The effectiveness of liposomal doxorubicin hydrochloride in combination with cyclophosphan in the treatment of breast cancer in an experiment

Purpose of the study. To evaluate the antitumor efficacy of liposomal doxorubicin hydrochloride in combination with tamoxifen in the treatment of breast cancer.Materials and methods. The study included mongrel white rats (n = 30). A model of carcinogenesis (Walker 256 tumors) was created for all animals. Then we divided these rats into 3 equal groups: 1 control group (n = 10) - animals were monitored without treatment; 2 group (n = 10) - animals received neoadjuvant therapy: liposomal doxorubicin hydrochloride + cyclophosphan; 3 group (n = 10) - animals received neoadjuvant therapy with doxorubicin hydrochloride (non-liposomal) and cyclophosphan. Animals of the second and third groups received two cycles of neoadjuvant therapy. All animals were monitored for 1.5 months. We evaluated the effectiveness of antitumor therapy by measuring the size of tumors, the dynamics of their regression, and counting the number of metastases in the lungs. The toxic effects of doxorubicin hydrochloride were assessed by blood parameters: platelet and lymphocyte levels.Results. We recorded a significant inhibition of the growth of tumor nodes in the second group of rats on the 25th day from the start of the experiment compared with the first and third groups: 36004.7, 86112.1 and 38962.4 mm3, respectively. By the end of the 3rd week of the experiment, we also noted the formation of a tumor regression trend in the 2nd and 3rd groups of animals, which was reliably maintained until the end of the observation. At the end of the experiment, the number of metastases in the first group of animals was 3 times more, in the third group almost 1.5 times more than in the second (p < 0.05)Conclusion. The treatment of Walker 256 tumor with liposomal doxorubicin showed better efficacy and safety in comparison with non-liposomal doxorubicin. The tumor volume becomes smaller against the background of neoadjuvant chemotherapy with liposomal doxorubicin hydrochloride compared with its non-liposomal form, while there is no pronounced decrease in platelets and lymphocytes. We also recorded a significantly lower number of lung metastases in animals of the second group compared to other groups.

Walker-256 Tumour-Induced Cachexia Altered Liver Metabolomic Profile and Function in Weanling and Adult Rats

Cancer cachexia occurs in up to 85% of advanced cancer patients, affecting different tissues and organs, mainly the liver, which plays a central role in body metabolism control. However, liver responses to cancer cachexia progression are still poorly understood. Considering the possible different challenges provided by the rodent’s phase of life and the cachexia progression, we evaluated the liver metabolic alterations affected by Walker-256 tumour growth in weanling and young-adult rats. For this, we applied a metabolomics approach associated with protein and gene expression analyses. Higher amino acid levels and impaired glucose metabolism were important features in tumour-bearing animals’ liver tissue. The weanling hosts had more pronounced cachexia, with higher carcass spoliation, liver lipid metabolism and impaired CII and CIV mitochondrial complexes. The liver alterations in young adult tumour-bearing rats were related to energy status and nucleotide metabolites, such as uridine, NAD+, xanthosine, hypoxanthine and inosine. In conclusion, the Walker-256 tumour-induced cachexia impaired liver metabolism, being more severe in the weanling hosts. Further studies are needed to correlate these changes in the preclinical model, which can be correlated to the clinical features of cancer cachexia, allowing for a translational potential involving the liver function and its responses to potential treatments.

Leucine-Rich Diet Improved Muscle Function in Cachectic Walker 256 Tumour-Bearing Wistar Rats

Skeletal muscle atrophy occurs in several pathological conditions, such as cancer, especially during cancer-induced cachexia. This condition is associated with increased morbidity and poor treatment response, decreased quality of life, and increased mortality in cancer patients. A leucine-rich diet could be used as a coadjutant therapy to prevent muscle atrophy in patients suffering from cancer cachexia. Besides muscle atrophy, muscle function loss is even more important to patient quality of life. Therefore, this study aimed to investigate the potential beneficial effects of leucine supplementation on whole-body functional/movement properties, as well as some markers of muscle breakdown and inflammatory status. Adult Wistar rats were randomly distributed into four experimental groups. Two groups were fed with a control diet (18% protein): Control (C) and Walker 256 tumour-bearing (W), and two other groups were fed with a leucine-rich diet (18% protein + 3% leucine): Leucine Control (L) and Leucine Walker 256 tumour-bearing (LW). A functional analysis (walking, behaviour, and strength tests) was performed before and after tumour inoculation. Cachexia parameters such as body weight loss, muscle and fat mass, pro-inflammatory cytokine profile, and molecular and morphological aspects of skeletal muscle were also determined. As expected, Walker 256 tumour growth led to muscle function decline, cachexia manifestation symptoms, muscle fibre cross-section area reduction, and classical muscle protein degradation pathway activation, with upregulation of FoxO1, MuRF-1, and 20S proteins. On the other hand, despite having no effect on the walking test, inflammation status or muscle oxidative capacity, the leucine-rich diet improved muscle strength and behaviour performance, maintained body weight, fat and muscle mass and decreased some protein degradation markers in Walker 256 tumour-bearing rats. Indeed, a leucine-rich diet alone could not completely revert cachexia but could potentially diminish muscle protein degradation, leading to better muscle functional performance in cancer cachexia.

