WO2024091201A1 - A combined drug for the treatment of triple negative breast cancer - Google Patents

A combined drug for the treatment of triple negative breast cancer Download PDF

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WO2024091201A1
WO2024091201A1 PCT/TR2023/051131 TR2023051131W WO2024091201A1 WO 2024091201 A1 WO2024091201 A1 WO 2024091201A1 TR 2023051131 W TR2023051131 W TR 2023051131W WO 2024091201 A1 WO2024091201 A1 WO 2024091201A1
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treatment
capecitabine
mocetinostat
cells
breast cancer
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PCT/TR2023/051131
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French (fr)
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Onur EROGLU
Hacer KAYA CAKIR
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Bilecik Seyh Edebali Universitesi
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid

Definitions

  • the present invention relates to a combined drug with synergistic effect for use in the treatment of triple negative breast cancer (TNBC).
  • TNBC triple negative breast cancer
  • This combined drug provides low- dose, fast and effective treatment for breast cancer.
  • State of the Art Cancer along with cardiovascular diseases, is one of the leading deadly diseases in the world; it is the uncontrolled or abnormal growth and proliferation of cells as a result of DNA damage in cells.
  • TNBC triple negative breast cancer
  • TNBC triple-negative breast cancer
  • ER estrogen hormone receptor
  • PR progesterone hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • TNBC which accounts for 15% to 20% of all breast cancer cases, is characterized by aggressive tumor behavior, distant organ metastasis, and limited options for targeted therapy due to negative ER, PR and Her-2 receptors. For this reason, TNBC has a more severe profile than hormone receptor positive tumors, with higher recurrence rates and shorter life expectancy.
  • Chemotherapy which is the most commonly used method for the treatment of breast cancer, is administered to prevent the proliferation of cancer cells, to slow down the spread of cancer cells, to control the disease, to improve the quality of life, to facilitate local treatments to be performed before surgery or radiotherapy, or to reduce disease recurrence after surgery or radiotherapy. Almost all chemotherapy drugs are distributed throughout the body via the bloodstream and reach cells that proliferate uncontrollably, killing them or preventing them from growing uncontrollably.
  • Adjuvant and neoadjuvant drugs used in the state of the art in breast cancer treatment include anthracyclines such as doxorubicin and epirubicin, taxanes such as paclitaxel and docetaxel, 5-fluorouracil (5-FU), capecitabine, cyclophosphamide, carboplatin.
  • drugs such as paclitaxel, docetaxel and taxanes such as albumin-bound paclitaxel, anthracyclines (doxorubicin, pegylated liposomal doxorubicin and epirubicin), platinum agents (cisplatin, carboplatin), vinorelbine, capecitabine, gemcitabine, Ixabepilone, eribulin are used.
  • anthracyclines doxorubicin, pegylated liposomal doxorubicin and epirubicin
  • platinum agents cisplatin, carboplatin
  • vinorelbine cisplatin, carboplatin
  • capecitabine ccitabine
  • gemcitabine Ixabepilone
  • eribulin eribulin
  • Apoptosis one of the mechanisms that prevent cancer formation and development, is programmed cell death and is triggered by the activation of a genetically controlled self-destruction mechanism.
  • the primary aim of apoptosis is to get rid of cells that cannot be repaired, that the body no longer needs or that are not normal. Therefore, this prevents problems that may arise in the future due to problematic cells.
  • Apoptosis formation is prevented in tumor cells as a result of disruption of the balance of pro-apoptotic and anti-apoptotic proteins, decrease in caspase activity and disruption of death receptor signals [2]. Apoptosis mechanism is still dominant in breast cancer [3].
  • Epigenetics refers to the alteration of gene expression by histone protein modifications without changes in nucleotide sequence. The most important histone protein modifications are histone acetylation and deacetylation.
  • epigenetic mechanisms are known to play a role in the initiation and progression of TNBC, and therefore the mechanisms, molecules and signalling pathways of genes that express and play a role in epigenetic regulation in carcinogenesis have attracted attention [4].
  • Histone deacetylase (HDAC) and histone acetylase (HAT) enzymes responsible for histone deacetylation and acetylation ensure that the epigenic system is in balance and gene transcription is carried out smoothly.
  • the interaction of acetylated histone with DNA is reduced and gene transcription is activated by easy binding of transcription factors.
  • Deacetylation of histone leads to the formation of condensed chromatin as a result of increased interaction with DNA. Transcription factors cannot bind to this tightly structured chromatin and gene transcription is repressed.
  • Cancer cell formation is triggered by the suppression of gene transcription involved in the regulation of DNA replication, cell cycle and apoptosis. In relation to this situation, it has been reported that HDAC enzyme is found more in cancer cells than in normal cells.
  • HDACi HDAC inhibitors
  • Capecitabine an antimetabolite, is a powerful chemotherapeutic drug used in the treatment of many types of cancer, especially breast cancer, and is administered orally.
  • Capecitabine dose intervals used in the current technique vary, but are 2500 mg/2m 2 per day.
  • Capecitabine was created based on the observation of high concentrations of the enzyme thymidine phosphorylase in many human tumors.
  • Capecitabine which has low toxicity and is easy to administer, acts during the S phase of the cell cycle by inhibiting DNA synthesis by limiting the availability of thymidylate and inducing apoptosis in cells [9].
  • capecitabine is effective on breast cancer cells, it also damages normal cells and causes many side effects.
  • IC50 values of capecitabine were as follows: HCT1162850 uM, HT291590 uM, SW620 4190 uM, HCT85957 uM, HCT155840 uM, COLO205863 uM cells for 24 hours (10).
  • Mocetinostat is a benzamide histone deacetylase inhibitor (HDACi) that has undergone clinical trials for the treatment of various cancers, including follicular lymphoma, Hodgkin's lymphoma and acute myelogenous leukemia, and is administered orally (In the Phase II study, patients were given 85 mg and 110 mg).
