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31ЛЕЧЕНИЕ КОЛОРЕКТАЛЬНОГО РАКА И РОЛЬ ВИТАМИНА D В ЭТОМ
ПРОЦЕССЕ
Вахобов Лутфулло Ахмедов Шавкатбек Абдурахимов Абдухалим Нугманов Озодбек
Андижанский государственный медицинский институт
Колоректальный рак - опасное заболевание. Хирургия, химиотерапия, лучевая терапия и иммунотерапия играют ключевую роль в ее лечении. В настоящее время науке также известно, что существует связь между витамином D и этим заболеванием. Поэтому в этой статье мы сосредоточимся на витамине D в сочетании со всеми видами лечения.
Ключевые слова: химиотерапия, лучевая терапия, иммунотерапия.
KOLOREKTAL SARATON KASALLIGINI DAVOLASH VA BU JARAYONDA D VITAMININING AHAMIYATI
Kolorektal saraton xavfli kasallik hisoblanadi. Uni davolashda jarrohlik amaliyoti, kimyoterapiya, radiatsion terapiya va immunoterapiya asosiy o'rinni egallaydi. Shuningdek, hozirda vitamin D va bu kasallik orasida bog'liqlik bor ekanligi fanga ma'lum. Shuning uchun, ushbu maqolada barcha davolash usullari bilan birgalikda, asosan D vitaminiga e'tibor qaratamiz.
Kalit so'zlar: Kimyoterapiya, radiatsion terapiya, immunoterapiya.
TREATMENT OF COLORECTAL CANCER AND THE ROLE OF VITAMIN D IN THIS
PROCESS
Colorectal cancer is a dangerous disease. Surgery, chemotherapy, radiation therapy and immunotherapy play a key role in its treatment. It is also now known to science that there is a link between vitamin D and this disease. Therefore, in this article, along with all the treatments, we will focus mainly on vitamin D.
Keywords: Chemotherapy, radiation therapy, immunotherapy.
DOI: 10.24411/2181-0443/2020-10085
Introduction: Colorectal cancer begins when healthy cells in the lining of the colon or rectum change and grow out of control, forming a mass called a tumor. A tumor can be cancerous or benign. A cancerous tumor is malignant, meaning it can grow and spread to other parts of the body. A benign tumor means the tumor can grow but will not spread. These changes usually take years to develop. Both genetic and environmental factors can cause the changes.
According to the January 2020 edition of the American Cancer Society (ACS) colorectal cancer is the third most common cancer diagnosed in both men and women each year in the United States, excluding skin cancer. This year, an estimated 147,950 adults in the United States will be diagnosed with colorectal cancer. These numbers include 104,610 new cases of colon cancer (52,340 men and 52,270 women) and 43,340 new cases of rectal cancer (25,960 men and 17,380 women). Colorectal cancer mainly affects older adults, but there is a rising incidence in younger people (see Risk Factors and Prevention). While incidence rates dropped by 3.6% each year from 2007 to 2016 in adults age 55 and older,
they rose by 2% each year in adults under age 55. This year, colorectal cancer is estimated to be the fourth most commonly diagnosed cancer in U.S. men and women age 30 to 39. It is estimated that 53,200 deaths (28,630 men and 24,570 women) will be attributed to colorectal cancer this year. Colorectal cancer is the second leading cause of cancer death in the United States for men and women combined. It is the third leading cause of cancer death in men and the third leading cause of cancer death in women. When colorectal cancer is found early, it can often be cured. The death rate from this type of cancer in 2017 was 54% less than what it was in 1970. This is due to improvements in treatment and increased screening, which finds colorectal changes before they turn cancerous and cancer at earlier stages. However, while death rates for adults over age 55 decreased by 2.6% each year from 2008 to 2017, they increased by 1% each year in adults under age 55. Currently, there are over 1 million colorectal cancer survivors in the United States. Overall, the 5-year survival rate tells you what percent of people live at least 5 years after the cancer is found. Percent means how