Toxic Side Effects Of Chemotherapy Research Articles

Fertility protective effects of Brillantaisia patula leaf extract against cyclophosphamide-induced ovarian damage in Wistar rats

BackgroundThe primary indication of infertility is the incapacity to conceive, and in females, the majority of instances of female infertility stem from ovulation disorders. This study evaluated the female fertility-enhancing effects and safety of aqueous leaf extract of Brillantaisia patula (ALEBP) in a cyclophosphamide (CYP) model of sterility in Wistar rats.MethodSixty-six female rats randomly allotted to six groups (n = 11) were administered with the appropriate regimen for 21 days and then mated with male rats. Group 1 (control) received distilled water. Groups 2–6 were treated with a single dose (200 mgkg− 1 body weight) of cyclophosphamide intraperitoneally and, in addition, received the same volume (0.5 mL) of distilled water, 18, 36, 72 mgkg− 1 body weight of ALEBP and 200 mg per body weight of vitamin C orally. Mating lasted 11 days; on day 20, the female Wistar rats were sacrificed. Data were analysed using One-way Analysis of Variance (ANOVA) followed by Dunett’s posthoc analysis, and GraphPad (at p < 0.05).ResultsResults herein showed that ALEBP significantly (p < 0.05) increased the diminution in activities/levels of glutathione peroxidase (GPx), reduced glutathione (GSH), total antioxidant capacity (TAC), cholesterol, alkaline phosphatase (ALP), acid phosphatase (ACP), estrogen (ES), and luteinising hormone (LH) induced by cyclophosphamide. ALEBP further reversed the increased level of malondialdehyde (MDA), tumour necrosis factor-α (TNFα), interleukin 8 (IL-8), and follicle-stimulating hormone (FSH) caused by cyclophosphamide (p < 0.05). In addition, ALEBP, while it significantly increased the cyclophosphamide-induced reduction in the number of implantations in each animal, the total number of viable fetuses, the total number of corpora lutea, and the fertility index, also significantly reduced the number of fetal resorptions in each animal and pre-implantation loss that was increased by cyclophosphamide. Moreover, the cyclophosphamide-induced degenerative and necrotic changes in the ovarian cells and uterus were reversed by ALEBP.ConclusionsConsidered as a whole, the aqueous leaf extract of Brillantaisia patula reversed oxidative stress and inflammatory side effects of cyclophosphamide, preserving ovarian function and fertility in the rats. This may suggest its exploration as a safe agent against toxic side effects of chemotherapy and fertility-related disorders of the uterus and ovary.

Sensing of endogenous retroviruses-derived RNA by ZBP1 triggers PANoptosis in DNA damage and contributes to toxic side effects of chemotherapy

Excessive DNA damage triggers various types of programmed cell death (PCD), yet the regulatory mechanism of DNA damage-induced cell death is not fully understood. Here, we report that PANoptosis, a coordinated PCD pathway, including pyroptosis, apoptosis and necroptosis, is activated by DNA damage. The Z-DNA binding protein 1 (ZBP1) is the apical sensor of PANoptosis and essential for PANoptosome assembly in response to DNA damage. We find endogenous retroviruses (ERVs) are activated by DNA damage and act as ligands for ZBP1 to trigger PANoptosis. By using ZBP1 knock-out and knock-in mice disrupting ZBP1 nucleic acid-binding activity, we demonstrate that ZBP1-mediated PANoptosis contributes to the toxic effects of chemotherapeutic drugs, which is dependent on ZBP1 nucleic acid-binding activity. We found that ZBP1 expression is downregulated in tumor tissue. Furthermore, in colorectal cancer patients, dsRNA is induced by chemotherapy and sensed by ZBP1 in normal colonic tissues, suggesting ZBP1-mediated PANoptosis is activated by chemotherapy in normal tissues. Our findings indicate that ZBP1-mediated PANoptosis is activated by DNA damage and contributes to the toxic side effects of DNA-damage-based chemotherapy. These data suggest that ZBP1 could be a promising therapeutic target to alleviate chemotherapy-related side effects.

