Guidance for medical personnel on the safe handling of anticancer drugs. Cytotoxic agents
Catad_tema Breast cancer - articles
New principles of cytotoxic systemic therapy for primary breast cancer
L. Norton
Weill Medical College of Cornell University,
Department clinical oncology Sloan-Kettering Cancer Center, New York, USA
More than forty years ago, trials of alkylating agents were first initiated, and since then significant progress has been made in the field of systemic therapy for breast cancer (BC). Based on two most important achievements, namely the use hormonal methods treatment and use of trastuzumab, lies the paradigm of targeting molecules associated with the malignant phenotype. The first of these approaches involves the use of drugs that bind to the estrogen receptor (an example of such a drug is tamoxifen) or agents that prevent the receptor from interacting with endogenous estrogen (for example, aromatase inhibitors). The second approach involves using a monoclonal antibody to inactivate the HER-2 receptor, which is sometimes (25% of the time) overexpressed in breast tumors. HER-2, a member of the epidermal growth factor receptor family, participates in the tyrosine kinase cascade that begins at cell membrane and provides transcriptional control of various molecules that have regulatory effects on growth. However, there are numerous other targets of anticancer drugs in the biology of malignant growth, despite the fact that most of these drugs are also active against normally dividing cells. For example, TAXOL targets microtubules, which are necessary for many normal processes in organism. Why drugs acting on such universal processes have a specific anticancer effect is one of the greatest mysteries modern biology.
It is generally accepted that, with the exception of two specific examples, hormone therapy and the use of trastuzumab, most of our successes in the field of treatment oncological diseases based on an empirical approach, and not at all on the rational creation of drugs. It seems to me that this point of view is a typical example of a distortion of history and is unfair to our predecessors in the field of medical oncology. Approaches based on extrapolation of results obtained in other fields of knowledge are not a new concept, despite the fact that the scientific arsenal has been enormously enriched over the past few years. Extrapolation and clinical studies always try to use the highest level of scientific understanding of their time, even if by modern standards this understanding appears primitive. Moreover, it is safe to say that today's science will also seem primitive in the near future, but this does not mean that we are unreasonable in our scientific research. We should be encouraged by the realization that much progress has been made without a satisfactory understanding of biology. Our capabilities will continually expand and our optimism will grow as our knowledge of the regulation of mitosis, apoptosis, stromal and vascular biology, immune mechanisms, and thousands of other issues of enormous potential importance expands.
To date, we have established a number of key facts regarding systemic cytotoxic therapy:
- Chemotherapy can kill cancer cells
- Most cells are resistant to certain drugs
- Some cells are resistant to all currently available drugs used in therapeutic doses
- Combination chemotherapy increases remission duration
- Sequential chemotherapy improves the overall length of time the disease is controlled
- Going into remission means controlling disease symptoms and improving survival
- The use of adjuvant therapy increases disease-free interval and overall survival
- In conditions clinical application The dose-response curve of a drug is not necessarily strictly ascending.
- How exactly does chemotherapy work?
- How can we predict remission?
- What is the optimal treatment regimen (doses and administration schedule)?
- How can we ensure maximum effectiveness with minimal toxicity?
- How do we the best way can we apply our knowledge of tumor and host biology to optimize clinical outcomes?
The study showed that the overall remission rate in the AC group was 42%, and in the AC + trastuzumab group it was 56% (P = 0.0197). In the case of TAXOL, the corresponding figures increased from 17% to 41% (P = 0.0002). In patients receiving AC plus trastuzumab (n=143), the mean (median) time to disease progression was 7.8 months, while for patients treated with the AC protocol alone it was 6.1 months (n=138) (P=0.0004). For the TAXOL arm, the benefit associated with trastuzumab was even more impressive: 6.9 months (n=92) versus 3.0 (n=96) (P=0.0001). (The short duration of time to disease progression in the group receiving TAXOL alone is likely due to the very poor prognosis of patients in this group. This makes the results obtained in the group of patients receiving TAXOL in combination with trastuzumab, in whom the prognosis was equally poor, even more more interesting). The time to treatment failure also increased with the addition of trastuzumab, from 5.6 to 7.2 months for AC and from 2.9 to 5.8 months for TAXOL; As follows from the data obtained, this led to a highly significant increase in overall survival by approximately 25%. When treated with the combination of trastuzumab/doxorubicin/cyclophosphamide, cardiotoxic complications were observed in 27% of patients (compared to 7% who received AC alone). For TAXOL, the corresponding figures were 12% in combination with trastuzumab and 1% in the case of monotherapy; It should be remembered that almost all patients in the trial group who received TAXOL had previously received anthracycline treatment as an adjuvant therapy. The cardiotoxicity of TAXOL in combination with trastuzumab, which is significantly less pronounced than the cardiotoxicity of the anthracycline + trastuzumab combination, may reflect a “memory” effect of previously occurring subclinical toxicity of the anthracycline.
These results indicate significant progress in the treatment of patients with metastatic breast cancer with overexpression of HER-2, but their significance does not stop there. Conclusions from the data obtained are important for creating more advanced forms of treatment in the future. This trial demonstrates the importance of combined targeting of targets, in this case microtubulin and HER-2. In addition, targeting membrane-bound tyrosine kinases from the epidermal growth factor receptor family is only one possible approach to therapeutically targeting mitotic signaling. For example, a universal mechanism for controlling cell growth is the pathway determined by the ras gene. For the functioning of this gene it protein product must be processed in the cell by an enzyme called farnesyl transferase. Many tumors (about 30%) have an abnormal Ras gene, which allows tumor cells to evade the normal mechanisms that control growth. To treat these tumors, a class of drugs called farnesyl transferase inhibitors (FTIs) have been developed, which are remarkably nontoxic to normal cells. However, breast tumors only in some cases have abnormal Ras, so it was previously assumed that in most cases IFTs would not have antitumor activity. However, scientists at Sloan-Kettering Cancer Center have shown that, contrary to expectations, IFT does cause breast cancer cell death despite the presence of normal Ras, possibly because IFT increases p21 and p53. Of even greater interest is the pronounced synergy between IFT and TAXOL and antibodies to HER-2 and epidermal growth factor receptors. This is clearly an area of outstanding interest and clinical studies are currently being planned.
Although the processes of regulation of mitosis still remain the main target of cytotoxic drug therapy, recent advances in vaccine technology may herald an era of effective immunotherapy. IN Oncology center Sloan-Kettering, for example, we immunized three groups of breast cancer patients classified as high-risk with three different MUC1 peptides containing 30-32 amino acids (1_ repeats of the 20-amino acid repeat of MUC1). All patients had a serological response to the peptides used for immunization, and antibodies were detected in high titers, although the resulting sera reacted only minimally or not at all with MUC1 fixed on cancer cells. It has recently become clear that glycosylation of the serine and threonine residues in MUC1 can alter or even increase the antigenicity of MUC1, and it has been possible to obtain glycosylated MUC1 glycopeptides in sufficient quantities for clinical vaccination trials currently underway. Many other targets exist for a similar immunological attack on breast cancer cells, and we plan to begin a multicenter trial of a multivalent vaccine before the end of 2000.