  • Mocetinostat is a class I and IV selective HDACi that has been shown to have potent and selective antiproliferative effects in various human cancer cells in pre-clinical studies [6]. Mocetinostat has been observed to be tolerable in clinical trials with advantageous pharmacokinetic and pharmacodynamic properties and promising antitumor activity in many hematological diseases [7]. Another effective strategy for the treatment of solid tumors is to combine mocetinostat with other antitumor agents [8]. Mocetinostat is often used to treat lymphoma and is known to be effective.
  • the IC50 values of mocetinostat on colon cancer were as follows: HCT1160,29 ⁇ M, HCT150,72 ⁇ M, HT290,76 ⁇ M, DU1450,67 ⁇ M, MDA-MB231 0,61 ⁇ M, T24 0,66 ⁇ M, A549 0,9 ⁇ M, BxPc3 0,0 ⁇ M, BxPc3 0,0 ⁇ M Histiocytic lymphoma 0,11 ⁇ M, HL60 Promyelocytic leukemia 0,18 ⁇ M, RPMI-8226 0,15 ⁇ M, MV-4-11 0,1 ⁇ M, HMEC Breast normal epithelium 20 ⁇ M and MRHF Foreskin fibroblasts 15 ⁇ M [11].
  • mocetinostat has also been used in combination with another antitumor. Some researchers have found that mocetinostat in combination with gemcitabine affects cell growth and induces apoptosis in LMS (Leiomyosarcoma) cells [12, 13]. Here, mocetinostat treatment was 1 uM to 5 uM in DU-145 and PC-3 cells for 72 hours and induced significant levels of apoptosis [14]. In chemotherapy, drugs can be administered alone or in combination with another drug. The single use of drugs (monotherapy) requires high concentrations (high doses) and is effective on cancer cells while damaging normal cells.
  • CDI drug interaction formula
  • AB is as follows: The ratio of combined drug administration to the control group is used [A: ratio of single drug administration to the control group, B: ratio of single drug administration to the control group].
  • CDI ⁇ 1 indicates synergy
  • CDI >1 indicates antagonism [16].
  • combination therapy is considered as a treatment option that can limit treatment resistance, reduce toxicity and increase drug efficacy.
  • the drugs to be used in the combined treatment should be pharmacologically compatible with each other, should not interact in a way that would cause additional side effects, and the damage to healthy cells should not be increased while increasing the effectiveness on cancerous cells. Only when all of these conditions are met and a positive synergistic effect is achieved can combined therapy be successful.
  • chemotherapeutic agents is indispensable in the treatment of triple-negative breast cancer, the resistance developed by cancer cells against existing drugs and therefore the decrease in efficacy is the most important factor in the decrease in the success of treatment.
  • the present invention relates to a combination drug with synergistic effect for use in the treatment of triple negative breast cancer (TNBC).
  • TNBC triple negative breast cancer
  • the combination drug subject to the invention comprises mocetinostat and capecitabine.
  • This combination drug prevents triple negative breast cancer cell proliferation by arresting the cell cycle of triple negative breast cancer cells and inducing death by apoptosis.
  • the treatment of triple negative breast cancer is effectively realized.
  • One aim of the invention is to provide an effective treatment for triple negative breast cancer by administering low doses of chemotherapy drugs.
  • the dose range applied to provide an effective treatment in case mocetinostat and capecitabine in the combined drug subject to the invention are administered alone in cancer treatment is 1,625 ⁇ M, 3,125 ⁇ M, 6,25 ⁇ M, 12,5 ⁇ M or 25 ⁇ M for mocetinostat; 800 ⁇ M, 900 ⁇ M, 1000 ⁇ M, 1200 ⁇ M, 1400 ⁇ M, 1600 ⁇ M, 1700 ⁇ M, 1800 ⁇ M or 2000 ⁇ M for capecitabine.
  • the most effective dose of the drugs in single use is 1700 ⁇ M for capecitabine and 3,125 ⁇ M for mocetinostat.However, mocetinostat is administered at a dose of 1,5 ⁇ M and capecitabine at a dose of 50 ⁇ M with the combined treatment of the present invention; although the dosages are reduced, a much more effective treatment is provided than the treatment effectiveness obtained when both drugs are administered separately with the help of the synergistic interactions of the drugs with each other.
  • Combined treatment with capecitabine shows a high success rate compared to single treatment and an unexpected synergistic effect with the prolonged activity of the mocetinostat inhibitor in tumor tissue and its tolerability to side effects.
  • mocetinostat inhibits cancer cells as HDACi.
  • cancerous cells cannot resist drugs that have different mechanisms and have a synergistic effect, and treatment is successful.
  • Another aim of the present invention is to reduce chemotherapy drug-induced side effects during the treatment of triple negative breast cancer.
  • the side effects of the drugs administered cause the patient to discontinue the treatment or, even if the treatment is continued to the end, the patient's body cannot tolerate it due to strong side effects, resulting in death.
  • the drug combination of the present invention provides effective treatment while at the same time both drugs (mocetinostat and capecitabine) are used at lower doses than when used alone.
  • the combination drug of the present invention comprising mocetinostat and capecitabine has a synergistic effect on cancerous cells and provides rapid treatment, they cause less damage to healthy cells than when used alone. Furthermore, the combined treatment significantly reduces and avoids the toxic effect, as different pathways are targeted to reduce the proliferating cancer cells.
  • a combined drug is provided in the treatment of breast cancer, especially in the treatment of triple negative breast cancer (TNBC), which is much more effective on cancerous cells than single use, reduces damage to healthy cells, provides effective treatment with low doses and breaks the resistance of cancerous cells with the help of the combined application.
  • TNBC triple negative breast cancer
  • Figure 2 Time-dependent morphological image of 4T1 cells treated with mocetinostat, capecitabine, and the combination of the two drugs (Nikon Eclipse TS100).
  • Figure 3 Time dependence of viability of 4T1 breast cancer cells after treatment with capecitabine, mocetinostat and capecitabine+mocetinostat
  • Figure 4 DNA laddering image performed in an agarose gel in control and treatment groups to support apoptosis induction by capecitabine, mocetinostat and capecitabine+mocetinostat for 48 hours
  • Figure 5 Wound healing analysis in 4T1 breast cancer cells; (1) control (without any treatment), (2) 1700 ⁇ m capecitabine, (3) 3,125 ⁇ m mocetinostat and (4) 50 ⁇ m capecitabine, 1,5 ⁇ m mocetinostat.