Implications of chronic moderate protein-deficiency malnutrition on doxorubicin pharmacokinetics and cardiotoxicity in early post-weaning stage

BackgroundMalnutrition is a common problem in developing countries, and the impact of severe malnutrition on optimal treatment outcomes of chemotherapy in pediatric cancer patients is well documented. However, despite being a more prevalent and distinct entity, moderate malnutrition is until now unexplored for its effects on treatment outcomes. AimsIn this study we aimed to investigate the molecular basis of altered pharmacokinetics and cardiotoxicity of doxorubicin observed in early-life chronic moderate protein deficiency malnutrition. Materials and methodsWe developed an animal model of early-life moderate protein-deficiency malnutrition and validated it using clinical samples. This model was used to study pharmacokinetic and toxicity changes and was further utilized to study the molecular changes in liver and heart to get mechanistic insights. Key findingsHere we show that moderate protein-deficiency malnutrition in weanling rats causes changes in drug disposition in the liver by modification of hepatic ABCC3 and MRP2 transporters through the TNFα signalling axis. Furthermore, malnourished rats in repeat-dose doxorubicin toxicity study showed higher toxicity and mortality. A higher accumulation of doxorubicin in the heart was observed which was associated with alterations in cardiac metabolic pathways and increased cardiotoxicity. SignificanceOur findings indicate that moderate malnutrition causes increased susceptibility towards toxic side effects of chemotherapy. These results may necessitate further investigations and new guidelines on the dosing of chemotherapy in moderately malnourished pediatric cancer patients.

The Effect of Quercetin in the Yishen Tongluo Jiedu Recipe on the Development of Prostate Cancer through the Akt1-related CXCL12/ CXCR4 Pathway.

It remains a challenge to effectively treat prostate cancer (PCa) that affects global men's health. It is essential to find a natural alternative drug and explore its antitumor mechanism due to the serious toxic side effects of chemotherapy. The targets and signaling pathways were analyzed by network pharmacology and verified by molecular docking and LC-MS. The proliferation, apoptosis, invasion, and migration of DU145 cells were detected by the CCK-8 method, flow cytometry, and Transwell, respectively. The Bcl-2, caspase-3, CXCL12, and CXCR4 expressions and Akt1 phosphorylation were determined by Western blot. Akt1 overexpression was applied to identify the involvement of the Akt1- related CXCL12/CXCR4 pathway in regulating PCa. Nude mouse tumorigenesis was performed to analyze the effect of quercetin on PCa in vivo. Network pharmacology analysis displayed that quercetin was the main active component of the Yishen Tongluo Jiedu recipe and Akt1 was the therapy target of PCa. LC-MS analysis showed that quercetin existed in the Yishen Tongluo Jiedu recipe, and molecular docking proved that quercetin bound to Akt1. Quercetin inhibited the proliferation of DU145 cells by upregulating caspase-3 and downregulating Bcl-2 expression, promoting apoptosis and reducing invasion and migration abilities. In vivo, quercetin downregulated CXCL12 and CXCR4 expressions and inhibited PCa development by the Akt1-related CXCL12/CXCR4 pathway. As the active component of the Yishen Tongluo Jiedu recipe, quercetin inhibited PCa development through the Akt1-related CXCL12/CXCR4 pathway. This study provided a new idea for PCa treatment and a theoretical basis for further research.

Abstract 1883: A MUC1 antibody-conjugated with a tubulysin B analog, DXC005, demonstrates excellent synergistic effect in combination with gemcitabine for treatment of pancreatic tumors

