproductive age or younger, one of the key concerns after cancer therapy is their ability to father children, since anticancer drugs exert cytotoxic effects on germ cells. Considering the incidence of cancer in children and adolescents and the vulnerability of these developmental phases to chemical injuries, this review is an attempt to highlight the importance of juvenile experimental models to test new anticancer drugs and agents with protective action. There is a relative scarcity of studies investigating the effects of chemotherapy in juvenile animals and an urgent need for further information. As far as this review was able to recover, available data about reproductive toxicology related to peripubertal treatment with anticancer drugs includes only the following pharmaceuticals: toposide, doxorrubicin, cisplatin, ciclophosphamide, cytarabine, flutamide and procarbazine. Together with the evaluation of adverse effects of anticancer drugs, is necessary to investigate possible protective agents to be pre-, co-, or post administrated with chemotherapy. Modern technologies and increasing knowledge about the cancer biology have allowed studies of new chemotherapy strategies, more effective and selective. Many of these compounds are derived from toxins and metabolites of microorganisms, plants, and animals, being a number of them isolated from marine sources, a relatively unexplored environment. Investment in research programs in bioprospecting, especially in marine environments, and pharmaceutical field, including toxicology risk evaluation, are crucial to discovery and improve new anticancer treatments.

Adverse effects of high-dose methotrexate therapy

To investigate the adverse effects of high-dose methotrexate (HDMTX) therapy, and to provide a theoretical basis for optimizing clinical treatment. A retrospective analysis was performed for the clinical data of 120 children with acute lymphoblastic leukemia or non-Hodgkin lymphoma who underwent 601 times of HDMTX therapy. The adverse effects of various systems were analyzed according to the WHO criteria for the classification of adverse effects of anticancer drugs. Almost all the children experienced bone marrow suppression, and 93.3% had granulocytopenia. The most common adverse effects in the digestive system and urinary system were elevated glutamic-pyruvic transaminase (60.4%) and proteinuria (9.2%) respectively. For skin symptoms, skin erythema had the highest incidence rate (7.2%). The adverse effects in the nervous system (hyperpathia, numbness of extremities, or headache) were only observed in 7 cases. Serious adverse effects were only seen in the blood system and digestive system. Compared with the 3 g/m2 methotrexate (MTX) group, the 5 g/m2 HDMTX group had a significantly higher 24-hour plasma MTX concentration, significant reductions in hemoglobin and platelet count, and significantly higher incidence rates of oral mucositis, proteinuria, and skin symptoms (P<0.05). Serious adverse effects of HDMTX therapy mainly involve the blood system and digestive system, and the adverse effects such as bone marrow suppression, oral mucositis, proteinuria, and skin symptoms occur in a dose-dependent manner.

Hollow mesoporous ZSM-5 zeolite/chitosan ellipsoids loaded with doxorubicin as pH-responsive drug delivery systems against osteosarcoma.

The toxic risks and adverse effects of anticancer drugs on healthy tissues limit their wide clinical application. Herein, we for the first time fabricated hollow mesoporous ZSM-5/chitosan ellipsoids loaded with doxorubicin (HM-ZSM-5/CS/DOX) as pH-responsive drug delivery systems against osteosarcoma. The HM-ZSM-5 ellipsoids including a hollow core and a mesoporous shell could efficiently load DOX drugs with a loading efficiency of 95.8%. The CS layer was uniformly distributed on the HM-ZSM-5 ellipsoids that contributed to the pH-responsive release of DOX drugs. The controlled DOX release kinetics from the HM-ZSM-5/CS/DOX ellipsoids was fitted well with the Korsmeyer-Peppas model. The HM-ZSM-5/CS/DOX ellipsoids exhibited good biocompatibility due to the low DOX release rate in the neutral media that simulated healthy tissues or blood. Moreover, the cellular uptake of the HM-ZSM-5/CS/DOX ellipsoids took place in tumor cells, and the quick release of DOX significantly promoted the apoptosis of MG63 cells. The levels of MDA, LDH and CK markers for the HM-ZSM-5/CS/DOX group were lower than those for the free DOX group, suggesting no systemic toxicity to the heart. Therefore, the HM-ZSM-5/CS/DOX ellipsoids as novel pH-responsive drug delivery systems can effectively treat osteosarcoma without systemic toxicity.

Effect of Juzentaihoto/Shi-Quan-Da-Bu-Tang on malignant progression and metastasis of tumor cells

A Japanese herbal (Kampo, [INSIDE:1]) medicine, [INSIDE:2] (juzentaihoto/Shi-Quan-Da-Bu-Tang), is one of the nourishing agents, a so-called “[INSIDE:3] (Hozai/Bu-Ji),” that is used for improving disturbance and imbalances in the homeostatic condition of the body. This formulation is orally administered to patients in various weakened states, including postsurgery patients and patients with chronic illness, where it can alleviate general symptoms such as extreme fatigue, pale complexion, loss of appetite, dry or scaly skin, night sweating, and dryness of the mouth. Recently, juzentaihoto/Shi-Quan-Da-Bu-Tang has been shown to have a variety of biological activities, including activation of natural killer cells and macrophages, cytokine induction, antibody production, antitumor effects in combination with surgical excision or other drugs, and protection against the adverse effects of anticancer drugs and radiation, including immunosuppression and bone marrow toxicity. This article focuses on the antitumor and antimetastatic properties of some Kampo medicines and mainly describes the effects of juzentaihoto and its related formulations on tumor development, progression, and metastasis in vivo. We also discuss the inhibitory mechanism of action and the importance of the prescription and constituent crude drugs in determining the efficacy.