  • FIG. 6 Western blot analysis results of capecitabine, mocetinostat, capecitabine+mocetinostat (Here bands were quantified by densitometry and normalized to model control values, a statistical analysis of ⁇ -actin adjusted proteins was performed. Data are shown as the mean standard deviation of three separate experiments. *P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001) Detailed Description of the Invention
  • the present invention relates to a combination drug with synergistic effect for use in the treatment of triple negative breast cancer (TNBC).
  • TNBC triple negative breast cancer
  • mocetinostat in the invention; it has multiple mechanisms of action, is active in tumor tissue for a long time, can tolerate side effects, its half-life is approximately 7 - 11 hours and it is one of the HDAC inhibitors that shows higher success in combined treatment compared to single treatment, it also shows a favorable pharmacokinetic profile with dose-dependent exposure compared to other HDAC inhibitors.
  • the combination of mocetinostat with capecitabine allows the administration of capecitabine at a lower initial dose and reduces the side effects commonly observed when capecitabine is used alone.
  • various assays were performed to investigate the antitumor effects of mocetinostat and capecitabine treatment alone and the combined treatment of these two drugs on breast cancer 4T1 cells.
  • mice were used in the assays because it can accurately mimic the response to immune receptors and the response to targeting therapeutic agents.
  • Stock solutions of these drugs were prepared and administered to mice to be used in the analysis to determine the properties of the combined drug subject to the present invention against triple negative breast cancer.
  • Mocetinostat was prepared as 1 mg in 2,52 ml DMSO for a 1mM stock solution and diluted with medium.
  • Capecitabine was prepared as 5 mg in 2,78 ml DMSO for a 5 mM stock solution and diluted with the medium.
  • 1,625 ⁇ M, 3,125 ⁇ M, 6,25 ⁇ M, 12,5 ⁇ M or 25 ⁇ M doses were determined for mocetinostat; 800 ⁇ M, 900 ⁇ M, 1000 ⁇ M, 1200 ⁇ M, 1400 ⁇ M, 1600 ⁇ M, 1700 ⁇ M, 1800 ⁇ M or 2000 ⁇ M doses were determined for capecitabine.
  • Capecitabine and mocetinostat doses are determined as follows respectively; 25 ⁇ M+2 ⁇ M, 30 ⁇ M +2 ⁇ M,30 ⁇ M +1,5 ⁇ M, 20 ⁇ M +2, 25 ⁇ M +1 ⁇ M, 40 ⁇ M +1,5 ⁇ M, 50 ⁇ M +1,5 ⁇ M, 100 ⁇ M +1 ⁇ M, 100 ⁇ M +2 ⁇ M, 100 ⁇ M +1,5 ⁇ M.
  • the most effective dose of the drugs in single use is 1700 ⁇ M for capecitabine and 3,125 ⁇ M for mocetinostat.
  • the combined therapy subject to the present invention has been shown to effectively treat mocetinostat at a dose of 1,5 ⁇ M and capecitabine at a dose of 50 ⁇ M.
  • the potent inhibitory effects of capecitabine, mocetinostat, capecitabine+ mocetinostat time-dependence on 4T1 cell viability are shown in Figure 1.
  • IC50 values obtained from MTT results were determined as 1700 ⁇ M for capecitabine, 3,125 ⁇ M for mocetinostat, 50 ⁇ M+1.5 ⁇ M (1.5 ⁇ M+50 ⁇ M) for capecitabine+mocetinostat combined treatment. Therefore, the application dosages will also be in this way.
  • Trypan blue staining is the technique used to count live cells and dead cells. While living cells cannot absorb the dye, dead cells can absorb the dye and are observed in blue.
  • Treatment of 4T1 cells treated with capecitabine, mocetinostat, capecitabine+mocetinostat appears to cause abnormal changes such as condensation of the cell nucleus, reduction in cell density and number, reduction in cell size, and loss of cell extensions and rounded shape. These changes in 4T1 cells showed the effects of the drugs at different times and at different concentrations.
  • Figure 3 shows the morphological characteristics of the drug-treated and control groups 24, 48, 72 and 96 hours after the 4T1 cell line was cultured. In a time-dependent manner, drug-treated cell lines have a significant reduction in cell proliferation.
  • Dead and live cell ratios were calculated and capecitabine increased the lethal effect by 24%, 45.2%, 69.1% and 86.6%; mocetinostat increased the lethal effect by 28%, 42%, 61.5% and 77.8%; capecitabine+mocetinostat caused a 16%, 34.3%, 51.5% and 88.2% increase in lethality at 24, 48, 72 and 96 hours, respectively, compared to the control group.
  • the number of dead cancer cells (apoptotic cell number) increased in a time-dependent manner by administering these drugs at an effective dose.
  • One of the methods to determine apoptosis is genomic DNA fragmentation.
  • Figure 4 shows the DNA fragmentation of 4T1 cells treated with 1700 uM capecitabine, 3,125 uM mocetinostat and 50 uM capecitabine+1.5 uM mocetinostat. DNA fragmentation was observed in a time-dependent manner with both high molecular weight DNAs. Intact DNA bands were observed in the control group treated with 0.1% DMSO. As a supporting effect, DNA laddering was also observed in drug-treated cells. The treated cells have a DNA laddering pattern. As a result of the analysis; single drugs and their combinations triggered DNA fragmentation and apoptotic pathway in 4T1 cells and a characteristic ladder pattern indicating apoptosis-mediated cell death was observed.
  • the average wound width of the control group was recorded as 851,7 ⁇ m at hour 0 and was completely closed at the end of the 72nd hour.
  • control was recorded as 456,05 ⁇ m, capecitabine as 866,50 ⁇ m, mocetinostat as 825,17 ⁇ m and capecitabine+mocetinostat as 856,14 ⁇ m.