Abstract Pancreatic cancer is a malignant tumor with high incidence and mortality. It is difficult to diagnose and detect in the early stage, with low surgical resection rate and high recurrence and metastasis rate after surgery. At present, the clinical therapeutic strategy is extremely limited. The first-line Standard of Care (SOC) for unresectable pancreatic cancer is chemotherapy. The preferred regimen includes gemcitabine combined with albumin paclitaxel or FOLFIRINOX (5-FU+Oxaliplatin+Irinotecan). Due to the limited long-term benefits and toxic side effects of chemotherapy, targeted therapy combined with chemotherapy has become a new therapeutic strategy. MUC1 is a highly glycosylated transmembrane mucin located on the lumen surface of epithelial cells. It can protect cells from extreme factors and plays an important role in tumor cell metabolism, apoptosis, epithelial-mesenchymal transition (EMT) and metastasis. Previous studies have confirmed that MUC1 is highly expressed in a variety of tumors, including pancreatic cancer, and is closely related to poor prognosis. DXC005 is a novel MUC1-targeting antibody-drug conjugate (ADC), generated by conjugating a Tubulysin B analogue to a recombinant humanized anti-Muc1 monoclonal antibody. DXC005 is the first MUC1-ADC IND in China, and is currently in phase I clinical trials. Preclinical studies have confirmed the efficacy of DXC005 monotherapy (2.5 mg/kg, 5 mg/kg, 10 mg/kg in one administration) in the HuPrime ® pancreatic cancer PDX model (PA1194). The tumor growth inhibition (TGI) was 42.53 %, 70.77 %, and 95.58 %, respectively. We want to further clarify whether DXC005 combined with chemotherapeutic drug Gemcitabine can ensure or even improve the efficacy while reducing the dosage of Gemcitabine. In PA1194 xenograft model, DXC005 (3 mg/kg or 6 mg/kg) in combination with Gemcitabine (10 mg/kg) showed significant anti-tumor efficacy with 58.77% and 93.17% TGIs, respectively. In contrast, the treatment with 10 mg/kg of Gemcitabine alone exhibited much less TGI. Furthermore, complete response (CR) was observed in some animals after treatment with DXC005 (6 mg/kg) plus Gemcitabine (10 mg/kg). All groups of treatment are tolerated well, no abnormal animal behavior and body weight loss were observed in the study. The above results concluded that DXC005 combined with Gemcitabine can achieve synergistic effect even with reduced dose of Gemcitabine, which will serve as a support for synergistic application in clinical studies. Citation Format: Xiaobo Cai, Min Cao, Huihui Guo, Qingliang Yang, Yongxiang Chen, Xiangfei Kong, Yong Du, Zhicang Ye, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Binbin Chen, Yanlei Yang, Meng Dai, Robert Y. Zhao. A MUC1 antibody-conjugated with a tubulysin B analog, DXC005, demonstrates excellent synergistic effect in combination with gemcitabine for treatment of pancreatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1883.

GSH-Activatable Metal-Phenolic Networks for Photothermal-Enhanced Chemotherapy and Chemodynamic Therapy.

Chemotherapy (CT) plays an important role in the antitumor process, but the unsatisfactory therapeutic efficacy and the obvious toxic side effects of CT seriously restrict its application. To overcome the limitations of CT, the strategy of chemotherapy enhanced by chemodynamic therapy (CDT) and photothermal therapy (PTT) has been considered a promising approach to improve the anticancer effect. Herein, a novel GSH-activatable Cu2+-Quercetin network (QC) was synthesized via a convenient strategy to load Au nanoparticles (NPs) and DOX, named QCDA, for the synergistic therapy of CT/CDT/PTT. The results showed that QCDA exhibited GSH-sensitive degradation and "cargos" release in cancer cells, and then PTT and CDT caused by Au NPs and Cu+ significantly enhanced the CT effect of DOX and Quercetin on anticancer. More importantly, the PTT and depleted GSH accelerated the Fenton-like ionization process resulting in facilitating the CDT efficiency. Collectively, the multi-mode synergistic strategy of CT/CDT/PTT, which showed an excellent therapeutic effect, maybe a potential therapeutic pathway for anticancer.

Integrated radiochemotherapy study of ZIF-8 coated with osteosarcoma-platelet hybrid membranes for the delivery of Dbait and Adriamycin.

