Morphological Aspects of Reparative Bone Tissue Regeneration under the Influence of Antitumor Chemotherapy

The occurrence of fractures in the development of cancer in the body is due to changes in bone metabolism in the form of osteoporosis and metastatic bone damage. Their appearance leads to the postponement or cessation of treatment of cancer, which affects the life expectancy of such patients and the chances of recovery. Antitumor chemotherapy, as one of the main methods of cancer treatment, is prescribed for long-term courses and affects the healing of fractures. However, according to the literature, the effect of antitumor chemotherapeutics on reparative regeneration is poorly understood today. The purpose of the work is to study the morphological features of reparative osteogenesis under the influence of antitumor chemotherapy. Materials and methods. The study was performed on 96 white laboratory male rats 7 months of age weighing 230±10 g. All animals had a perforated defect with a diameter of 2 mm spherical cutter to the bone marrow canal in the middle third of the femoral shaft. Animals were divided into control (n = 24, without chemotherapy) and three experimental groups (I, II, III, n = 72), which after injury and every 21 days of the study were administered intraperitoneal anticancer chemotherapeutics: I (n = 24) – doxorubicin (60 mg / m²), II (n = 24) – 5-fluorouracil (600 mg / m²), III (n = 24) – methotrexate (40 mg / m²). On the 15th, 30th, 45th, 60th days after injury, the animals were removed from the experiment, followed by removal of the injured long tubular bones. Histological preparations stained with hematoxylin-eosin, followed by their morphometry, scanning electron microscopy with the method of X-ray energy dispersion spectroscopy, immunohistochemical examination were performed. Results and discussion. Antitumor chemotherapeutics causes delayed callus formation, which is manifested by an increase in the area of connective and reticulofibrous bone tissue in the regenerate, along with the slow formation of lamellar bone tissue. Chemotherapy leads to disorders of phosphorus-calcium metabolism both in the regenerate and in the maternal bone in the form of reducing the intensity of mineralization of the newly formed bone matrix and slowing down the remodeling activity of the maternal bone. Chemotherapy is accompanied by an increase in the expression of the bone resorption marker cathepsin K and a decrease in the expression of the osteopontin bone marker, which indicates a delay in the formation of regenerate in the area of injury and a decrease in the rate of reparative regeneration. Conclusion. The most pronounced delay in the processes of remodeling of bone regenerate was found with the use of doxorubicin and methotrexate, while 5-fluorouracil showed less inhibitory effect on these processes

An Overview of Bioactive Natural Products-Based Nano-Drug Delivery Systems in Antitumor Chemotherapy

Many bioactive natural products are derived from traditional Chinese medicine. Some of them showed good treatment potential in tumor chemotherapy. However, limited by the poorly solubility and non-selective toxicity of most of bioactive natural products, their antitumor efficacy could not be further applied in clinicals. Nano-drug delivery systems provided good platforms for bioactive natural products in antitumor treatment, and many tumor microenvironment-responsive nano-delivery carriers facilitated them to achieve more accurate tumor targeting and less toxicity, and finally improved antitumor ability of bioactive natural products.

Self-assembled natural small molecule diterpene acids with favorable anticancer activity and biosafety for synergistically enhanced antitumor chemotherapy

Four new self-assembled natural small molecule tricyclic diterpene acids with favorable anticancer activity were discovered for construction of biocompatible antitumor drugs for highly efficient, safe, and synergistic antitumor chemotherapy.

Natural molecules as modulators of epigenetic silencing in human cells for cancer care and aging

The etiology and pathogenesis of malignant tumor growth are associated with impaired gene expression, leading to accelerated proliferation, evasion of apoptosis, and metabolic deregulations with abnormal blood supply and innervation. Currently, hundreds of tumor suppressor genes and proto-oncogenes are known. Mutations, epigenetic alterations, exposure to viruses, and other environmental factors can cause pathological changes in gene expression. The key mechanisms of carcinogenesis are now considered to be linked to epigenetic events. A better understanding of epigenetic targets and pathways is needed to develop new strategies in antitumor chemotherapy. The majority of modern cancer drugs were taken from nature, yet only a small fraction of natural molecular diversity has been explored to date. Therefore, there is great interest in identifying new natural molecules for modulating gene expression by rewiring epigenetic pathways. This review is focused on examples of known natural molecules available to biomedicine, especially ones capable of modulating epigenetic landscapes and therefore relevant for cancer prevention and aging.