We can expect that targeted immunotherapies will be most valuable within a cytoreduction-based approach, which optimally utilizes the latest knowledge regarding the regulation of mitosis and its disorders. Respectively, modern research in Clinical Oncology are targeting some of the biggest “unknown areas” as we explore the cellular mechanisms that are so conveniently damaged by old and new forms of drug manipulation of mitosis. The knowledge gained from such research will not only help us create more effective medications, but also choose the most effective forms treatments based on the rational construction of a cancer cell profile, as, for example, in the case of determining HER-2 and related molecules. These approaches, combined with advances in our understanding of tumor growth kinetics, will certainly lead to improved breast cancer therapy, which is our ultimate goal.
Lesson 28
BLEEDING PROMOTIONS
ANTI-TUMOR DRUGS
The formed elements of blood are short-lived:
Red blood cells live 3 – 4 months
Granulocytes – several days (up to a week)
Platelets – 7-12 days
Proliferation and primary differentiation of stem cells towards erythro- and leukopoiesis are regulated by tissue-specific hormones - protein growth factors
The main stimulator that triggers the differentiation and proliferation of erythropoiesis cells is the glycoprotein hormone of the kidneys - erythropoietin.
Antianemic drugs
Iron deficiency or hypochromic anemia
This is one of the most common forms of anemia
Causes of iron deficiency in the body
A. Increased needs
1. In newborns, especially premature ones
2. In children during periods of rapid growth
3. In women during pregnancy and lactation
4. Extreme conditions for the body
Long stay in the highlands
B. Inadequate absorption
5. After gastrectomy
6. For severe diseases of the small intestine that lead to the syndrome
generalized malabsorption (a combination of hypovitaminosis, anemia and
hypoproteinemia caused by malabsorption in the small intestine)
Menstrual bleeding
Asymptomatic bleeding in the gastrointestinal tract
Massive blood loss if compensation for the BCC deficit was carried out
plasma substitutes
The main treatment for hypochromic anemia is iron supplements.
The daily requirement for iron in food for a healthy adult is approximately 0.2 mg/kg (considering that approximately 5–10% of iron is resorbed). It is 3 times higher in young children and 5 times higher in infants
It is children who often develop iron deficiency with
Slowing growth and development,
Pale skin,
Lethargy,
Weakness
dizzy
Fainting
Distribution of iron in the body
1. Up to 70% of iron (3 - 4 grams) is part of hemoglobin
2. Approximately 10 – 20% of iron is deposited in the form of ferritin and hemosiderin
3. Approximately 10% of iron is part of muscle protein - myoglobin
4. Approximately 1% of iron is contained in the respiratory enzymes cytochromes and other enzymes,
and also in combination with the blood transport protein – transferrin
Sources of iron and its pharmacokinetics
1. Many foods are sources of iron:
Mostly leafy vegetables
Citrus
To a lesser extent - other vegetables and fruits
Cereals
Meat and fish
2. Iron absorption is improved by organic acids
Ascorbic
Apple
Lemon
Fumarovaya
3. Impair absorption (forming precipitated and non-resorbable compounds with iron)
Calcium salts
Phosphates
Tetracyclines
4. Iron absorption occurs only! in the duodenum and in the upper jejunum
5. Only the reduced (ferrous) form of iron (Fe2+) is absorbed
into divalent and only then is resorbed into the blood
7. Ferrous ferrous diffuses into the blood, where it binds to the transport protein
plasma - transferrin and along with it is supplied to consumer organs
8. Part of the food iron unclaimed by transferrin is bound in the cells of the intestinal mucosa
with a special protein apoferritin and is deposited in the form of ferritin
9. As needed, apoferritin donates iron to transferrin, but mainly! protects
the body from excess iron (the so-called ferritin curtain)
10. The main depot of ferrous iron in the body is:
Spleen
11. As needed, it is again taken up by transferrin and delivered to the tissues in need
and above all to the bone marrow
12. There is no special mechanism for removing iron from the body.
13. Small amounts of iron are lost to intestinal epithelial cells
14. Trace amounts of iron are excreted in bile, urine and sweat.
15. All of the above losses amount to no more than 1 mg of iron per day
16. Since the body’s ability to excrete iron is limited, regulation of the level
iron is achieved by changing the intestinal absorption of iron depending on
body needs
Treatment with iron supplements
Treatment with iron supplements is carried out mainly orally.
Previously popular preparations of ferric iron, its salts with phytic acid and glycerophosphate are today considered irrational
At the moment, only ferrous iron salts are practically used:
1. Sulfate – Ferrogradumet, Tardiferon, Ferroplex
2. Gluconate – Ferronal
3. Chloride – Hemopher
4. Fumarate – Heferol
Therapy for hypochromic anemia continues for 3–6 months, and the first signs of improvement with rational treatment appear after 5–7 days (increase in the number of reticulocytes in the blood). The amount of hemoglobin begins to increase only after 2 - 3 weeks and reaches normal after 1 - 3 months.
To the treatment plan also includes:
1. Good nutrition
2. Providing the body with vitamins C, B6, Bc, B1, etc.
3. Providing the body with microelements – Cu, Co, Zn
Dosing is carried out based on the following considerations:
1. In case of hypochromic anemia, to build hemoglobin, you need to supply 50 - 100 mg of elemental
ferrous iron per day
2. On average, 25% of iron taken orally is absorbed (sulfate and fumarate are better, gluconate is worse)
3. Different iron preparations contain different amounts of ferrous iron (usually from 40 to 70-100
Many hematologists are skeptical to long-acting iron preparations coated with an acid-resistant coating, since such dosage forms release iron below the physiological zone of resorption and its degree decreases.
Parenteral therapy Iron supplementation is carried out only in cases of proven iron deficiency when patients are unable to tolerate or absorb oral medications, as well as in patients with chronic blood loss, when oral administration is not enough. It's about O:
Patients after resection of the stomach and duodenum
Patients with inflammatory diseases of the proximal small intestine
Patients with malabsorption
Patients with significant chronic blood loss from injuries that cannot be
resect (for example, with hereditary hemorrhagic telangiectosis - a form
angiectasia is a local dilation of capillaries and small vessels, often on the skin of the face.
The disease is polyetiological, sometimes drug-determined, for example, with
use of corticosteroids)
Side effects of iron therapy
For enteral use
1. Nausea
2. Discomfort in the epigastric region
3. Cramping pain in the abdomen
6. Black feces
For parenteral use
1. Local soreness
2. Phlebitis
3. Brown staining of tissues at the injection site
4. Headache
5. Dizziness
6. Fever
7. Nausea
9. Arthralgia
10. Pain in the back and joints
11. Hives
12. Bronchospasm
13. Tachycardia
14. Allergic reactions
15. Sometimes – anaphylactic shock
Acute poisoning with iron preparations
Occurs almost exclusively in children. If adults tolerate large doses oral iron supplements without serious consequences, then in children taking just 10 tablets can be fatal. Therefore, all iron supplements should be kept in tightly closed containers away from children.