Introduction: The toxic side effects of systemic high-dose chemotherapy and poor sensitivity to radiotherapy hinder the survival rate of patients with osteosarcoma (OS). Nanotechnology offers new solutions for OS treatment; however, conventional nanocarriers suffer from inadequate targeting of tumors and short in vivo circulation time. Methods: Here, we designed a novel drug delivery system, [Dbait-ADM@ZIF-8]OPM, which uses OS-platelet hybrid membranes to encapsulate nanocarriers, to enhance the targeting and circulation time of nanocarriers, thereby enabling high enrichment of the nanocarriers in OS sites. Results: In the tumor microenvironment, the pH-sensitive nanocarrier, which is the metal-organic framework ZIF-8, dissociates to release radiosensitizer Dbait and the classical chemotherapeutic agent Adriamycin for the integrated treatment of OS via radiotherapy and chemotherapy. Benefiting from the excellent targeting ability of the hybrid membrane and the outstanding drug loading capacity of the nanocarrier, [Dbait-ADM@ZIF-8]OPM showed potent anti-tumor effects in tumor-bearing mice with almost no significant biotoxicity. Conclusion: Overall, this project is a successful exploration of the combination of radiotherapy and chemotherapy of OS treatment. Our findings solve the problems of the insensitivity of OS to radiotherapy and the toxic side effects of chemotherapy. Furthermore, this study is an expansion of the research of OS nanocarriers and provides new potential treatments for OS.

Fe3O4 Composite Superparticles with RGD/Magnetic Dual-Targeting Capabilities for the Imaging and Treatment of Non-Small Cell Lung Cancer.

In clinical practice, the incidence and mortality of non-small cell lung cancer are increasing year by year, which is a serious threat to the health of patients. Once the optimal surgical window is missed, the toxic side effects of chemotherapy have to be confronted. With the rapid development of nanotechnology in recent years, medical science and health have been greatly impacted. Therefore, in this manuscript, we design and prepare chemotherapeutic drug vinorelbine (VRL)-loaded polydopamine (PDA) shell-coated Fe3O4 superparticles, and further graft the targeted ligand RGD onto their surface. Because of the introduction of the PDA shell, the toxicity of the prepared Fe3O4@PDA/VRL-RGD SPs is greatly reduced. At the same time, due to the existence of Fe3O4, the Fe3O4@PDA/VRL-RGD SPs also have MRI contrast capability. Under the dual-targeting effect of RGD peptide and external magnetic field, Fe3O4@PDA/VRL-RGD SPs can accumulate into tumors effectively. The accumulated superparticles in the tumor sites can not only effectively identify and mark the location and boundary of the tumor under MRI, guideing the application of near-infrared laser, but also release the loaded VRL under the stimulation of the acidic microenvironment of the tumor to play the role of chemotherapy. On further combination with photothermal therapy under laser irradiation, A549 tumors are completely eliminated without recurrence. Our proposed RGD/magnetic field dual-targeting strategy can effectively improve the bioavailability of nanomaterials and contribute to better imaging and therapeutic effects, which has a promising application prospect in the future.

Therapeutic poly(amino acid)s as drug carriers for cancer therapy

As one of the top global health problems, the effective treatment of cancer is one of the most urgent clinical challenges. Currently, the main treatments for cancer include surgery, chemotherapy, radiotherapy, and gene therapy etc. Chemotherapy is one of the most commonly used treatments, however it has limitations such as highly toxic side effects and low drug utilization rate that limit its application. Gene therapy, as an emerging cancer treatment, has limitations such as drug instability, off-target effects and low internalization efficiency. Poly(amino acid)s carriers with good biocompatibility, degradability and multifunctionality as drug carriers have received much attention, as they can reduce the toxic side effects of chemotherapy, improve drug utilization, and enhance the internalization efficiency and utilization of gene drugs. However, little attention has been paid to the nature of the carriers themselves. This paper reviews the immunomodulatory, anti-inflammatory, antioxidant, internalization-promoting and apoptosis-promoting functions of poly(amino acid)s drug carriers in tumor therapy to provide a theoretical basis for different carrier-drug-adapted synergistic therapies.