  • capecitabine mocetinostat and capecitabine+mocetinostat on apoptotic signaling pathway in 4T1 cells were confirmed by Western blot analysis after treatment with capecitabine 1700 uM, mocetinostat 3,125 uM and capecitabine 50uM+mosetinostat 1.5 uM for 48 hours.
  • capecitabine and mocetinostat stimulates the apoptotic pathway by increasing the expression of caspase-3 and caspase-7 proteins involved in the intrinsic pathway.
  • the level changes in the proteins that are effective in the regulation of the apoptotic pathway in the combined use of these two drugs supported that the cells went to apoptosis and the drugs used directed the cells to apoptosis and killed the cells.
  • the combination of mocetinostat and capecitabine appears to be able to significantly inhibit the growth of triple-negative breast cancer in vitro and trigger apoptosis pathways even at very low concentrations.

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Abstract

The present invention relates to a combined drug for use in the treatment of triple negative breast cancer (TNBC). This combined drug provides low-dose, fast and effective treatment for breast cancer. Said combined drug has a synergistic effect and provides an effective treatment with reduced side effects.

Description

DESCRIPTION A COMBINED DRUG FOR THE TREATMENT OF TRIPLE NEGATIVE BREAST CANCER Technical Field of the Invention The present invention relates to a combined drug with synergistic effect for use in the treatment of triple negative breast cancer (TNBC). This combined drug provides low- dose, fast and effective treatment for breast cancer. State of the Art Cancer, along with cardiovascular diseases, is one of the leading deadly diseases in the world; it is the uncontrolled or abnormal growth and proliferation of cells as a result of DNA damage in cells. Although there are many different types of cancer, most begin with the uncontrolled growth of abnormal cells and, if left untreated, can cause serious illness and even death. Since the disease is multifactorial and has many subtypes, researchers are searching for new approaches to treatment every day. According to statistics published by the International Agency for Research on Cancer (IARC), one in every five people in the world develops cancer, it is known that the incidence of breast cancer among cancer cases is one in every eight women. Breast cancer, which is one of the most common types of cancer worldwide, is also the second leading cause of death from cancer, while this statistic ranks first for women. The average age at which breast cancer is seen in women is between 40 and 50, with the risk increasing especially with age. In the current state of the art, breast cancer is treated with surgery, radiation therapy, hormone therapy, chemotherapy (drug therapy) or hormone therapy, depending on the stage of the disease, the patient's characteristics and general health. Chemotherapy, a chemical drug treatment used to destroy rapidly growing cancer cells in the body, and radiotherapy, which uses high-energy beams to kill cancer cells, are the first line of treatment for most cancer patients. Triple-negative breast cancer (TNBC) is a type of breast cancer in which three receptors, estrogen hormone receptor (ER), progesterone hormone receptor (PR) and human epidermal growth factor receptor 2 (HER2), are absent in the cell membrane [1]. TNBC, which accounts for 15% to 20% of all breast cancer cases, is characterized by aggressive tumor behavior, distant organ metastasis, and limited options for targeted therapy due to negative ER, PR and Her-2 receptors. For this reason, TNBC has a more severe profile than hormone receptor positive tumors, with higher recurrence rates and shorter life expectancy. For hormone therapies to work in breast cancer, the cells must have high levels of receptors for these hormones. Since ER and PR proteins are not present in this type of cancer cells, hormone therapy or drugs targeting HER2 cannot be used in treatment, chemotherapy is therefore becoming the main systemic treatment option. Chemotherapy, which is the most commonly used method for the treatment of breast cancer, is administered to prevent the proliferation of cancer cells, to slow down the spread of cancer cells, to control the disease, to improve the quality of life, to facilitate local treatments to be performed before surgery or radiotherapy, or to reduce disease recurrence after surgery or radiotherapy. Almost all chemotherapy drugs are distributed throughout the body via the bloodstream and reach cells that proliferate uncontrollably, killing them or preventing them from growing uncontrollably. However, while chemotherapy drugs destroy these bad cells, they also affect normal cells in the body. This causes a number of chemotherapy-related side effects in the body. The most common possible side effects of chemotherapy are fatigue, nausea, vomiting, hair loss, low blood counts, decreased immunity, mouth sores, diarrhea or constipation, darkening, peeling or redness of the skin. Adjuvant and neoadjuvant drugs used in the state of the art in breast cancer treatment include anthracyclines such as doxorubicin and epirubicin, taxanes such as paclitaxel and docetaxel, 5-fluorouracil (5-FU), capecitabine, cyclophosphamide, carboplatin. In the treatment of advanced breast cancer, drugs such as paclitaxel, docetaxel and taxanes such as albumin-bound paclitaxel, anthracyclines (doxorubicin, pegylated liposomal doxorubicin and epirubicin), platinum agents (cisplatin, carboplatin), vinorelbine, capecitabine, gemcitabine, Ixabepilone, eribulin are used. The main strategies followed in drugs intended to be used in cancer treatment are aimed at preventing growth, angiogenesis, invasion and metastasis in tumor tissues by various cellular mechanisms. In particular, classical chemotherapy involves the use of genotoxic and cytotoxic compounds that accelerate the progression of rapidly dividing tumor cells to apoptosis. In addition, new generation drug designs that target various pathways in the cell and key molecules in these pathways, inactivating specific mechanisms that may vary according to cancer type, thus enabling the destruction of tumor tissue, have also taken their place in cancer therapies. Apoptosis, one of the mechanisms that prevent cancer formation and development, is programmed cell death and is triggered by the activation of a genetically controlled self-destruction mechanism. The primary aim of apoptosis is to get rid of cells that cannot be repaired, that the body no longer needs or that are not normal. Therefore, this prevents problems that may arise in the future due to problematic cells. Apoptosis formation is prevented in tumor cells as a result of disruption of the balance of pro-apoptotic and anti-apoptotic proteins, decrease in caspase activity and