Large amounts of oral iron can cause gastroenteritis with bloody diarrhea followed by shortness of breath, altered consciousness, and shock. There is often some improvement, but severe metabolic acidosis, coma, and death may follow.
Chronic poisoning with iron preparations
Chronic iron toxicity or overload is also known as hemochromatosis or hemosiderosis.
It is characterized by the deposition of excess iron in the heart, liver, pancreas and other organs and tissues, which can lead to organ failure and death.
To remove excess iron, complexons are used that strongly bind to iron and accelerate its release by 4-5 times - deferoxamine
Megaloblastic or hyperchromic anemia
MBAs are caused by vitamin B12 deficiency and (less commonly) folic acid deficiency.
This type of anemia may result from:
1. Primary loss internal factor"gastric mucosa - Addison-Birmer disease
2. Total gastrectomy for cancer or ulcers
3. Atrophic processes in the mucous membrane of the stomach and duodenum
4. Broad tapeworm infestations
5. Eating exclusively plant foods
6. Use of cytostatic agents - antimetabolites, as well as alkylating agents
Mechanism of violation
Since the main defect in these vitamin deficiencies is a violation of DNA synthesis, cell division is suppressed while protein and RNA synthesis is preserved.
This results in the formation of large (macrocytic) red blood cells with a high RNA:DNA ratio.
Such red blood cells are abnormal and extremely sensitive to destructive consequences.
In addition, their ability to carry oxygen is sharply reduced.
A morphological examination of the bone marrow reveals an abundance of cells, an increase in the number of abnormal red blood cell precursors (megaloblasts), but an extremely small number of cells that mature into normal red blood cells.
Vitamins B 12 and B With
Vitamin B12 consists of a porphyrin-like ring with a central cobalt atom bound to a nucleotide
Vitamin B12 food contains:
4. Dairy products
However, the main source is microbial synthesis, since this vitamin is not synthesized by plants or animals.
Sometimes vitamin B12 is called “ external factor“Castla is in contrast to intrinsic factor, which is secreted in the stomach.
Folic acid consists of a pteridine heterocycle, PABA and glutamic acid.
Richest sources:
4. Green vegetables
Pharmacokinetics B 12 and B With
With a normal mixed diet, a person receives 5–20 mcg of vitamin B12 per day, of which 1–5 mcg is normally absorbed with a daily requirement of 2 mcg.
Vit.B12 is absorbed in physiological quantities only in the presence of intrinsic Castle factor, a glycoprotein with a molecular weight of about 50 thousand daltons, which is secreted by the parietal cells of the stomach lining.
In combination with vitamin B12, released from food in the stomach and duodenum, this factor is absorbed in the distal cecum through a highly specific receptor transport mechanism.
After absorption, vitamin B12 bound to the plasma glycoprotein transcobalamin II is transported into the cell.
Excess vitamin B12 is deposited in the liver (up to 300 - 5000 mcg).
Only trace amounts are lost in urine and feces.
Since the body’s normal needs are about 2 mcg, it will take a full 5 years for the body to use up all of its reserves if vitamin B12 absorption stops and MBA begins.
The daily requirement for vit.Vs is about 0.2 mg, but pregnant and lactating women require double amounts.
In the cells of the intestinal mucosa, reductase restores vit.Bc into tetrahydrofolic acid, and if this process is disrupted, absorption suffers.
Usually, the absorption of vitamin B occurs in the small intestine quickly and almost completely.
The body of an adult contains 7–12 mg of folate, of which 50–70% is in the liver. This reserve is enough for 3 – 5 months with a complete cessation of the supply of vitamin from the outside.
Physiological role B 12 and B With
In cells, vitamin B12 controls two very important reactions:
1. Conversion of methylmalonic acid to succinic acid
2. Conversion of homocysteine to methionine (this reaction is associated with vit.Bc)
Violation of the first reaction leads to the formation and incorporation of abnormal fatty acids into cell membranes with damage to their function and the process of formation of myelin sheaths nerve fibers, primarily in the central nervous system.
The result is numerous progressive neurological disorders
Violation of the second reaction is accompanied by the accumulation of homocysteine and the removal of vit.Bc from its circulation in biochemical reactions DNA synthesis
The role of tetrahydrofolic acid in biochemical reactions is:
1. Transfer of one-carbon radicals (methyl, formate, etc.) to the nitrogen atom of amino acids and other compounds, that is, participation in the assembly of purine and pyrimidine bases of RNA, DNA and macroergs.
Of particular importance is the synthesis (together with vitamin B12) of thymidine nucleotide, which is deficient for cells and limits the rate of DNA replication and cell division.
The cofactors formed by tetrahydrofolic acid are different in these processes:
In the synthesis of purine bases N 10 -formed-THF is a cofactor:
- for enzymephosphoribosylglycinamide formyltransferase, carrying out the transformation FR-glycinamide in FR-formylglycinamide , and
- for enzymeFR-aminoimidazole carboxamide-formyltransferase, transforming FR-5-amino-4-imidazolecarboxamide in FR-5-formamidoimidazole-4-carboxamide
In the synthesis of pyrimidine bases THFasN 5 , N 10 -methylene-THFis a cofactorthymidylate synthasein synthesis dTMP from dUMP .
In the synthesis of methionine from homocysteine THFasN 5 -methyl-THFis a cofactor for the enzyme5-methyltetrahydrofolatehomocysteine-S-methyltransferase.
2. Participation in the exchange of histidine, serine, glycine, glutamic acid, and together with vitamin B12 – in the synthesis of methionine (indirectly in the protection of the vascular endothelium at the early stage of sclerotic changes)
3. The specific role of the reducing agent in the first stages of the synthesis of CA and serotonin.
Treatment of megaloblastic anemias
The dosage and treatment regimen for vitamin B12 is determined by a hematologist.
Typically, vitamin B12 or (which is better) hydroxocobalamin is injected into the muscle in high doses (100 - 1000 mcg) (in order to restore its depot in the liver) daily or every other day for 1 - 2 weeks. Then maintenance therapy is carried out once a month throughout life.
Erythropoiesis responds to treatment already in the first two days, reticulocytes appear in the blood on days 2–3, their number reaches a maximum by days 5–10, the nature and content of hemoglobin in them returns to normal after 1–2 months
Vitamin B12 is well tolerated even in high doses, does not cause adverse reactions and complications
Clinics often encounter secondary vitamin B deficiency in the treatment of concomitant diseases:
1. Some anticonvulsants (diphenine, hexamidine, phenobarbital, etc.)
2. Isoniazid
3. Hormonal contraceptives
4. Hemolytic anemia
5. Leukemia
6. Oncological diseases
7. Alcoholism
Since folate is well absorbed, the deficiency can be covered by oral administration of 10 - 20 mg per day.
The response to treatment for anemia is rapid:
Hemoglobin levels begin to increase already in the first week of treatment.