Polyethylenimine modified graphene oxide for effective chemo-gene-photothermal triples therapy of triple-negative breast cancer and inhibits metastasis

Triple-negative breast cancer (TNBC) is currently the most difficult breast cancer to treat, especially for addressing the toxic side effects of chemotherapy. To surmount this challenge, a well-designed drug delivery system based on functionalized graphene oxide (GO) and docetaxel (DTX) was proposed in this investigation. In detail, GO with a photothermal therapy effect was first modified by polyethyleneimine (PEI) to enhance stability, and DTX was loaded on the surface of GO through the π-π stacking effect. In addition, anti-miRNA21 was also combined with PEI-modified GO by strong electrostatic interactions between PEI and negatively charged anti-miRNA21. Finally, a multifunctional antitumor system with drug-gene and photothermal therapy was constructed. The results from the study revealed that the constructed multifunctional system showed an excellent inhibitory effect on TNBC cells. We expect that the accomplishment of this research could provide beneficial information for designing a promising combination therapy for the treatment of TNBC.

Nobiletin and Xanthohumol Sensitize Colorectal Cancer Stem Cells to Standard Chemotherapy.

Simple SummaryColorectal cancer stem cells (CR-CSCs) play a pivotal role in the therapy resistance and relapse of CRC patients. Herein we demonstrate that new treatment approaches comprising polymethoxyflavones and prenylflavonoids extracted from Citrus sinensis and Humulus lupulus, respectively, hamper the viability of CR-CSCs as well as synergizing with 5-fluorouracil and oxaliplatin (FOX)-based chemotherapy. Extract fractions containing Nobiletin and Xanthohumol, in combination with chemotherapy, decreased stemness properties of CR-CSCs and restrained the outgrowth of chemoresistant metastatic CR-CSCs. These data pinpoint Nobiletin and Xanthohumol as efficacious anti-cancer compounds in metastatic settings.Colorectal cancer (CRC) mortality is mainly caused by patient refractoriness to common anti-cancer therapies and consequent metastasis formation. Besides, the notorious toxic side effects of chemotherapy are a concurrent obstacle to be tackled. Thus, new treatment approaches are needed to effectively improve patient outcomes. Compelling evidence demonstrated that cancer stem cells (CSCs) are responsible for treatment failure and relapse. New natural treatment approaches showed capabilities to selectively target the CSC subpopulation by rendering them targetable by standard cytotoxic compounds. Herein we show the anti-cancer properties of the polymethoxyflavones and prenylflavonoids extracted from Citrus sinensis and Humulus lupulus, respectively. The natural biofunctional fractions, singularly and in combination, reduced the cell viability of CRC stem cells (CR-CSCs) and synergized with 5-fluorouracil and oxaliplatin (FOX) chemotherapy. These phenomena were accompanied by a reduced S and G2/M phase of the cell cycle and upregulation of cell death-related genes. Notably, both phytoextracts in combination with FOX thwarted stemness features in CR-CSCs as demonstrated by the impaired clonogenic potential and decreased Wnt pathway activation. Extracts lowered the expression of CD44v6 and affected the expansion of metastatic CR-CSCs in patients refractory to chemotherapy. Together, this study highlights the importance of polymethoxyflavones and prenylflavonoids as natural remedies to aid oncological therapies.

3D-Printed Drug Capture Materials Based on Genomic DNA Coatings.

The toxic side effects of chemotherapy have long limited its efficacy, prompting expensive and long-drawn efforts to develop more targeted cancer therapeutics. An alternative approach to mitigate off-target toxicity is to develop a device that can sequester chemotherapeutic agents from the veins that drain the target organ before they enter systemic circulation. This effectively localizes the chemotherapy to the target organ, minimizing any hazardous side effects. 3D printing is ideal for fabricating these devices, as the geometric control afforded allows us to precisely dictate its hemodynamic performance in vivo. However, the existing materials compatible with 3D printing do not have drug-binding capabilities. Here, we report the stable coating of genomic DNA on a 3D-printed structure for the capture of doxorubicin. Genomic DNA is an effective chemotherapeutic-agent capture material due to the intrinsic DNA-targeting mechanism of action of these drugs. Stable DNA coatings were achieved through a combination of electrostatic interactions and ultraviolet C (UVC, 254 nm) cross-linking. These UVC cross-linked DNA coatings were extremely stable-leaching on average 100 pg of genomic DNA per mm2 of 3D-printed structure over a period of 30 min. In vitro studies of these materials in phosphate buffered saline and human serum demonstrated that they were able to capture, on average, 72 and 60 ng of doxorubicin per mm2 of structure, respectively. The stability and efficacy of these genomic DNA-coated 3D-printed materials represent a significant step forward towards the translation of these devices to clinical applications for the potential improvement of chemotherapy treatment.