Effect of metformin on the development of Sarcoma Walker-256

There has been a great deal of interest in veterinary medicine in drugs that support the body during chemotherapeutic treatment. The authors conducted a study of the drug’s effect on the development of carcinosarcoma in the mono regimen. The growth pattern of artificially induced Walker-256 sarcoma in 3-month-old Wistar rats in the post-lactation period was studied. The study was conducted at the Department of Pharmacology and General Pathology, Faculty of Veterinary Medicine.The study was conducted at the Department of Pharmacology and General Pathology, Faculty of Veterinary Medicine. The objects of the study were Wistar rats, female rats of three months of age, weighing 150-200 g in the post-lactation period. Rats of both groups were infected with Walker 256 sarcoma by injection into the thigh muscle at a dose of 106 ml/head. Rats in the experimental group were additionally administered metformin at 30 mg/head daily with water. Histological, cytological and haematological studies were performed on days 14 and 21 from the time of infection of the rats with the tumour. Under the action of metformin, the number of erythrocytes, leukocytes, lymphocytes, monocytes and granulocytes in Walker-256 sarcoma-infected rats increased, the concentration of haemoglobin decreased, and the number of platelets did not change. In the biopsy specimen of control rats compared to the counterparts of the experimental groups, the concentration of monocytes was increased. The number of eosinophils and nuclear polymorphism was decreased under the influence of metformin. In addition, metformin-induced neuropsychiatric abnormalities in rats, such as appetite perversion and cannibalism. The more pronounced inflammatory response in the experimental group indicates that further study of the drug’s effect on the development of various neoplasms is necessary, as this is an essential factor in the choice of the treatment strategy.

THE EFFECT OF CYTOSTATIC DRUGS ON THROMBOCYTOPOIESIS IN RATS WITH WALKER-256 CARCINOMA

Among malignant neoplasms of women, breast cancer (BC) takes the leading place and is the cause of high mortality and complications. Side effects in the form of anemia, thrombocytopenia, bleeding, etc. often develop during cytostatic therapy, which is the main method of treatment and prevention of further development of the oncological process. In this regard, the problem of reducing side metabolic disorders remains relevant and creates a search field for the use of drugs aimed at stabilizing functions, both at the cellular and organ levels. The aim of the study was to evaluate the effect of cytostatic drugs on thrombocytopoiesis in rats with WALKER-256 carcinoma. The study included 60 rats, which, depending on the type of treatment, were divided into 5 groups. A week after the start of chemotherapy, the greatest increase in the number of platelets was in the presence of liposomal ethylmethylhydroxypyridine succinate. We recorded that the myeloprotective effect was 1/3 better in liposomal ethylmethylhydroxypyridine succinate compared to its non-liposomal form. Therefore, individuals those receiving cytostatic drugs in the treatment of breast cancer need protection from myelopoiesis. In the studies carried out by us, it was shown that oxidative stress occurred in animals against the background of treatment with cytostatics. It was its rapid development that caused damage to the platelet cell membranes. In this regard, we have proposed a drug with a pronounced antioxidant efficacy. The introduction of an antioxidant into the generally accepted standard treatment of a tumor process has made it possible to experimentally select methods for delivering the drug to the targets of damage using liposomal forms. The study obtained data proving the effectiveness of the use of liposomal ethylmethylhydroxypyridine succinate (50 mg / kg), in contrast to its free form, which prevents the development of thrombocytopenia induced by the administration of cytostatic drugs to rats with Walker-256 carcinoma.

Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression

Bone cancer pain (BCP) is a common pathologic pain associated with destruction of bone and pathological reconstruction of nervous system. Current treatment strategies in clinical is inadequate and have unacceptable side effects due to the unclear pathology mechanism. In the present study, we showed that transplantation of Walker 256 cells aggravated mechanical allodynia of BCP rats (**p &lt; 0.01 vs. Sham), and the expression of ASIC3 (Acid-sensitive ion channel 3) and TRPV1 was obviously enhanced in L4-6 dorsal root ganglions (DRGs) of BCP rats (**p &lt; 0.01 vs. Sham). ASIC3 and TRPV1 was mainly expressed in CGRP and IB4 positive neurons of L4-6 DRGs. While, TRPV1 but not ASIC3 was markedly upregulated in L4-6 spinal dorsal horn (SDH) of BCP rats (**p &lt; 0.01 vs. Sham). Importantly, intrathecal injection of CPZ (a TRPV1 inhibitor) or Amiloride (an ASICs antagonist) markedly increased the paw withdraw threshold (PWT) of BCP rats response to Von Frey filaments (**p &lt; 0.01 vs. BCP + NS). What’s more, intraperitoneally injection of Metformin or Vinorelbine markedly elevated the PWT of BCP rats, but reduced the expression of TRPV1 and ASIC3 in L4-6 DRGs and decreased the TRPV1 expression in SDH (*p &lt; 0.05, **p &lt; 0.01 vs. BCP + NS). Collectively, these results suggest an effective analgesic effect of Metformin on mechanical allodynia of BCP rats, which may be mediated by the downregulation of ASIC3 and TRPV1.

CORRECTION OF THROMBOCYTOPOIESIS IN RATS WITH WALKER-256 CARCINOMA USING AN ANTIOXIDANT SUPPLEMENT IN THE SETTING OF CYTOSTATICS

— In this study, we’ve evaluated the myelotoxic effect of treating Walker-256 carcinoma with cytostatics, followed by correction of thrombocytopenia with liposomal and liposome-free mexidol. The study included 60 rats, which, depending on the type of treatment, were divided into 5 groups. We recorded the greatest increase in the number of platelets on the background of liposomal mexidol both on the 3rd and 7th day after the start of chemotherapy. At the end of the monitoring, the myeloprotective effect was 30% higher in the liposomal mexidol compared to its non-liposomal form. Conclusion: Activation of thrombocytopoiesis on the background of cytostatic therapy helps to reduce the complications related to the use of chemotherapy.