Complete correction of anemia, including BC-dependent MBA, is achieved within
12 months
Sun is well tolerated even in excess doses, allergic reactions are observed only in very rare cases
Hypoplastic (aplastic) anemia and pancytonemia
This pathology is associated with damage to the initial (basal) mechanisms of hematopoiesis:
Or at the level of stem cells - in this case, all branches of hematopoiesis suffer (pancytopenia) and the content of red blood cells, leukocytes and platelets in the blood decreases.
Or in the first stages of erythropoiesis - in this case, predominantly the erythroid branch suffers with deep (aplastic form) or less deep (hypoplastic form) suppression of erythropoiesis.
These disorders pose a threat to the patient's life and are difficult to treat. There are quite a few reasons for such violations:
I. Direct effect on bone marrow
Industrial poisons (eg benzene)
Bacterial toxins
Some drugs (chloramphenicol, khingamine, quinine, PAS, difenin, hexamedine, butadione,
gold preparations, mercury preparations, arsenic preparations, many antitumor
funds, etc.)
II. Damage can be caused by ionizing radiation and radionucleotides (especially the radioactive isotope strontium)
III. In many cases, the mechanism appears to be more complex and involves toxic-allergic reactions (“autoimmune aggression”)
Almost not amenable treatment of aplastic anemia and practically incurable aplastic pancytopenia (panmyelophthisis)
Some success in the treatment of hypoplastic anemia is associated with the discovery of hematopoietic growth factors
Erythropoietin is a glycopeptide hormone of the kidneys (mm > 30 thousand daltons) - produced by the interstitial cells of the tubules and secreted as a corrector of erythropoiesis in response to hypoxia of various origins:
1. Blood loss
2. Circulatory disorders
3. Drop in hemoglobin levels
4. Deficiency of iron and red blood cell count
5. Severe stress (cells have beta-2-AR on their membranes)
The degree of autoregulation of erythropoiesis is quite high, but it is sharply disrupted with parallel kidney diseases. It is then that erythropoietin preparations have the greatest therapeutic effect.
Erythropoiesis reacts weaker to the administration of erythropoietin in patients with healthy kidneys - they also have a lot of their own hormone. Nevertheless, there is a therapeutic effect, but large doses are required to obtain it.
Erythropoietin preparations and treatment
The industry produces a human recombinant hormone - epoetin-alpha = eprex.
Epoetin alfa = eprex is dosed in units and administered subcutaneously or intravenously.
T 0.5 about 4 – 13 hours
The regimen of use is determined by a hematologist based on the results of laboratory control.
Treatment duration is usually about 3 weeks
Indications for use of epoetin alfa=eprex
1. Anemia accompanying chronic kidney disease
2. Hypo- and aplastic anemia
3. Malignant bone marrow diseases
4. In premature babies
5. Anemia accompanying treatment of AIDS with zidovudine, etc.
6. For cancer
7. For sepsis
8. Iron overload
With a positive reaction to the drug, the increase in the number of reticulocytes in the blood begins on the 10th day, and in hemoglobin and hematocrit – on the 2nd – 6th week of treatment
Lack of response to the hormone is most often due to: 1) insufficient dosage, 2) iron deficiency, 3) vitamin B deficiency.
Epoetin alfa=Eprex is well tolerated. If treatment is too forced and insufficient control is possible, there may be an increase in blood pressure (caution with hypertension) and a tendency to thrombus formation
In the future, it is possible to use colony-stimulating factor of stem cells, which stimulate proliferation at the earliest stage of hematopoiesis, for aplastic anemia and pancytopenia.
In the initial forms of aplastic anemia and its moderately severe course (hypoplastic form), treatment with anabolic steroids (Nerobol, etc.) may be successful. Anabolic steroid used in long courses (10–20 months) with daily administration.
Any method of treating aplastic anemia requires mandatory provision of the process with a full range of vitamins, microelements and amino acids. IN urgently and in the course of pharmacotherapy, when the patient’s condition worsens, they resort to blood transfusions, red blood cells, and antibiotics are used according to indications.
Hemolytic anemia
Intravascular and bone marrow hemolysis is most often caused by LV.
In its acute form, hemolytic anemia can be life-threatening, as it leads to increasing oxygen starvation and a drop in renal function with severe oliguria (decrease in urination to 800 - 300 ml of urine per day) and the development of uremia (self-poisoning of the body due to retention of nitrogenous wastes in the blood, acidosis , disturbances of electrolyte, water and osmotic balance).
The immediate cause of hemolysis is damage to red blood cell membranes as a result of:
1. Direct cytotoxic effect of xenobiotics, including drugs
Membrane lipid oxidation
The formation of methemoglobin is a derivative of Hb (MtHb), which lacks the ability to carry oxygen
Enzyme inhibition
Most often these side effects cause:
1) Aminazine and its analogues
2) Salicylates
3) Sulfonamides
4) Paracetamol
6) Barbiturates, etc.
2. Binding of drugs to erythrocyte membranes, resulting in a change in the antigenic properties of the membrane surface.
She turns out to be “stranger” to immune system and the latter responds by producing antibodies that lyse altered red blood cells
This mechanism of hemolysis is characteristic of 7) penicillins, 8) cephalosporins, 9) methyldopa, etc.
3. Binding of drugs to plasma proteins, which, when modified, also acquire antigenic properties.
In response to this, the immune system produces antibodies that bind into a drug-protein-antibody complex and activate complement (an immunological system consisting of 18 various proteins blood serum) and as a result, the membranes of red blood cells are damaged.
It is believed that at some stage of damage to erythrocyte membranes, aggressive agents are included in the pathological free radicals, which oxidize membrane lipids and dramatically disrupt their functions, including the property of semi-permeability.
Therefore, it is considered advisable to immediately prescribe antioxidants in sufficient doses. Vitamin E, acetate of which is usually used oil solution taken orally in gradually decreasing doses, starting from 300–500 mg/day at the beginning of therapy and until hemolysis stops.
The drug that caused hemolysis is naturally discontinued.
In case of acute increasing hemolysis, they resort to intravenous administration of glucocorticoids (prednisolone, etc.) and infusion of red blood cells.
Monitoring and maintaining renal function plays an important role; in severe cases, hemodialysis is used
DRUGS AFFECTING LEUKOPOIESIS
Pathogenesis
Damage to the myeloid branch of hematopoiesis occurs for the same reasons as the erythroid branch, but with a greater tropism for white blood cells of poisons, toxic-allergic factors, radiation, etc.
Many drugs suppress leukopoiesis in one way or another
Pyrazolones – analgin, butadione
Sulfonamides, including antidiabetic and diuretics of this structure
Antiepileptics and many others
Often leukopoiesis is disrupted with erythropoiesis, apparently as a result primary action poisons on bone marrow stem cells (pancytopenia), up to the extreme aplastic form (panmyelophthisis) with a poor prognosis
The term “leukopenia” is more general (essentially referring to the impairment of white blood cell production in general).