many out of 100. The 5-year survival rate for people with colorectal cancer is 64%. However, survival rates for colorectal cancer can vary based on several factors, particularly the stage. The 5-year survival rate of people with localized stage colorectal cancer is 90%. About 39% of patients are diagnosed at this early stage. If the cancer has spread to surrounding tissues or organs and/or the regional lymph nodes, the 5-year survival rate is 71%. If the cancer has spread to distant parts of the body, the 5-year survival rate is 14%. However, for patients who have just 1 or a few tumors that have spread from the colon or rectum to the lung or liver, surgical removal of these tumors can sometimes eliminate the cancer, which greatly improves the 5-year survival rate for these patients. Survival rates are also available for colon cancer and rectal cancer separately. For colon cancer, the overall 5-year survival rate for people is 63%. If the cancer is diagnosed at a localized stage, the survival rate is 90%. If the cancer has spread to surrounding tissues or organs and/or the regional lymph nodes, the 5-year survival rate is 71%. If colon cancer has spread to distant parts of the body, the 5-year survival rate is 14%. For rectal cancer, the overall 5-year survival rate for people is 67%. If the cancer is diagnosed at a localized stage, the survival rate is 89%. If the cancer has spread to surrounding tissues or organs and/or the regional lymph nodes, the 5-year survival rate is 71%. If the cancer has spread to distant parts of the body, the 5-year survival rate is 15%. It is important to remember that statistics on the survival rates for people with colorectal cancer are an estimate. The estimate comes from annual data based on the number of people with this cancer in the United States. Also, experts measure the survival statistics every 5 years. This means that the estimate may not show the results of better diagnosis or treatment available for less than 5 years.
Surgery. Surgery is the removal of the tumor and some surrounding healthy tissue during an operation. It is often called surgical resection. This is the most common treatment for colorectal cancer. Part of the healthy colon or rectum and nearby lymph nodes will also be removed. While both general surgeons and specialists may perform colorectal surgery, many people talk with specialists who have additional training and experience in colorectal surgery. [1] A safe pathway to offer standard high-quality surgery to colorectal cancer patients during the COVID-19 pandemic is feasible.
Radiation therapy. Radiation therapy is the use of high-energy x-rays to destroy cancer cells. It is commonly used for treating rectal cancer because this tumor tends to recur near where it originally started. A doctor who specializes in giving radiation therapy to treat cancer is called a radiation oncologist. A radiation therapy regimen, or schedule, usually consists of a specific number of treatments given over a set period of time. [2] Selective internal radiotherapy (SIRT) with yttrium-90 (Y-90)-labeled resin microspheres may have a role in consolidating the response to chemotherapy in patients with metastatic
colorectal cancer unamenable to resection after assessment of the best response to firstline chemotherapy.
Chemotherapy. Chemotherapy is the use of drugs to destroy cancer cells, usually by keeping the cancer cells from growing, dividing, and making more cells. A chemotherapy regimen, or schedule, usually consists of a specific number of cycles given over a set period of time. A patient may receive 1 drug at a time or a combination of different drugs given at the same time. Chemotherapy may be given after surgery to eliminate any remaining cancer cells. For some people with rectal cancer, the doctor will give chemotherapy and radiation therapy before surgery to reduce the size of a rectal tumor and reduce the chance of the cancer returning.