A preliminary study on molecular target identification of drugs in individualized treatment of malignant solid tumors in children

Objective: To explore the role of drug-related molecular target identification in the individualized treatment of malignant solid tumors in children. Methods: The clinical data of 40 patients diagnosed with malignant solid tumors from Beijing Tongren Hospital, Capital Medical University, between June 2017 and March 2019 were retrospectively analyzed. Immunohistochemistry, polymerase chain reaction and sequencing methods were used to determine the expression levels and mutations of tumor drug molecular targets, and to compare the efficiency as well as the incidence of toxic side effects of chemotherapy using anti-tumor drugs with various molecular targets. Results: A total of 4 tumor drug-related targets were identified in 40 tumor tissue samples, namely DNA topoisomerase-ⅡA (TOPOⅡA), β(3)-tubulin (Tubulinβ(3)), DNA topoisomerase-Ⅰ(TOPOⅠ) and dihydrofolate reductase gene polymorphisms [DHFR (C829T)]. The effective rates of platinum-based agents, methotrexate, irinotecan, vinblastine and anthracycline for malignant solid tumors in children were 90.0% (36/40), 85.0% (34/40), 70.0% (28/40), 67.5% (27/40), 62.5% (25/40), respectively. The effective rates of chemotherapy with irinotecan, methotrexate, and vinblastine in mesenchymal tumors were 68.9% (20/29), 62.1% (18/29), 68.9% (20/29), respectively, which were considerably higher than 18.2% (2/11), 36.4% (4/11) and 36.4% (4/11) in non-mesenchymal tumors, with significant differences (χ(2)=5.487, 15.345, 17.278, all P<0.05). The effective rate of chemotherapy of platinum-based drugs for non-mesenchymal tumors was 72.3% (8/11), which was significantly higher than 58.6% (17/29) in mesenchymal tumors, and the difference was statistically significant (χ(2)=11.231, P<0.05). The intensity of toxic side effects in order from high to low was anthracycline > platinum > methotrexate > vinblastine > irinotecan. Conclusion: Tumor drug-related molecular targets and the sensitivity of tumors of different origins to the same anti-tumor drug as well as side effects are predicted, which provides a theoretical and clinical basis for individualized treatment of malignant tumors in children.