If we mean predominantly inhibition of neutrophils (granulocytes), we speak of neutropenia, granulocytopenia or agranulocytosis. In medical usage, all these terms are used interchangeably.
Often the first recorded manifestations of leukopenia are:
Agranulocytic tonsillitis
Persistent pustular lesions of the skin and its appendages
The result of a joint or partial disorder in the production of megakaryocytes is thrombocytopenia with microhemorrhages in skin and mucous membranes with slight pressure or bruises.
To treat severe forms of leukopenia, blood, leukocyte and platelet transfusions are used as temporary measures.
Pharmacotherapy with non-steroidal anabolic steroids - methyluracil, pentoxyl - as well as certain drugs with an unclear mechanism of action - leukogen, etc. - is the most accessible, but is effective only for moderate forms of leukopenia
Therapy with recombinant colony-stimulating factor (CSF) preparations, which are produced from:
Granulocyte CSF=Neurogen=Granocyte
Granulocyte-macrophage CSF=Leucomax
These are physiological natural cytokines of a polypeptide nature (mm of 5 thousand Daltons or more), which are produced by cells of the bone marrow, vascular endothelium, lymphocytes and, apparently, other tissues.
Indications for use of Leukomax and Leukogen
1. Severe disorders of myeloid hematopoiesis with pancytopenia (aplastic anemia)
2. Prevention and treatment of leukopoiesis lesions during chemotherapy with cytostatics
oncological (excluding myeloid) diseases, HIV infections and its complications
3. Septic conditions with suppression of leukopoiesis and immunity
4. Conditions after bone marrow transplantation
Colony-stimulating factors
These “factors” are a recently discovered group of endogenous physiologically active compounds of high molecular weight polypeptide structure related to cytokines.
They have the specific ability to bind to receptors of hematopoietic cells and stimulate their proliferation, differentiation and functional activity.
By enhancing the differentiation of myeloid blood cell precursors, they accelerate the formation of granulocytes and macrophages.
Different compounds of this group differ in their effect on hematopoietic colonies. Some stimulate predominantly the formation of granulocytes, while others have a greater influence on the formation of macrophages. They do not have a pronounced effect on red blood cells and platelets.
These compounds are considered as endogenous stimulators of neutropoiesis - antineutropenic substances.
In the 1990s. Using genetic engineering methods, it was possible to create recombinant colony-stimulating factors and introduce them into medical practice as drugs.
The currently used drugs in this group are: Filgrastim, Sargramostim, Molgramostim, Lenograstim.
Indications for use
1. Prevention and treatment various types neutropenia (and prevention of the associated decrease in resistance to infectious complications)
2. Prevention and treatment of complications in cancer patients undergoing myelosuppressive chemotherapy
3. Myelodysplastic syndrome and aplastic anemia
4. Improving the tolerability of immunosuppressive drugs during bone marrow transplantation
5. Reducing the toxic effect on blood cell sprouts of ganciclovir, used to treat AIDS
6. Prevention of hematopoietic disorders and improvement of immune status in people infected with HIV and other infections.
Filgrastim=Neupogen=Neupogen
Polypeptide (non-glycolysed) containing 175 amino acid residues. Molecular weight 8,800 daltons.
Obtained by genetic engineering using Escherichia coli.
Stimulates granulocytopoiesis. By interacting with receptors on the surface of hematopoietic cells, it accelerates the biosynthesis and release of neutrophils in the bone marrow.
Used intravenously and subcutaneously.
Doses are set individually depending on the indications, severity of the process and the patient’s sensitivity to the drug.
Drugs that inhibit erythropoiesis
Used for polycythemia (erythremia) - one of the options chronic leukemia, but only erythrocytes are the substrate. The disease manifests itself:
1. Cherry-red skin color,
2. Itchy skin
3. Pain in bones and fingers
4. Numerous thromboses
5. Numerous bleedings
6. Hemoglobin above 180 g/l
7. Increase in hematocrit
One such remedy is a solution of sodium phosphate labeled with phosphorus-32 (Na 2 H 32 PO 4). Its use leads to a decrease in the number of red blood cells and platelets. Administered intravenously or orally. Dosed in millicuries (mCi)
Antitumor (antiblastoma) drugs
I. Non-hormonal drugs
A. Alkylating agents
1. Cyclophosphamide = Cyclophosphamide
2. Thiophosphamide=ThioTEF
3. Busulfan=Myelosan
4. Nitrosomethylurea = Metinur
5. Cisplastin=Platidiam
6. Carboplatin=Paraplatin
B. Antimetabolites
A) Folic acid
7. Methotrexate=Trexan
B) Purine nucleotides
8. Mercaptopurine=Leukerine
B) Pyrimidine nucleotides
9. Fluorouracil=Fluorouracil
B. Drugs plant origin
10. Vincristine = Onkovin
11. Etoposide=Vepezid
12. Paclitaxel=Taxol
D. Antitumor antibiotics
13. Dactinomycin=Actinomycin-D
14. Doxorubicin=Adriamycin
15. Mitoxantrone
D. Modifiers of biological reactions
A) Interleukins
16. Aldesleukin = Roncoleukin – recombinant interleukin-2
B) Interferons
17. Reaferon = Realdiron – recombinant α-interferons
18. Imukin – recombinant γ-interferon
B) Retinoids
19. Tretinoin=Vesanoid
E. Non-hormonal drugs of different groups
20. Asparaginase = Krasnitin
21. Rituximab=MabThera
22. Imatinib=Gleevec
II. Hormonal and antihormonal drugs
A. Glucocorticoids
23. Prednisolone
24. Methylprednisolone=Urbazon
B. Inhibitors of glucocorticoid synthesis
25. Chloditan=Mitotane
26. Aminoglutethimide = Mamomit
B. Androgenic drugs
27. Testosterone propionate = Androfort
28. Medrosterone propionate = Drostanolone propionate
D. Antiandrogen drugs
29. Cyproterone acetate = Androcur
30. Flutamide=Flucinom
D. Estrogen drugs
31. Phosfestrol=Honvan
32. Ethinylestradiol=Microfollin
E. Antiestrogens
33. Temoxifen=Nolvadex
34. Toremifene=Fareston
G. Progestin drugs
35. Norethisterone=Norkolut
36. Medroxyprogesterone acetate = Provera
H. Analogues of gonadotropin-releasing hormone of the hypothalamus
37. Buserelin=Suprefact
38. Goserelin=Zoladex
1. Cytotoxic agents
– a large group of heterogeneous drugs that form the specific basis of cancer chemotherapy.
A. Alkylating agents
Capable of forming irreversible covalent bonds of their alkyl radicals with various elements of the cell.
