Metronomic mode of administration of hybrid organotin compounds: results and prospects

According to the WHO experts, “cancer is one of the main causes of morbidity and mortality worldwide” [1]. In 2022, 624,835 cases of malignant neoplasms were detected for the first time in the Russian Federation. An increase in this indicator compared to 2021 is 7.6%. In 2022, 34.4% of malignant neoplasms were diagnosed at stage I of the disease (in 2021 - 32.4%), 24.9% - at stage II (in 2021 - 25.5%), 16.8% - at stage III (in 2021 - 17.2%), and 19.8% of malignant neoplasms in Russia were diagnosed at stage IV (in 2021 - 20.5%) [2]. One of the complex and still unresolved problems is the provision of high-quality medical care to patients with common forms of malignant neoplasms (MN) in a situation where radical treatment options have been already exhausted [3].

Chemotherapy remains one of the main methods of treating tumor processes. This method of treatment plays a decisive role in the provision of high-quality palliative care [4]. Patients with disseminated tumor processes have a reduced functional status, which limits the possibility of using highly toxic therapy regimens and determines the development of combined and metronomic methods for the administration of cytostatic drugs under the real clinical practice con-24 | Cardiometry | Issue 33. November 2024

ditions and at the stages of preclinical development of substances with an expected antitumor effect [2]. The therapeutic concept of continuous administration of chemotherapeutic agents at doses lower than the maximum tolerated dose (MTD) without medication interruptions over long periods of time, known as metronomic chemotherapy, is a promising approach to anti-angiogenic cancer therapy, and compared with MTD chemotherapy regimens, metronomic chemotherapy has been shown to have lower toxicity.

Metal-containing substances are currently being actively studied as promising anticancer drug candidates, and tin compounds are of particular interest in this regard. Organotin compounds have shown varying degrees of pharmacological activity in the in vitro and in vivo model systems [5,6]. The search for new strategies for the introduction of cytostatic agents in palliative chemotherapy remains a priority area for research in the field of pathological physiology, as well as experimental pharmacology and oncology. In this regard, the development of methods for combined and metronomic introduction of leading hybrid organotin compounds (HOTC) for the treatment of disseminated tumor processes is an urgent task.

The aim of the study was to evaluate the effect of hybrid organotin compounds and their combination with cisplatin produced on the growth and development of melanoma B16 in C57Bl/6 mice in the met- ronomic administration mode and identify the key pathogenetic mechanisms of their antitumor action.

MATERIALS AND METHODS

The hybrid organotin compounds Me-3 and Me-5 were supplied by the Chair of Organic Chemistry and Fine Organic Synthesis, Faculty of Chemistry, Lomonosov Moscow State University, headed by Prof. E.R.Milaeva, Doctor of Chemical Sciences [7,8].

Table 1

Chemical formulas of the objects of study

Note: Designation of radicals: tBu – tret-butyl, Ph – phenyl

RESULTS

When analyzing the effect of compounds Me-3 and Me-5 produced on the development of melanoma B16 in the classical and metronomic administration regimens, we can conclude that the most pronounced inhibition rate of the melanoma B16 growth was revealed for Me-3. However, in the metronomic mode, the above inhibition rate was higher as compared to the classical mode. The same results were also observed in case of changes in the inhibition index of metastasis.

It should be noted that in the experiment the studied substances were used in small (threshold) doses, but the results of the specific efficiency were comparable with the data of antitumor and antimetastatic effects of hybrid OTC with the classical version of administration according to Sofyina Z.P. The results of the comparative scoring of the general condition of experimental animals with the classical and metronomic administration of HOC-Sn (IV) 16 days after the first administration of the tested compounds are reported. With the comparable pharmacological efficacy, the general condition in the animals in the metronomic administration mode has been assessed to be moderate that is especially important in the treatment of disseminated tumor process for the palliative purposes.

The latest scientific studies demonstrate the role of chemotherapy not only in providing symptom control, preventing complications, prolonging life, but also in improving the quality of life in patients with incurable malignant neoplasms. This understanding of the objectives of chemotherapeutic treatment is fully consistent with palliative therapy in oncology. In connection with the obtained results, we consider it appropriate to continue the study of HOTC in relation to the treatment of disseminated tumor process in metronomic mono- and combined administration modes.

The formation of a new vascular network is based on various mechanisms, such as vasculogenesis, vascular sprouting, intussusception and coalescent angiogenesis, as well as vascular co-option, vasculogenic mimicry and lymphangiogenesis. Vascular homeostasis is regulated by a large number of pro- and anti-angiogenic factors. When they are in equilibrium, the vasculature is quiescent, and endothelial cells are non-proliferative. The initiation of blood vessel formation is induced when pro-angiogenic signaling dominates, a process that has been termed as “the angiogenic switch” in tumors. The angiogenic switch awakens tumors from dormancy and induces rapid growth of malignant cells coupled with the formation of new blood vessels. Endothelial cells are normally dormant, but however they can be stimulated to sprouting and initiating angiogenesis due to pro-angiogenic factors, including the vascular endothelial growth factor (VEGF). In cancer, VEGF is produced and secreted by tumor cells, and the surrounding stroma and is associated with tumor progression, increased vascular density, invasiveness, metastasis, and tumor recurrence. Metronomic chemotherapy with the tested compounds has revealed some changes in the amount of VEGF-A and its receptor VEGFR2 that may contribute an additional component to the implementation of both antitumor and antimetastatic effects. When conducting a search-related immunohistochemical analysis in the metronomic mode of administration of the tested compounds, identified has been another possible mechanism for the implementation of antitumor and antimetastatic action through a change in the activity of neoangiogenesis, more pronounced for compound Me-3 that required its further study [7]. Me-3 locked the formation of vessels; to a greater extent it suppressed the expression of vascular endothelial growth factor (VEGF A) and the endothelial cell marker CD34 in the B16 melanoma cells, but at the same time affected the expression of the VEGF A receptor with less intensity.

The pathogenetic mechanism of the implementation of the antitumor and antimetastatic action of hybrid organotin compounds in the most effective dose with the classical administration regimen via pro/an-ti-oxidant activity of a tumor cell implies a reduction in the amount of reactive oxygen species (ROS), an increase of activity of anti-oxidant defense enzymes: Superoxide dismutases (SODs), catalase (CAT), in a decrease in the levels of malone dialdehyde, 8-Hy-droxy-2 ′ -deoxyguanosine and cytochrome C and an elevation of the resistance of the tissue to metas-tastasis. Taken together, all this results in a moderate antitumor and high antimetastatic effect. The mechanism of the moderate antitumor and high antimetastatic effect produced by hybrid organotin compounds in their maximum effective dose in the metronomic administration mode via change in angiogenesis is implemented through a decrease in activity of neoangiogenesis, a reduction in the VEGF-A expression, alteration of the vasculogenic mimicry phenomenon and a decrease in the growth of the primary tumor focus and metastasis.

CONCLUSION

The results of the study allowed us to develop and substantiate the fundamental pathogenetic bases for the use of the above innovative class of organotin compounds in the metronomic mode of administration as promising candidates for antitumor drugs for use in palliative chemotherapy tactics in the experiment.