ASSESSMENT OF THE TOXICOLOGICAL PROPERTIES OF DOCETAXEL LOADED FOLATE-MODIFIED POLYMER PARTICLES IN VIVO

Introduction One of the perspective approaches to the development of anticancer chemotherapy drugs is the use of submicron vectorized delivery systems that increase the selectivity of action and reduce the toxic side effects of chemotherapy. A delivery system of docetaxel (DOC) loaded poly(lactide-co-glycolide) (PLGA) particles modified with folic acid dodecylamide (FAD) was developed (PLGA-DOC-FAD). The aim of the research was a comparative toxicological study of DOC-loaded particles and standard docetaxel solution form in acute and subchronic experiments in mice after intravenous administration. Materials and methods The research was conducted in female C57BL/6 mice. During the study of acute toxicity, drugs were administered in the following dose range: 20, 60, 90, 120, 160 mg/kg. Over 30 days, mortality and body weight were evaluated, pathomorphological studies were performed. The study of toxicity in conditions of subchronic administration of medicine was conducted using three times daily administration in single doses of 11 and 22 mg/kg. Subchronic toxicity of the drugs was studied with three times daily administration in single doses of 11 and 22 mg/kg. The necessary studies were performed within 30 days. Results With a single injection of PLGA-DOC-FAD in doses of 20, 60, 90 mg/kg, the death of animals wasn’t observed; at doses of 120 and 160 mg/kg, the death of animals was detected in 1–4 days. In the case of administration of the DOC substance, the death of animals occurred within a day after the administration of doses of 60, 90, 120, 160 mg/kg. The pattern of intoxication was similar in case of compared drugs and manifested in hypodynamia, impaired movement coordination, hind limbs paresis, though the manifestation degree thereof was more expressed in the groups with the introduction of DOC than in the case of the introduction of PLGA-DOC-FAD. It was detected that the LD 50 for PLGA-DOC-FAD is 140 mg/kg, and for the DOC substance – 112 mg/kg. In case of subchronic administration, the detected toxic properties of drug depend on the size of the dose applied. The administration of a single dose of 22 mg/kg of PLGA - DOC-FAD caused lethal effects (2/10), reversible delay in weight gain and leucopenia in surviving animals, and an increase in the relative mass of the spleen. The use of PLGA-DOC-FAD in a single dose of 11 mg/kg didn’t cause death, was well tolerated and characterized by similar toxicity with the docetaxel substance. Conclusion Based on experimental data, the toxic dose levels of PLGA-DOC-FAD were determined under acute and subchronic administration. The results obtained allowed us to recommend PLGA-DOC-FAD for further examination.

In Vitro Cytotoxicity and Antitumor Activity of Dual-Targeting Drug Delivery System Based on Modified Magnetic Carbon by Folate

A dual-targeting drug delivery system (DTDDS) with magnetic targeting and active targeting was obtained to improve the targeting and drug-loading capacity of magnetic drug nanocarriers. An ultraviolet-visible spectrophotometer and flow cytometry were used to investigate the drug-loading and release capacity, cytotoxicity, and inhibition of tumor cell proliferation, separately. Results show that DTDDS has obvious magnetic characteristics, on which the modification amount of folic acid is 64.82 mg g-1. Doxorubicin was taken as a template drug to evaluate its drug-loading capacity, which was as high as 577.12 mg g-1. Good biocompatibility and low cytotoxicity of DTDDS were further confirmed. Moreover, DTDDS can target the folate receptor on the surface of HeLa cells and deliver doxorubicin into HeLa cells, thereby increasing the proliferation inhibition for cancer cells. Therefore, this new dual-targeting drug delivery system shows potential in significantly reducing the toxic side effects of chemotherapy and improving chemotherapy efficiency.

Acid-Responsive H2 -Releasing 2D MgB2 Nanosheet for Therapeutic Synergy and Side Effect Attenuation of Gastric Cancer Chemotherapy.

The hydrogen molecule is recognized as a high potential to attenuate toxic side effects of chemotherapy and also enhance chemotherapeutic efficacy, and the development of a novel hydrogen-generating prodrug for facile, safe, and efficient hydrogen delivery is vitally important for combined hydrogenochemotherapy but is still challenging. Here, targeting gastric cancer, a 2D magnesium boride nanosheet (MBN) is synthesized as a new type of acid-responsive hydrogen-releasing prodrug by an ultrasound-assisted chemical etching route, which is used to realize hydrogenochemotherapy by combination of facile oral administration of polyvinylpyrrolidone (PVP)-encapsulating MBN (MBN@PVP) pills with routine intravenous injection of doxorubicin (DOX). The MBN@PVP pill has high stability in normal tissues/blood environments as well as high gastric acid-responsiveness with sustained release behavior, which matches well with its metabolism rate in the stomach in great favor of continuous and long-term hydrogen administration. Hydrogenochemotherapy with DOX+MBN@PVP has remarkably prolonged the survival time of gastric tumor-bearing mice by reducing the toxic side effects of chemotherapy. The mechanism for therapeutic synergy and side effect attenuation of hydrogenochemotherapy is discovered to be derived from the selectivity of hydrogen molecules in inhibiting aerobic respiration of gastric cells but activating aerobic respiration of normal cells including marrow mesenchymal stem cells and cardiac, hepatic, and splenic cells.