The bond with the guanidine bases of DNA is most important
As a result of this, the following are formed:
1. Cross-linking of helix turns and adjacent DNA strands
2. Circuit breaks
3. The inability of spirals to diverge
4. Codes are read
5. Reduplication
6. Mutations occur in genes
These drugs are classified as multifunctional agents acting on tumor cells at different phases of their life cycle
All of them are highly toxic and can cause:
1. Nausea and vomiting (need protection with antiemetics)
2. Suppress hematopoiesis (neutropenia, thrombocytopenia)
3. Ulceration of the gastrointestinal mucosa, bladder
Antimetabolites
They are structural analogues of normal metabolites
Their mechanism of action differs from that of alkylating agents, but final result is the same
Modified molecules of purines, pyrimidines, and folic acid compete with normal metabolites, replace them in reactions, but cannot perform their function. The processes of synthesis of DNA and RNA nucleic bases are blocked
Unlike alkylating agents, they act on fissile cancer cells
The complications are the same as with alkylating agents with the exception of mercaptopurine and thioguanine.
Antitumor antibiotics
Produced by certain species of streptomycetes and actinomycetes.
They represent a chemically heterogeneous class with a different mechanism of cytotoxic action
Some of them are inserted between DNA nucleotides, preventing RNA synthesis and chromosome reduplication.
Others form aggressive free radicals and damage cell membranes (including myocardial ones)
Most of them are cyclone-specific, but some - bleomycin - act on dividing cells
Like antimetabolites, they show some tropism for certain types of tumors
Side effects are numerous
1. Nausea
3. Severe fever with dehydration
4. Hypotension
5. Allergic reactions
6. Anaphylactic shock
Antitumor plant alkaloids
Several natural substances of Vinca (vinca) (vinblastine, vincristine), colchicum (colchamine), podophylla (podophyllin, etoposide), yew (paclitaxel).
They block the formation or functioning of microtubules, which are formed in the cell before division and stretch two duplicate DNA strands into daughter cells.
Division stops, DNA strands degrade and the cell dies.
Naturally, they act only on cells in the active phase of division, and in addition they have relative tissue tropism.
There are many complications and they are basically the same as with other cytostatics.
Recipe for lesson 28 (Hematopoiesis and antitumor drugs)
1. Drug for the treatment of megaloblastic (hyperchromic) anemia
Rp.: Sol. Cyanocobalamin 0.01% (0.02%; 0.05%) – 1 ml
D.t.d. N.10 in amp.
S. IM, SC, IV 1 ml once a day or every other day
2. A drug for the treatment of iron deficiency (hypochromic) anemia
Rp.: Sol. Ferrum Lek 2 ml
D.t.d. N. 10 in amp.
S. IM 2-4 ml every other day
Rp.: Tab. Ferrum Lek N. 50
D.S. Orally, 2 tablets 3 times a day before meals.
3. A drug from the group of cytokines for the treatment of hypoplastic anemia
Rp.: Epoetin alfa 0.5 ml (1000 ED)
D.t.d. N. 10 in amp.
S. SC, IV (slow) 500 – 10,000 IU 3 times a week
4. A drug from the group of cytokines for the treatment of agranulocytosis
Rp.: Filgrastim 1 ml (30,000,000 ME)
S. P/c 500,000 – 1,000,000 IU according to the scheme
5. Antimetabolite folic acid for the treatment of lung cancer
Rp.: Tab. Methotrexate 0.0025 N.50
D.S. Inside (dosages and treatment regimens are selected individually)
6. Alkylating drug for the treatment of ovarian cancer
Rp.: Tab. Cyclophosphamide 0.05 N.50
D.S. Orally according to the scheme (maintenance dose 0.05 - 0.2 2 times a week)
Cytotoxic drugs are different from others medicines ability to cause irreversible cell damage. Despite the fact that cytotoxics, as a rule, also have immunosuppressive activity, the term “cytotoxic” is not synonymous with the term “immunosuppressant”. A number of drugs have immunosuppressive activity. pharmacological drugs(for example, HA), which are not cytotoxic.
Cytotoxic drugs have general mechanisms effects on immunoinflammatory processes associated with the elimination or suppression of the functional activity of sensitized and non-sensitized lymphocidal cells (A. S. Fauci and R. Young, 1993).
For treatment rheumatic diseases Cytotoxic drugs of 3 main classes are used: alkylating agents (cyclophosphamide, chlorambucil), purine analogues (azathioprine) and folic acid antagonists (methotrexate). As already noted, the latter does not have obvious cytotoxic activity in low doses.
Alkylating agents
CP and CB are derivatives of nitrogen mustard (nitroge mustard). Native molecules of these substances do not have any biological activity; the formation of active metabolites occurs in the liver due to oxidation in the smooth endoplasmic reticulum. Active forms Both drugs have 2 polyfunctional chloroethyl groups that form reactive ions, through which the substances bind to the sulfhydryl, amino, phosphate, hydroxyl and carboxyl groups of various molecules. This reaction determines the ability of alkylating agents to cause cross-linking of DNA, RNA and some proteins. For example, cross-linking of two strands of a DNA molecule occurs between nearby pairs of guanine bases, which leads to disruption of DNA replication and translation and cell death.Cyclophosphamide
Pharmacological properties
CF is well adsorbed in the gastrointestinal tract and has minimal protein-binding capacity. Active and inactive metabolites of CP are eliminated by the kidneys. The half-life of the drug is about 7 hours, peak serum concentrations are reached within 1 hour after administration. Impaired renal function can lead to an increase in the immunosuppressive and toxic activity of the drug.Mechanism of action
Active metabolites of CP give overall effect for all rapidly dividing cells, especially those in the S phase cell cycle. One of the important metabolites of CP is acrolein, the formation of which is the cause toxic damage Bladder. CP has the ability to influence various stages of the cellular and humoral immune response (A. S. Fauci and K. R. Young, 1993).It calls:
1) absolute T- and B-lymphopenia with predominant elimination of B-lymphocytes;
2) suppression of blast transformation of lymphocytes in response to antigenic, but not mitogenic stimuli;
3) suppression of antibody synthesis and delayed cutaneous hypersensitivity;
4) decrease in the level of immunoglobulins, development of hypogammaglobulinemia;
5) suppression of the functional activity of B-lymphocytes in vitro.
However, along with immunosuppression, the immunostimulating effect of CP has been described, which is believed to be associated with the different sensitivity of T and B lymphocytes to the effects of the drug. The effects of CP on the immune system depend to a certain extent on the characteristics of the therapy. For example, there is evidence that long-term, constant use of low doses of CP causes depression to a greater extent cellular immunity, and intermittent administration of high doses is associated primarily with suppression of humoral immunity.
In recent experimental studies performed on transgenic mice for spontaneously developing autoimmune diseases, it was shown that CP affects different subpopulations of T-lymphocytes that control the synthesis of antibodies and autoantibodies to an unequal extent. It has been established that CP suppresses Th2-dependent to a greater extent than Th1-dependent immune reactions, which explains the reasons for the more pronounced suppression of autoantibody synthesis during treatment of autoimmune diseases with CP (S. J. Schulman and D. Lo, 1994).