Soy-Based Multiple Amino Acid Oral Supplementation Increases the Anti-Sarcoma Effect of Cyclophosphamide.

The use of a mixture of amino acids caused a selective apoptosis induction against a variety of tumor cell lines, reduced the adverse effects of anti-cancer drugs and increased the sensitivity of tumor cells to chemotherapeutic agents. We evaluated the effects and underlying mechanisms of soy-derived multiple amino acids’ oral supplementation on the therapeutic efficacy of low-dose cyclophosphamide (CTX) and on tumor growth, apoptosis, and autophagy in severe combined immunodeficiency (SCID) mice that were injected with sarcoma-180 (S-180) cells. 3-methyladenine or siRNA knockdown of Atg5 was used to evaluate its effect on sarcoma growth. A comparison of mice with implanted sarcoma cells, CTX, and oral saline and mice with implanted sarcoma cells, CTX, and an oral soy-derived multiple amino acid supplement indicated that the soy-derived multiple amino acid supplement significantly decreased overall sarcoma growth, increased the Bax/Bcl-2 ratio, caspase 3 expression, and apoptosis, and depressed LC3 II-mediated autophagy. Treatment with 3-methyladenine or Atg5 siRNA elicited similar responses as CTX plus soy-derived multiple amino acid in downregulating autophagy and upregulating apoptosis. A low dose of CTX combined with an oral soy-derived multiple amino acid supplement had a potent anti-tumor effect mediated through downregulation of autophagy and upregulation of apoptosis.

Cardioprotection in women with neoplastic disease

Cardiotoxicity (CTX) is a serious adverse effect of anticancer drugs that impacts on quality of life and overall survival of cancer patients. Hypokinetic cardiomyopathy is the most typical form of CTX, and it is traditionally considered refractory to therapy. Prevention of CTX remains of paramount importance, and several measures, including serial cardiac function monitoring, reduction of cumulative anthracycline dose, use of anthracycline analogues and cardioprotective agents, have been proposed. Over the last decade, however, a new approach based on cardiac biomarkers has emerged as an effective alternative strategy for the early detection of subclinical cardiac injury. In particular, the role of troponin I in identifying patients at risk of CTX as well as of angiotensin-converting enzyme inhibitors in preventing left ventricular dysfunction and late cardiac events in high-risk patients, namely those with raised troponin I levels after chemotherapy, has been consistently demonstrated as an effective tool for CTX prevention.

Pharmacodynamic modeling of adverse effects of anti-cancer drug treatment.

PurposeAdverse effects related to anti-cancer drug treatment influence patient’s quality of life, have an impact on the realized dosing regimen, and can hamper response to treatment. Quantitative models that relate drug exposure to the dynamics of adverse effects have been developed and proven to be very instrumental to optimize dosing schedules. The aims of this review were (i) to provide a perspective of how adverse effects of anti-cancer drugs are modeled and (ii) to report several model structures of adverse effect models that describe relationships between drug concentrations and toxicities.MethodsVarious quantitative pharmacodynamic models that model adverse effects of anti-cancer drug treatment were reviewed.ResultsQuantitative models describing relationships between drug exposure and myelosuppression, cardiotoxicity, and graded adverse effects like fatigue, hand-foot syndrome (HFS), rash, and diarrhea have been presented for different anti-cancer agents, including their clinical applicability.ConclusionsMathematical modeling of adverse effects proved to be a helpful tool to improve clinical management and support decision-making (especially in establishment of the optimal dosing regimen) in drug development. The reported models can be used as templates for modeling a variety of anti-cancer-induced adverse effects to further optimize therapy.

Environmental enrichment protects against cognitive impairment following chemotherapy in an animal model.

Clinical studies indicate that up to 70% of cancer patients who receive chemotherapy experience cognitive impairment. The present study investigated environmental enrichment as a protective factor against the adverse effects of anticancer drugs on cognitive and biological processes in an animal model. Adult rats were housed in group cages with environmental stimulation or in standard cages for 3 months, before receiving 3 weekly injections of methotrexate + 5-fluorouracil, or equal volumes of saline. Rats were then administered tests of learning and memory that are sensitive to hippocampal or frontal lobe dysfunction. The relationship between cognitive performance and hippocampal neurogenesis was examined through sensitive time-dependent measures of neuronal maturation. Chemotherapy-treated rats in the standard environment were impaired on tests of spatial memory, nonmatching-to-sample (NMTS) rule learning, and delayed-NMTS. Chemotherapy-treated rats in the enriched environment performed at or near normal levels. The performance of the chemotherapy groups on the hippocampus-sensitive, spatial memory and delayed-NMTS tests correlated with neurogenesis levels. The results show that environmental enrichment can reduce the risk of chemotherapy-induced cognitive impairment, in part by promoting neuronal differentiation and growth during cell maturation. As well, they point to the importance of lifestyle factors in treating or preventing adverse effects of anticancer drugs on cognitive function. (PsycINFO Database Record