Bioinspired Composite, pH-Responsive Sodium Deoxycholate Hydrogel and Generation 4.5 Poly(amidoamine) Dendrimer Improves Cancer Treatment Efficacy via Doxorubicin and Resveratrol Co-Delivery

Maximizing the antitumor efficacy of doxorubicin (DOX) with a new drug delivery strategy is always desired in the field of biomedical science. Because the clinical applications of DOX in the treatment of cancer is limited by the side effects related to the dose. Herein, we report the co-loading of DOX and resveratrol (RESV) using an injectable in situ formed sodium deoxycholate hydrogel (Na-DOC-hyd) at the pH of the tumor extracellular microenvironment. The sequential, controlled, and sustained release of RESV and DOX for synergistic antitumor effects was confirmed by entrapping G4.5-DOX in the RESV-loaded Na-DOC hydrogel (Na-DOC-hyd-RESV). The synergistic antitumor activity of Na-DOC-hyd-RESV+G4.5-DOX was assessed on HeLa cell xenograft tumor in BALB/c nude mice. In the MTT biocompatibility assay, both the G4.5 PAMAM dendrimer and Na-DOC-hyd exhibited negligible cytotoxicity up to the highest dose of 2.0 mg mL−1 in HeLa, MDA-MB-231, and HaCaT cells. The release profiles of DOX and RESV from the Na-DOC-hyd-RESV+G4.5-DOX confirmed the relatively rapid release of RESV (70.43 ± 1.39%), followed by that of DOX (54.58 ± 0.62%) at pH 6.5 in the 7 days of drug release studies. A single intratumoral injection of Na-DOC-hyd-RESV+G4.5-DOX maximally suppressed tumor growth during the 28 days of the treatment period. Na-DOC-hyd-RESV+G4.5-DOX did not cause any histological damage in the major visceral organs. Therefore, this Na-DOC-hydrogel for dual drugs (DOX and RESV) delivery at the pH of the tumor extracellular microenvironment is a promising, safe, and effective combination for antitumor chemotherapy.

COMPUTED TOMOGRAPHY ASSESSMENT OF THE DYNAMICS OF FEMORAL SHAFT DEFECT HEALING UNDER ANTITUMOR CHEMOTHERAPY

An important problem in the treatment of cancer patients is the high incidence of bone fractures. According to the treatment protocols, the vast majority of such patients require long-term antitumor chemotherapy, thus, the processes of bone reparatation and regeneration occur against this background. The cases of fractures may be due to the development of osteoporosis in cancer and the occurrence of metastatic bone lesions. Bone fractures impair the quality of life of patients, result in the postponement or even discontinuation of further treatment of cancer patients. All this reduces the survival rate of such patients. Therefore, the aim of this study was to establish the effect of antitumor chemotherapeutics on the processes of reparative bone regeneration. The study involved 52 white laboratory rats, which had a perforated defect in the middle third of the femoral shaft. The animals were divided into control and experimental groups. Antitumor chemotherapeutics, which are the most often used in chemotherapy protocols in the treatment of cancer (doxorubicin for the first subgroup, 5-fluorouracil for the second subgroup, methotrexate for the third subgroup) were given to the animals of the experimental group on the second day since modelled injury and every twenty-first day of the experiment. On the 15th, 30th, 45th, and 60th days of the experiment, all animals in the control and experimental groups were check with computed tomography, which determined the optical density in the area of regeneration and the adjacent cortical layer of the maternal bone in Hounsfield units. Conclusions. CT assessment enables to quantify the state of the reparative process in the animals of the control and experimental groups, taking prescribed antitumor chemotherapy. In the animals of the control group, the timing and processes of bone reparative regeneration were not impacted. The CT demonstrated the preserved staging of bone callus formation, satisfactory X-ray morphological parameters (size, thickness of the callus). In the period from 45 to 60 days, according to CT, the complete consolidation of femoral fractures was visually observed. The difference between the parameters of the regenerated area and the maternal bone on the 60th day of the experiment indicated the incomplete process of bone remodelling. Reparative osteogenesis was not accompanied by the development of complications. In the animals of the experimental groups, there was a slowdown in the processes of reparative bone regeneration and an increase in its duration. Indices of callus formation on the background of antitumor chemotherapy were reduced that confirms the low optical density of regenerating area and maternal bone compared to the control group and their slow increase in the defect healing. Most of these changes were manifested during the course of methotrexate therapy.

Lighting up metallohelices: from DNA binders to chemotherapy and photodynamic therapy

DNA distortion induced by metallodrugs is one of the main subjects for drug design. In this Feature Article, the developments of DNA-targeted metallohelices for antitumor chemotherapy and photodynamic therapy are presented with future perspectives.