Clinical Application
CF is widely used in the treatment of various rheumatic diseases:1. SLE: glomerulonephritis, thrombocytopenia, pneumonitis, cerebrovasculitis, myositis
2. Systemic vasculitis: Wegener's granulomatosis, periarteritis nodosa, Takayasu's disease, Churg-Straus syndrome, essential mixed cryoglobulinemia, Behçet's disease, hemorrhagic vasculitis, rheumatoid vasculitis
3. PA
4. PM/DM
5. Goodpasture syndrome
6. SSD
There are 2 basic treatment plans for CF: oral administration at a dose of 1-2 mg/kg/day and intermittent bolus intravenous administration high doses (pulse therapy) of the drug (500-1000 mg/m2) during the first 3-6 months. monthly, and then once every 3 months. for 2 years or more. With both treatment regimens, they strive to maintain the level of leukocytes in patients within 4000 mm3. Typically, treatment with CP (with the exception of RA) is combined with the administration of moderate or high doses of GCs, including pulse therapy.
The prevailing opinion is that both treatment regimens are approximately equally effective, but against the background of intermittent intravenous administration, the frequency of toxic reactions is less than with constant oral administration (H. A. Austin et al., 1986), however, the latter has been proven only for lupus nephritis. At the same time, there are evidence that in patients with Wegener's granulomatosis, pulse therapy and oral administration of CP are equally effective only in terms of immediate results, but long-term remission can be achieved only with long-term oral administration daily intake drug (G. S. Hoffman et al., 1991).
Thus, pulse therapy and long-term administration of low doses of CP have different therapeutic profile(T. R. Cupps, 1991). According to T. R. Cupps (1990), in some cases, oral administration of low doses of CP has advantages over intermittent administration of high doses. For example, during the induction phase, the risk of bone marrow suppression is higher in patients treated with pulse therapy than in patients receiving low doses of CP.
Since the true change in the number of leukocytes in peripheral blood after pulse therapy it becomes obvious after 10-20 days, the dose of CP can be modified only after a month, while when taking the drug daily, the dose of CP can be adjusted based on continuous monitoring of the level of leukocytes in the peripheral blood and changes in renal function. According to the author, the danger of toxic reactions in the early stages of treatment with high doses of CP is especially great in patients with dysfunction of many organs, rapid progression renal failure, intestinal ischemia, as well as in patients receiving high doses GK.
During the treatment of CF, it is extremely necessary to carefully monitor laboratory parameters. At the beginning of treatment general analysis blood, determination of platelet levels and urinary sediment should be carried out every 7-14 days, and when the process and dose of the drug are stabilized - every 2-3 months. (P. J. Clements and Davis J.,
1986).
SLE
The effectiveness of CF in severe SLE has been proven in a series of open and controlled studies (D. T. Boumpas et al., 1990, 1992; W. J. McCune and D. T. Fox, 1989). According to long-term observations (10 years or more), the incidence of renal failure and the degree of progression of lupus nephritis are significantly lower in patients receiving combination treatment CP and GC than in patients treated with GC only (A. D. Steinberg and S. Steinberg, 1991). Thus, chronic renal failure developed in 75% of patients receiving only prednisolone, while in the group treated with cyclophosphamide, progression to chronic renal failure was observed in 10% of cases.However, unlike GCs, CP poorly controls many of the extrarenal manifestations of SLE that usually accompany disease activity. Therefore, in the vast majority of cases, CF is used together with HA. There are several reports of the effectiveness of intravenous administration of CP (in high or low doses) for thrombocytopenia resistant to GC and splenectomy (D. T. Boumpas et al., 1990; B. A. Roach and G. J. Hutchison, 1993), systemic vasculitis(T. J. Liang et al., 1988), interstitial lung damage (A. Eiser and H. M. Shanies, 1994), severe neuropsychiatric manifestations of the disease (D. T. Boumpas et al., 1991), GC-resistant myositis (D. Kono et al., 1990).
According to the recommendations of B. Hahn, monthly intravenous treatment CP at the maximum tolerated dose (without nausea and severe leukopenia) should be continued until an obvious clinical and laboratory effect is achieved, and then the interval between drug administrations should be increased to 4-6, 8, 12 weeks, and then treatment should be continued. within 2 years. At poor tolerance It is advisable to replace CF with AC.
According to F. A. Houssiau et al. (1991), a fairly effective treatment method (at least in terms of short-term prognosis) for patients with severe lupus nephritis is weekly intravenous administration of CP in low doses (500 mg) for 2-4 weeks. in combination with prednisolone in moderate doses (0.5 mg/kg/day). The advantage of this treatment method is low frequency infectious complications and the ability to quickly reduce the dose of GC.
Systemic vasculitis
CF is effective means treatment of Wegener's granulomatosis (A. S. Fauci et al., 1983; G. S. Hoffman et al., 1991.), periarteritis nodosa and Churg-Strauss syndrome (C. C. Chow et al., 1989; L. Guillevin et al., 1991; S. DeVita et al., 1991; W. J. McCune and A. W. Friedman, 1992).RA
Several open and controlled studies have demonstrated the effectiveness of CP (1.5 mg/kg/day) in PA (M. B. Yunus, 1988). However, the dose of CP that suppresses the formation of erosions is quite high (150 mg/day) and is often associated with the development of adverse reactions. Maximum effect achieved by the 16th week of treatment. By clinical effectiveness in RA, CF is not inferior to AC and is slightly superior to parenterally administered gold preparations. Intermittent pulse therapy CP is considered as the most effective method treatment of systemic rheumatoid vasculitis (D. G. L. Scott and R. A. Bason, 1984).SSD
CP at a dose of 2.0-2.5 mg/kg/day orally in combination with low doses of prednisolone causes a significant improvement in the functional state of the lungs in patients with SSc with pulmonary fibrosis (A. Akesson et al., 1994; R. M. Silver et al., 1993).PM/DM
According to M. E. Cronin et al. (1989), bolus administration of CP (0.75-1.375 g/m2 per month) to 7 patients in combination with GK therapy was accompanied by clinical improvement in only 1 case; in 3 patients, severe complications(1 patient died from heart failure). At the same time, S. Bombardieri et al. (1989) achieved a certain clinical effect in all 10 patients with GC-resistant PM/DM during treatment with CP at a dose of 500 mg every 3 weeks. There are isolated observations indicating effectiveness oral administration CF both in DM in children and adults.Cytotoxic effect is a damaging effect on the body, as a result of which deep functional and structural changes in cells, leading to their lysis. Cytotoxic T cells, or killer T cells, as well as cytotoxic drugs can have this effect.
Mechanism of action of cytotoxic T cells
Many pathogenic microorganisms are located inside the affected cells and are inaccessible to humoral factors immune response. To eliminate these pathogens, an acquired immune system has been formed, which is based on the functioning of cytotoxic cells. Such cells have the unique ability to detect a specific antigen and destroy cells exclusively with this foreign agent. Exists huge variety clones of T cells, each of which is “targeted” to a specific antigen.