3D Printed Absorber for Capturing Chemotherapy Drugs before They Spread through the Body.

Despite efforts to develop increasingly targeted and personalized cancer therapeutics, dosing of drugs in cancer chemotherapy is limited by systemic toxic side effects. We have designed, built, and deployed porous absorbers for capturing chemotherapy drugs from the bloodstream after these drugs have had their effect on a tumor, but before they are released into the body where they can cause hazardous side effects. The support structure of the absorbers was built using 3D printing technology. This structure was coated with a nanostructured block copolymer with outer blocks that anchor the polymer chains to the 3D printed support structure and a middle block that has an affinity for the drug. The middle block is polystyrenesulfonate which binds to doxorubicin, a widely used and effective chemotherapy drug with significant toxic side effects. The absorbers are designed for deployment during chemotherapy using minimally invasive image-guided endovascular surgical procedures. We show that the introduction of the absorbers into the blood of swine models enables the capture of 64 ± 6% of the administered drug (doxorubicin) without any immediate adverse effects. Problems related to blood clots, vein wall dissection, and other biocompatibility issues were not observed. This development represents a significant step forward in minimizing toxic side effects of chemotherapy.

Intravenous Vitamin C for Cancer Therapy - Identifying the Current Gaps in Our Knowledge.

The use of intravenous vitamin C (IVC) for cancer therapy has long been an area of intense controversy. Despite this, high dose IVC has been administered for decades by complementary health care practitioners and physicians, with little evidence base resulting in inconsistent clinical practice. In this review we pose a series of questions of relevance to both researchers and clinicians, and also patients themselves, in order to identify current gaps in our knowledge. These questions include: Do oncology patients have compromised vitamin C status? Is intravenous the optimal route of vitamin C administration? Is IVC safe? Does IVC interfere with chemotherapy or radiotherapy? Does IVC decrease the toxic side effects of chemotherapy and improve quality of life? What are the relevant mechanisms of action of IVC? What are the optimal doses, frequency, and duration of IVC therapy? Researchers have made massive strides over the last 20 years and have addressed many of these important aspects, such as the best route for administration, safety, interactions with chemotherapy, quality of life, and potential mechanisms of action. However, we still do not know the answers to a number of fundamental questions around best clinical practice, such as how much, how often and for how long to administer IVC to oncology patients. These questions point the way forward for both basic research and future clinical trials.

Forging new links between the microbiome and cancer

Forging new links between the microbiome and cancer

Slowing down glioblastoma progression in mice by running or the anti-malarial drug dihydroartemisinin? Induction of oxidative stress in murine glioblastoma therapy.

Influencing cancer metabolism by lifestyle changes is an attractive strategy as - if effective - exercise-induced problems may be less severe than those induced by classical anti-cancer therapies. Pursuing this idea, clinical trials evaluated the benefit of e.g. different diets such as the ketogenic diet, intermittent caloric restriction and physical exercise (PE) in the primary and secondary prevention of different cancer types. PE proved to be beneficial in the context of breast and colon cancer.Glioblastoma has a dismal prognosis, with an average overall survival of about one year despite maximal safe resection, concomitant radiochemotherapy with temozolomide followed by adjuvant temozolomide therapy. Here, we focused on the influence of PE as an isolated and adjuvant treatment in murine GB therapy.PE did not reduce toxic side effects of chemotherapy in mice administered in a dose escalating scheme as shown before for starvation. Although regular treadmill training on its own had no obvious beneficial effects, its combination with temozolomide was beneficial in the treatment of glioblastoma-bearing mice. As PE might partly act through the induction of reactive oxygen species, dihydroartemisinin - an approved anti-malarial drug which induces oxidative stress in glioma cells - was further evaluated in vitro and in vivo. Dihydroartemisinin showed anti-glioma activity by promoting autophagy, reduced the clonogenic survival and proliferation capacity of glioma cells, and prolonged the survival of tumor bearing mice. Using the reactive oxygen species scavenger n-acetyl-cysteine these effects were in part reversible, suggesting that dihydroartemisinin partly acts through the generation of reactive oxygen species.