According to scientists [3]: Symptoms and complications associated with metastatic colorectal cancer (mCRC) differ by metastatic sites. In clinical practice, the differences among several distinct types of mCRC have been apparent for decades. Best survival is achieved among those for whom a combination of contemporary systemic chemotherapy and a surgical resection is possible. Respective 5-year survival rates for selected populations are nearly 60%, 40%, and 20% to 51% among those with resectable hepatic, pulmonary, and peritoneal metastases [4-14]. Peritoneal carcinomatosis from CRC (pcCRC) has been historically associated with a very poor prognosis. Studies including systemic chemotherapy and symptom-directed surgery without cytoreduction demonstrated a median survival ranging from 5.2 to 7 months in the era of fluorouracil (FU) -only treatment. A subset of patients presenting with bowel obstruction owing to peritoneal carcinomatosis have an even worse prognosis, with a median overall survival (OS) for those actively treated of approximately 3 to 4 months and a 17% 1-year survival rate [15-20]. The combination of systemic chemotherapy after aggressive cytoreduction surgery with concurrent intraperitoneal chemotherapy has demonstrated a remarkable improvement in survival for highly selected patients with pcCRC (hazard ratio [HR] = 0.55) in a prospective randomized trial and in several retrospective surgical studies. Nevertheless, there is a paucity of prospectively collected outcome data for patients with peritoneal carcinomatosis treated with systemic chemotherapy. Therefore, we characterized the clinical course of patients with pcCRC enrolled in two cooperative group prospective randomized trials of systemic chemotherapy and contrasted that with mCRC with a different metastatic pattern (non-pcCRC). We hypothesized that pcCRC is associated with worse prognosis. If pcCRC is indeed a prognostic factor for mCRC, stratification of future systemic chemotherapy trials and exploration of other modalities for pcCRC should be considered [18-22].
Immunotherapy. Immunotherapy, also called biologic therapy, is designed to boost the body's natural defenses to fight the cancer. It uses materials made either by the body or in a laboratory to improve, target, or restore immune system function.
Checkpoint inhibitors are an important type of immunotherapy used to treat colorectal cancer. Learn more about the basics of immunotherapy.
According to a group of scientists [23]: Colorectal cancer is a third-most common malignant tumor worldwide, and it is imperative to find out more effective and safer strategies for colorectal cancer treatment. Owing to its high therapeutic efficacy, immunotherapy has been approved for the treatment of diverse cancers (e.g., melonoma, colorectal cancer) in the past several years. Among them, anti-programmed cell death protein-1 (anti-PD-1) immunotherapy has been shown to exhibit high therapeutic efficacy to those advanced and metastasis colorectal cancer patients featured with mismatch repair defects (dMMR) and microsatellite instability-high (MSI-H). However, such anti-PD-1 therapy only shows limited therapeutic efficacy to the majority of colorectal cancer patients ascribing to the immunosuppressive tumor microenvironment (TME). For instance, the high expression of indoleamine 2,3-dioxygenase 1 (IDO1) within the tumor
can promote the induction of immunosuppressive regulatory T cells (Tregs) and in the meanwhile arrest the growth of infiltrating T cells in G1 phase by catalyzing the essential tryptophan to kynurenine. Therefore, IDO1 has been selected as a new target for developing new immunotherapeutics. To date, several different IDO1 inhibitors have been synthesized and shown to be an efficient immune modulator to synergize with other therapies (e.g., chemotherapy) by reversing the immunosuppressive TME. However, resulted from the limited aqueous solubility and bioavailability of those commercially available IDO inhibitors, it is urgent to develop suitable delivery carriers to enable efficient tumor targeted delivery of those IDO inhibitors.