disruption of death receptor signals [2]. Apoptosis mechanism is still dominant in breast cancer [3]. Epigenetics refers to the alteration of gene expression by histone protein modifications without changes in nucleotide sequence. The most important histone protein modifications are histone acetylation and deacetylation. In the current state of the art, epigenetic mechanisms are known to play a role in the initiation and progression of TNBC, and therefore the mechanisms, molecules and signalling pathways of genes that express and play a role in epigenetic regulation in carcinogenesis have attracted attention [4]. Histone deacetylase (HDAC) and histone acetylase (HAT) enzymes responsible for histone deacetylation and acetylation ensure that the epigenic system is in balance and gene transcription is carried out smoothly. The interaction of acetylated histone with DNA is reduced and gene transcription is activated by easy binding of transcription factors. Deacetylation of histone leads to the formation of condensed chromatin as a result of increased interaction with DNA. Transcription factors cannot bind to this tightly structured chromatin and gene transcription is repressed. Cancer cell formation is triggered by the suppression of gene transcription involved in the regulation of DNA replication, cell cycle and apoptosis. In relation to this situation, it has been reported that HDAC enzyme is found more in cancer cells than in normal cells. HDAC inhibitors (HDACi) have been shown to inhibit tumor growth, induce apoptosis and control cellular functions ranging from metastasis to angiogenesis in cancer cells. Furthermore, HDACi have been shown to cause significantly less cytotoxicity in normal cells [5]. Capecitabine, an antimetabolite, is a powerful chemotherapeutic drug used in the treatment of many types of cancer, especially breast cancer, and is administered orally. Capecitabine dose intervals used in the current technique vary, but are 2500 mg/2m2 per day. Capecitabine was created based on the observation of high concentrations of the enzyme thymidine phosphorylase in many human tumors. Capecitabine, which has low toxicity and is easy to administer, acts during the S phase of the cell cycle by inhibiting DNA synthesis by limiting the availability of thymidylate and inducing apoptosis in cells [9]. However, while capecitabine is effective on breast cancer cells, it also damages normal cells and causes many side effects. Some of these side effects can be listed as follows (where percentages refer to the frequency of occurrence); • skin reaction on the hands and/or soles of the feet (hand-foot syndrome; mild 60%, severe 16-17%), • diarrhea (mild 46%, severe 11%), • nausea/vomiting (mild 36%, severe 3%), • low white blood cells (neutropenia; mild 32%, severe 2%), • fatigue (mild 23%, severe 1%), • mouth sores (mild 22%, severe 1-2%), • increase in liver enzymes (20-24%), • abdominal pain (mild 10%, severe 2%), • hair loss (mild 6%, complete 0%), • anemia (anemia, low red blood cells; 3%), • thrombosis (blood clots, 2%), • increased bleeding risk, low platelets, 1%), • heart disorders. Approximately 13% of patients discontinue capecitabine treatment due to these intolerable side effects. This can lead to treatment interruptions, cancer progression and even death. Zhang et al. showed that capecitabine alone had a modest inhibitory effect on 4T1LUC cell line and 3 µg/ml capecitabine (inhibition rate 35.3%, data not shown), and in combination with Lidamycin, survival rates for cells treated for 48 hours were 63.064.7 and 23.4%, respectively [11]. Another study in the state of the art showed that the IC50 values of capecitabine in cancer cells ranged from 860 μM to 6000 μM. The IC50 values of capecitabine were as follows: HCT1162850 uM, HT291590 uM, SW620 4190 uM, HCT85957 uM, HCT155840 uM, COLO205863 uM cells for 24 hours (10). Mocetinostat is a benzamide histone deacetylase inhibitor (HDACi) that has undergone clinical trials for the treatment of various cancers, including follicular lymphoma, Hodgkin's lymphoma and acute myelogenous leukemia, and is administered orally (In the Phase II study, patients were given 85 mg and 110 mg). Mocetinostat is a class I and IV selective HDACi that has been shown to have potent and selective antiproliferative effects in various human cancer cells in pre-clinical studies [6]. Mocetinostat has been observed to be tolerable in clinical trials with advantageous pharmacokinetic and pharmacodynamic properties and promising antitumor activity in many hematological diseases [7]. Another effective strategy for the treatment of solid tumors is to combine mocetinostat with other antitumor agents [8]. Mocetinostat is often used to treat lymphoma and is known to be effective. However, side effects such as thrombocytopenia, neutropenia, anemia, fatigue, diarrhea, nausea, vomiting, anorexia, constipation and dehydration have been observed in studies in which mocetinostat was administered; pericardial effusion was observed in a few patients. In the state of the art, the use of mocetinostat alone has also resulted in patient losses depending on the treatment modality. In this case, some modifications/improvements are required to reduce the toxicity of HDACs due to their side effects [15]. In a study of the state of the art, the IC50 values of mocetinostat on colon cancer were as follows: HCT1160,29 μM, HCT150,72 μM, HT290,76 μM, DU1450,67 μM, MDA-MB231 0,61 μM, T24 0,66 μM, A549 0,9 μM, BxPc3 0,0μM, BxPc3 0,0μM Histiocytic lymphoma 0,11 μM, HL60 Promyelocytic leukemia 0,18 μM, RPMI-8226 0,15 μM, MV-4-11 0,1 μM, HMEC Breast normal epithelium 20 μM and MRHF Foreskin fibroblasts 15 μM [11]. In the state of the art, mocetinostat has also been used in combination with another antitumor. Some researchers have found that mocetinostat in combination with gemcitabine affects cell growth and induces apoptosis in LMS (Leiomyosarcoma) cells [12, 13]. Here, mocetinostat treatment was 1 uM to 5 uM in DU-145 and PC-3 cells for 72 hours and induced significant levels of apoptosis [14]. In chemotherapy, drugs can be administered alone or in combination with another drug. The single use of drugs (monotherapy) requires high concentrations (high doses) and is effective on cancer cells while damaging normal cells. Again, the continuous use of a single compound in monotherapy increases the drug resistance of cancer cells and makes them more sensitive to the drug and reduces the treatment response. Moreover, given that chemotherapy is administered periodically at regular intervals, acquired drug resistance with continued use limits the clinical utility of even the most advanced drugs. At this point, the development of new drugs is conceivable, but even in this case there is the handicap that the introduction of new drugs to the market is very costly and requires