Motivated by the high passive tumor homing ability of nanodrug delivery systems, various oxaliplatin based nanodrugs have been prepared and exhibited significantly improved tumor targeted delivery efficacy. Liposomal oxaliplatin, prepared by encapsulating oxaliplatin with biocompatible lipids, has been demonstrated to show greatly diminished side effects compared to free oxaliplatin in a phase I clinical trial. In addition, preparation of oxaliplatin prodrugs has been shown to be another reasonable way to minimize the side effects of original oxaliplatin because these prodrugs only can be reduced to the toxic oxaliplatin inside the highly reductive cytosol of cancer cells. Furthermore, as the introduction of additional ligands in these oxaliplatin prodrugs, they are shown to be more easily formulated into various nanodrugs. As oxaliplatin can cause immunogenic cell death (ICD) for a large span of cancer cells to efficiently prime the host's immune system, the combination use of oxaliplatin with IDO1 inhibitors has shown to enable remarkably improved therapeutic efficacy. Motivated by the versatile drug loading capacity, long blood circulation time and excellent biocompatibility of liposomal nanocarriers, herein, we constructed a bifunctional liposomal nanomedicine via the self-assembly of both oxaliplatin and NLG919 prodrugs, together with commercial lipids including 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), cholesterol and polyethylene glycol-5000 conjugated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-mPEG5k). It was shown that the encapsulation efficiencies of oxaliplatin prodrug conjugated DSPE (Oxa(IV)- DSPE) and dodecanoyl chloride conjugated NLG919 (aNLG) within the obtained aNLG/Oxa(IV)-Lip liposomes were 93.03% and 40.87%, respectively. Such aNLG/Oxa(IV)-Lip could induce effective ICD of murine CT26 cancer cells, as convinced by enhanced release of damage associated molecular patterns (DAMPs) including calreticulin (CRT), high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP). Moreover, aNLG/Oxa(IV)-Lip was also able to effectively inhibit IDO1 mediated conversion of tryptophan (Trp) to immunosuppressive kynurenine (Kyn). Upon intravenous injection, aNLG/Oxa(IV)-Lip could gradually accumulate in the tumor, where it could not only promote the release of CRT and HMGB1, but also enable efficient reversion of immunosuppressive tumor microenvironment into immunosupportive one featured in enhanced maturation of dendritic cells (DCs), infiltration of CD8+ T cells, and the secretion of cytotoxic cytokines. As a result, such bifunctional aNLG/Oxa(IV)-Lip could synergistically suppress the growth of both subcutaneous and orthotopic mouse CT26 tumors via combined chemo-immunotherapy. This work highlights a new liposomal nanomedicine formulation for effective treatment of colorectal cancer, and promising for clinical translation attributing to its well-defined composition, tunable drug loading capacity and excellent biocompatibility.
In summary, they prepared a type of immunomodulatable liposomal nanomedicine with amphiphilic Oxa(IV) prodrug conjugated phospholipids, hydrophobic alkylated NLG919, and other commercial lipids via the classical liposome prepration method.
Vitamin D and colorectal cancer. Colorectal cancer (CRC) results from the accumulation of epigenetic and genetic changes in colon cells during neoplasic transformation, which the activation of Wingless (Wnt) signaling pathway is a common
mechanism for CRC initiation. The Wnt pathway is mainly regulated by Wnt antagonists, as secreted frizzled-related protein (SFRP) family. Indeed, SFRP2 is proposed as a noninvasive biomarker for CRC diagnosis. Vitamin D also antagonizes Wnt signaling in colon cancers cells. Several studies showed that vitamin D was able to alter DNA methylation [24]. Their results showed that higher circulating vitamin D is associated with low SFRP2 promoter methylation. Therefore, their results could suggest that vitamin D may have an epigenetic effect on DNA methylation. Finally, higher vitamin D could contribute to an improvement response to neoadjuvant treatment.
Higher circulating 25-hydroxyvitamin-D [25] (OH)D] concentrations are consistently inversely associated with colorectal cancer (CRC) risk in observational studies. However, it is unknown whether this association depends on the functional GC-rs4588*A (Thr436Lys) variant encoding the vitamin D-binding protein-2 (DBP2) isoform, which may affect vitamin D status and bioavailability. Their [25] results suggest that the 25(OH)D-CRC association may differ by DBP isoform, and those with a DBP2-encoding genotypeElinked to vitamin D insufficiency may particularly benefit from adequate 25(OH)D for CRC prevention.
Conclusion: In conclusion, this article presents the most modern and best ideas to be used in the treatment of colorectal cancer, the results of research. We hope that this article will serve as a basis for further research.
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