long periods of time. However, when chemotherapy drugs with known mechanisms of action on cancer cells are used together, the drugs can target multiple pathways and may be more effective on cancer cells if the appropriate combination is made. As different pathways are targeted in combination therapy to reduce proliferating cancer cells, combination therapy significantly reduces and prevents toxic effects if a suitable combination is made. The important thing here is that the drugs used in combined drug therapy have a synergistic effect. In the drug interaction formula (CDI) [(CDI= AB/(A×B); OD490nm for analyzing the synergistic inhibitory effect of drugs to be used in combination therapy, AB is as follows: The ratio of combined drug administration to the control group is used [A: ratio of single drug administration to the control group, B: ratio of single drug administration to the control group]. Here; CDI <1 indicates synergy, CDI=1 indicates additivity, and CDI >1 indicates antagonism [16]. In conclusion, combination therapy is considered as a treatment option that can limit treatment resistance, reduce toxicity and increase drug efficacy. However, finding the appropriate combination here requires detailed literature research, time-consuming experiments, preclinical analyzes and many trials. In addition, for the right combined treatment, the drugs to be used in the combined treatment should be pharmacologically compatible with each other, should not interact in a way that would cause additional side effects, and the damage to healthy cells should not be increased while increasing the effectiveness on cancerous cells. Only when all of these conditions are met and a positive synergistic effect is achieved can combined therapy be successful. Although the use of chemotherapeutic agents is indispensable in the treatment of triple-negative breast cancer, the resistance developed by cancer cells against existing drugs and therefore the decrease in efficacy is the most important factor in the decrease in the success of treatment. In addition to the resistance of cancer cells caused by the application of monotherapy, side effects also play an important role in interrupting treatment. Due to resistance to existing drugs and side effects interrupting treatment, many of the treatments fail to yield results and the process ends in death. Furthermore, while the doses of chemotherapy drugs currently used to provide effective treatment cause many side effects, the dose is not reduced to cure cancer and side effects are tolerated. It may be possible to avoid these problems by using combination therapy, but the appropriate combination of drugs can only be achieved by long studies with an unexpected synergistic effect and minimization of negative side effects. Therefore, there is a need for drugs that are more effective on cancerous cells, reduce damage to healthy cells, provide effective treatment even at low doses, and break the resistance of cancerous cells. Brief Description and Aims of the Invention The present invention relates to a combination drug with synergistic effect for use in the treatment of triple negative breast cancer (TNBC). The combination drug subject to the invention comprises mocetinostat and capecitabine. This combination drug prevents triple negative breast cancer cell proliferation by arresting the cell cycle of triple negative breast cancer cells and inducing death by apoptosis. Thus, the treatment of triple negative breast cancer is effectively realized. One aim of the invention is to provide an effective treatment for triple negative breast cancer by administering low doses of chemotherapy drugs. The dose range applied to provide an effective treatment in case mocetinostat and capecitabine in the combined drug subject to the invention are administered alone in cancer treatment is 1,625 µM, 3,125 µM, 6,25 µM, 12,5 µM or 25 µM for mocetinostat; 800 µM, 900 µM, 1000 µM, 1200 µM, 1400 µM, 1600 µM, 1700 µM, 1800 µM or 2000 µM for capecitabine. The most effective dose of the drugs in single use is 1700 µM for capecitabine and 3,125 µM for mocetinostat.However, mocetinostat is administered at a dose of 1,5 µM and capecitabine at a dose of 50 µM with the combined treatment of the present invention; although the dosages are reduced, a much more effective treatment is provided than the treatment effectiveness obtained when both drugs are administered separately with the help of the synergistic interactions of the drugs with each other. Combined treatment with capecitabine shows a high success rate compared to single treatment and an unexpected synergistic effect with the prolonged activity of the mocetinostat inhibitor in tumor tissue and its tolerability to side effects. When the combined drug of the invention is applied; while capecitabine acts as a DNA/RNA synthesis inhibitor, mocetinostat inhibits cancer cells as HDACi. In this way, cancerous cells cannot resist drugs that have different mechanisms and have a synergistic effect, and treatment is successful. Another aim of the present invention is to reduce chemotherapy drug-induced side effects during the treatment of triple negative breast cancer. In the state of the art, the side effects of the drugs administered cause the patient to discontinue the treatment or, even if the treatment is continued to the end, the patient's body cannot tolerate it due to strong side effects, resulting in death. However, the drug combination of the present invention provides effective treatment while at the same time both drugs (mocetinostat and capecitabine) are used at lower doses than when used alone. Thus, side effects that may occur due to drug are reduced and the sustainability and success rate of treatment are increased. In the present invention, due to the combined treatment with mocetinostat, a lower initial dose of capecitabine is used compared to the single use of capecitabine, thereby reducing the side effects commonly observed in the single use of capecitabine. Furthermore, the use of mocetinostat, an HDACi, in combination with an agent targeting different mechanisms (capecitabine) is more successful than monotherapy and leads to better clinical outcomes while minimizing side effects. Another aim of the present invention is to increase the efficacy on cancerous cells during the treatment of triple negative breast cancer, while reducing the impact on healthy cells. While the combination drug of the present invention comprising mocetinostat and capecitabine has a synergistic effect on cancerous cells and provides rapid treatment, they cause less damage to healthy cells than when used alone. Furthermore, the combined treatment significantly reduces and avoids the toxic effect, as different pathways are targeted to reduce the proliferating cancer cells. With the present invention, a combined drug is provided in the treatment of breast cancer, especially in the treatment of triple negative breast cancer (TNBC), which is much more effective on cancerous cells than single use, reduces damage to healthy cells, provides effective treatment with low doses and breaks the resistance of cancerous cells with the help of the combined application. Furthermore, with the present invention, since the combination of existing drugs (capecitabine and mocetinostat) is evaluated by applying combined treatment, both time and cost are saved in the treatment of triple negative breast cancer. Here, the increase in drug effectiveness in cancer treatment even at low doses and thus the successful outcome of cancer treatment is entirely due to the synergistic effect created by these two active substances. Description of the Figures Figure 1: The effect of capecitabine, mocetinostat and capecitabine+mocetinostat on 4T1 breast cancer cell viability for 48 hours (The effect of drugs on the survival rate of 4T1 cells was measured by the MTT method. Data are shown as the mean SD of three separate experiments with error bars indicating the SD. *P< 0.05, **P< 0.01, ***P<0.001, compared to untreated cells.) Figure 2: Time-dependent morphological image of 4T1 cells treated with mocetinostat, capecitabine, and the combination of the two drugs (Nikon Eclipse TS100). Figure 3: Time dependence of viability of 4T1 breast cancer cells after treatment with capecitabine, mocetinostat and capecitabine+mocetinostat Figure 4: DNA laddering image performed in an agarose gel in control and treatment groups to support apoptosis induction by capecitabine, mocetinostat and capecitabine+mocetinostat for 48 hours Figure 5: Wound healing analysis in 4T1 breast cancer cells; (1) control (without any treatment), (2) 1700 μm capecitabine, (3) 3,125 μm mocetinostat and (4) 50 μm capecitabine, 1,5 μm mocetinostat. Figure 6: Western blot analysis results of capecitabine, mocetinostat, capecitabine+mocetinostat (Here bands were quantified by densitometry and normalized to model control values, a statistical analysis of β-actin adjusted proteins was performed. Data are shown as the mean standard deviation of three separate experiments. *P<0.05, ** P<0.01, *** P<0.001) Detailed Description of the Invention The present invention relates to a combination drug with synergistic effect for use in the treatment of triple negative breast cancer (TNBC). The combination drug subject to the invention comprises mocetinostat and capecitabine. Reasons for using mocetinostat in the invention; it has multiple mechanisms of action, is active in tumor tissue for a long time, can tolerate side effects, its half-life is approximately 7 - 11 hours and it is one of the HDAC inhibitors that shows higher success in combined treatment compared to single treatment, it also shows a favorable pharmacokinetic profile with dose-dependent exposure compared to other HDAC inhibitors. The combination of mocetinostat with capecitabine allows the administration of capecitabine at a lower initial dose and reduces the side effects commonly observed when capecitabine is used alone. In the invention, various assays were performed to investigate the antitumor effects of mocetinostat and capecitabine treatment alone and the combined treatment of these two drugs on breast cancer 4T1 cells. To observe the effects of the drugs on 4T1 cells, these assays were performed by cell viability and migration assays, apoptosis analysis and Western blotting technique. The mouse breast cancer cell line 4T1 was used in the assays because it can accurately mimic the response to immune receptors and the response to targeting therapeutic agents. Stock solutions of these drugs were prepared and administered to mice to be used in the analysis to determine the properties of the combined drug subject to the present invention against triple negative breast cancer. Mocetinostat was prepared as 1 mg in 2,52 ml DMSO for a 1mM stock solution and diluted with medium. Capecitabine was prepared as 5 mg in 2,78 ml DMSO for a 5 mM stock solution and diluted with the medium. Stock solutions containing drugs were stored at -20°C until use. The drugs were administered to mice in combination, intraperitoneally. The reason for intraperitoneal administration of the combined drug is that the amount of drug administered by gavage may vary or there may be problems with gavage (such as the animal not standing still, not being able to take the drug). In addition, medium comprising 1% DMSO was used as solvent control group medium and untreated cells were used as control group. In the analyses related to the present invention; 1,625 µM, 3,125 µM, 6,25 µM, 12,5 µM or 25 µM doses were determined for mocetinostat; 800 µM, 900 µM, 1000 µM, 1200 µM, 1400 µM, 1600 µM, 1700 µM, 1800 µM or 2000 µM doses were determined for capecitabine. Capecitabine and mocetinostat doses are determined as follows respectively; 25 µM+2 µM, 30 µM +2 µM,30 µM +1,5 µM, 20 µM +2, 25 µM +1 µM, 40 µM +1,5 µM, 50 µM +1,5 µM, 100 µM +1 µM, 100 µM +2 µM, 100 µM +1,5 µM. The most effective dose of the drugs in single use is 1700 µM for capecitabine and 3,125 µM for mocetinostat. However, the combined therapy subject to the present invention has been shown to effectively treat mocetinostat at a dose of 1,5 µM and capecitabine at a dose of 50 µM. The potent inhibitory effects of capecitabine, mocetinostat, capecitabine+ mocetinostat time-dependence on 4T1 cell viability are shown in Figure 1. IC50 values obtained from MTT results were determined as 1700 μM for capecitabine, 3,125 μM for mocetinostat, 50 μM+1.5 μM (1.5 μM+50 μM) for capecitabine+mocetinostat combined treatment. Therefore, the application dosages will also be in this way. Here we investigated the cytotoxic and growth inhibitory effects of capecitabine, mocetinostat, capecitabine + mocetinostat on 4T1 cancer cells. According to the results of the analysis, the viability of 4T1 cells exposed to various concentrations of capecitabine, mocetinostat and capecitabine+mocetinostat decreased in a concentration- and time-dependent manner. This means that while the drugs have a lethal effect on cancer cells at high doses (1700 µM, 3,125µM) when used singly, the drugs have been shown to be effective on cancer cells at low doses when used in combination. Inverted microscope images of 4T1 breast cancer cells as a result of the cell morphology analysis are shown in Figure 2. Trypan blue staining is the technique used to count live cells and dead cells. While living cells cannot absorb the dye, dead cells can absorb the dye and are observed in blue. Treatment of 4T1 cells treated with capecitabine, mocetinostat, capecitabine+mocetinostat appears to cause abnormal changes such as condensation of the cell nucleus, reduction in cell density and number, reduction in cell size, and loss of cell extensions and rounded shape. These changes in 4T1 cells showed the effects of the drugs at different times and at different concentrations. Figure 3 shows the morphological characteristics of the drug-treated and control groups 24, 48, 72 and 96 hours after the 4T1 cell line was cultured. In a time- dependent manner, drug-treated cell lines have a significant reduction in cell proliferation. Dead and live cell ratios were calculated and capecitabine increased the lethal effect by 24%, 45.2%, 69.1% and 86.6%; mocetinostat increased the lethal effect by 28%, 42%, 61.5% and 77.8%; capecitabine+mocetinostat caused a 16%, 34.3%, 51.5% and 88.2% increase in lethality at 24, 48, 72 and 96 hours, respectively, compared to the control group. Here, with the combined drug administration, the number of dead cancer cells (apoptotic cell number) increased in a time-dependent manner by administering these drugs at an effective dose. One of the methods to determine apoptosis is genomic DNA fragmentation. Figure 4 shows the DNA fragmentation of 4T1 cells treated with 1700 uM capecitabine, 3,125 uM mocetinostat and 50 uM capecitabine+1.5 uM mocetinostat. DNA fragmentation was observed in a time-dependent manner with both high molecular weight DNAs. Intact DNA bands were observed in the control group treated with 0.1% DMSO. As a supporting effect, DNA laddering was also observed in drug-treated cells. The treated cells have a DNA laddering pattern. As a result of the analysis; single drugs and their combinations triggered DNA fragmentation and apoptotic pathway in 4T1 cells and a characteristic ladder pattern indicating apoptosis-mediated cell death was observed. Normally, a single band is obtained in the agarose gel, but when there are DNA breaks, it gives a cloudy, unclear image, which we call smear. With the combined application of drugs, the cells were induced to undergo apoptosis rather than the ability to proliferate, and the cells died. In the wound healing assay, 4T1 breast cancer cell migration at 24 hours, 48 hours and 72 hours after capecitabine, mocetinostat, capecitabine+mocetinostat treatment and closure of wound width at 24 hour intervals were examined and measurement results were taken and recorded in triplicate. It was observed that the migration rate of drug-treated cells was reduced compared to control groups. The average wound width of the control group was recorded as 851,7 μm at hour 0 and was completely closed at the end of the 72nd hour. At 48 hours, control was recorded as 456,05 µm, capecitabine as 866,50 µm, mocetinostat as 825,17 µm and capecitabine+mocetinostat as 856,14 µm. These results show that cell proliferation decreases and wound width increases with drug treatment in 4T1 cells over time (Figure 5). Since no drug was applied to the control group, the opening opened by the interaction between the cells, their extensions and each other was closed in a short time. With combined drug administration, this opening was opened further as the cells were affected by the drugs and the width was not closed. The cells have also lost their appendages and their ability to proliferate. The effects of capecitabine, mocetinostat and capecitabine+mocetinostat on apoptotic signaling pathway in 4T1 cells were confirmed by Western blot analysis after treatment with capecitabine 1700 uM, mocetinostat 3,125 uM and capecitabine 50uM+mosetinostat 1.5 uM for 48 hours. As a result of the analysis, it was observed that the expression of Bcl2, Hdac I, Akt, PI3K, c-myc and HDAC III proteins, which are active proteins in the apoptotic pathway, decreased significantly with the co- administration of capecitabine and mosetinostat and Bax, Cas-3, Pten, C-Parp, Cas- 7, Cas-9, p53 and C-cas9 protein expression was observed to increase significantly with capecitabine and mocetinostat treatment (significant differences: * P<0.05, ** P<0.01, ***P<0.001, Figure 6). Here, it is understood that coadministration of capecitabine and mocetinostat in 4T1 cells stimulates the apoptotic pathway by increasing the expression of caspase-3 and caspase-7 proteins involved in the intrinsic pathway. As a result of this analysis, the level changes in the proteins that are effective in the regulation of the apoptotic pathway in the combined use of these two drugs supported that the cells went to apoptosis and the drugs used directed the cells to apoptosis and killed the cells. When all analyzes are evaluated; the combination of mocetinostat and capecitabine appears to be able to significantly inhibit the growth of triple-negative breast cancer in vitro and trigger apoptosis pathways even at very low concentrations. Drug interaction formula to analyze the synergistic inhibitory effect of combined drug containing capecitabine and mocetinostat (CDI) [(CDI= AB/(A×B); optical density (OD) 490nm, AB: When using the ratio of combined drug administration to the control group, A: ratio of single drug administration to the control group, B: ratio of single drug administration to the control group; it was determined that the combined use of drugs had a synergistic effect according to the calculations made (CDI was found to be = 0,96). Since the combined drug subject to the present invention shows synergistic effect and lower drug dosages cause fewer side effects, the combined drug containing mocetinostat and capecitabine appears to be an effective chemotherapy agent against triple negative breast cancer.
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Claims

CLAIMS 1. A combined drug for use in the treatment of triple negative breast cancer, characterized in that, it comprises mocetinostat and capecitabine. 2. A combined drug according to claim 1, characterized in that, the IC50 value of mocetinostat is 1.5 μM and capecitabine is 50 μM. 3. A combined drug according to claim 1 or 2 for use in the treatment of triple- negative breast cancer, for preventing triple-negative breast cancer cell proliferation by inducing death by apoptosis in cancer cells through cell cycle arrest. 4. A combined drug to be administered in combination in the treatment of triple negative breast cancer, characterized in that, mocetinostat and capecitabine are co-administered.
PCT/TR2023/051131 2022-10-26 2023-10-17 A combined drug for the treatment of triple negative breast cancer WO2024091201A1 (en)

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HACER KAYA ÇAKIR: "In vitro anti-proliferative effect of capecitabine (Xeloda) combined with mocetinostat (MGCD0103) in 4T1 breast cancer cell line by immunoblotting", IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES, MASHHAD UNIVERSITY OF MEDICAL SCIENCE, MASHHAD, IRAN, vol. 24, no. 11, 1 November 2021 (2021-11-01), Mashhad, Iran, pages 1515 - 1522, XP093166742, ISSN: 2008-3866, DOI: 10.22038/IJBMS.2021.58393.12971 *
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