If the corresponding antigen penetrates into the body under the influence of T-helper cells, T-killer cells are activated and cell division of the clone begins. T cells are able to detect antigen only if it is expressed on the surface of the affected cell. Killer T cells detect antigen along with cell markers - MHC molecules ( main complex histocompatibility) class I. During recognition of a foreign agent, a cytotoxic cell interacts with the target cell and destroys it before reduplication. In addition, the T-lymphocyte produces gamma interferon, thanks to this substance the pathogenic virus is not able to penetrate into neighboring cells.
The targets of killer T cells are cells affected by viruses, bacteria, and cancer cells.
Cytotoxic antibodies that can cause irreversible damage cytoplasmic membrane of the target cell are the main element of antiviral immunity.
Most killer T cells are part of the CD8+ subpopulation and detect antigen in complex with MHC class I molecules. Approximately 10% of cytotoxic cells belong to the CD4+ subpopulation and detect antigen in complex with MHC class II molecules. Cancer cells, lacking MHC molecules, T-killers do not recognize.
Lysis of cells with a foreign antigen is carried out by T-lymphocytes by introducing special proteins perforins into their membranes and injecting toxic substances inside.
Formation of killer T cells
The development of cytotoxic cells occurs in thymus gland. Killer T cell precursors are activated by the MHC class I antigen-molecule complex and their proliferation and maturation occurs with the participation of interleukin-2 and poorly identified differentiation factors produced by T helper cells.
Formed cytotoxic cells circulate freely throughout the body; periodically they can return to the lymph nodes, spleen and other lymphoid organs. After receiving an activating signal from T helper cells, the multiplication of certain T lymphocytes begins.
The cytotoxic type develops such pathologies as autoimmune thyroiditis, anemia, drug allergy. Cytotoxic cerebral edema is also possible due to intracellular metabolic lesions.
Cytotoxic drugs
Cytotoxic effects can be exerted by certain medical supplies. Cytotoxicants damage or destroy cells in the body. At the same time, rapidly multiplying cells are most sensitive to the effects of such drugs. Therefore, these drugs are usually used for therapy cancer diseases. Also, such drugs can be used as immunosuppressants. Manufacturers produce these medications in tablet and injection forms. Maybe combined use some drugs with different types effects on the body.
Healthy cells of the body, especially bone marrow cells, are also susceptible to cytotoxic effects.
Cytotoxicants have Negative influence on the production of blood cells, resulting in increased susceptibility to infectious diseases, anemia, and bleeding.
Cytotoxics include:
- alkylating agents (Chlorobutin, Dopan, Myelosan, Oxaliplatin, Lomustine);
- antimetabolites (Cytabarin, Fluorouracil);
- antibiotics that have an antitumor effect (Carminomycin, Mitomycin, Dactinomycin, Idarubicin);
- drugs natural origin(Vinblastine, Taxol, Etoposide, Cohamine, Taxotere);
- hormones and their antagonists (Tetasterone, Tamoxifen, Triptorelin, Letrozole, Prednisolone);
- monoclonal antibodies (Herceptin);
- cytokines (Interferon);
- enzymes (L-asparaginase);
- antitubulins;
- intercalants;
- inhibitors of topoisomerase I (Irinotecan), topoisomerase II (Etoposide), tyrosine kinases (Tayverb).
Cytostatics are drugs that slow down the process of cell division. Maintaining the vital functions of the body is based on the ability of its cells to divide, with new cells taking the place of old ones, and old ones, accordingly, dying. The rate of this process is determined biologically in such a way that a strict balance of cells is maintained in the body, and it is noteworthy that in each organ the metabolic process proceeds at a different speed.
But sometimes the rate of cell division becomes too fast, and old cells do not have time to die. This is how neoplasms form, in other words, tumors. It is at this time that it becomes topical issue, about cytostatics - what they are and how they can help in the treatment of cancer. And in order to answer it, it is necessary to consider all aspects of this group of drugs.
Cytostatics and oncology
Most often in medical practice The use of cytostatics occurs in the field of oncology in order to slow down tumor growth. During time it affects all cells of the body, so a slowdown in metabolism occurs in all tissues. But only in malignant neoplasms the effect of cytostatics is expressed in full, slowing down the rate of cancer progression.
Cytostatics and autoimmune processes
Cytostatics are also used in the treatment of autoimmune diseases, when, as a result of pathological activity of the immune system, antibodies destroy not antigens that penetrate the body, but cells of their own tissues. Cytostatics affect the bone marrow, reducing the activity of the immune system, as a result of which the disease can go into remission.
Thus, cytostatics are used for the following diseases:
- malignant oncological tumors in the early stages;
- lymphoma;
- leukemia;
- systemic lupus erythematosus;
- arthritis;
- vasculitis;
- Sjögren's syndrome;
- scleroderma.
Having considered the indications for taking the drug and the mechanism of its effect on the body, it becomes clear how cytostatics work, what they are, and in what cases they should be used.
Types of cytostatics
Cytostatics, the list of which is given below, are not limited to these categories, but it is customary to distinguish these 6 categories of drugs.
1. Alkylating cytostatics are drugs that have the ability to damage the DNA of cells that have a high rate of division. Despite the high degree of effectiveness, the drugs are difficult to tolerate by patients; among the consequences of the course of treatment, pathologies of the liver and kidneys, as the main filtration systems of the body, often appear. Such means include:
- chlorethylamines;
- nitrosourea derivatives;
- alkyl sulfates;
- ethyleneimines.
2. Cytostatic alkaloids of plant origin - preparations similar action, but with a natural composition:
- taxanes;
- vinca alkaloids;
- podophyllotoxins.
3. Cytostatics-antimetabolites - drugs that inhibit substances involved in the process of tumor formation, thereby stopping its growth:
- folic acid antagonists;
- purine antagonists;
- pyrimidine antagonists.
4. Cytostatics-antibiotics - antimicrobials with antitumor effect:
- anthracyclines.
5. Cytostatic hormones are antitumor drugs that reduce the production of certain hormones.
- progestins;
- antiestrogens;
- estrogens;
- antiandrogens;
- aromatase inhibitors.
6. Monoclonal antibodies are artificially created antibodies, identical to the real ones, directed against certain cells, in this case tumors.
Drugs
Cytostatics, the list of drugs of which is presented below, are prescribed only by prescription and are taken only according to strict indications:
- "Cyclophosphamide";
- "Tamoxifen";
- "Flutamide";
- "Sulfasalazine";
- "Chlorambucil";
- "Azathioprine";
- "Temozolomide";
- "Hydroxychloroquine";
- "Methotrexate".
The list of drugs that fit the definition of “cytostatics” is very wide, but these drugs are most often prescribed by doctors. The drugs are selected individually for the patient very carefully, and the doctor explains to the patient what side effects cytostatics cause, what they are and whether they can be avoided.
Side effects
The diagnostic process must confirm that a person has a serious disease, the treatment of which requires cytostatics. The side effects of these drugs are very pronounced; they are not only difficult for patients to tolerate, but also pose a danger to human health. In other words, taking cytostatics is always a colossal risk, but in oncology and autoimmune diseases the risk from lack of treatment is higher than the risk from possible side effects of the drug.
The main side effect of cytostatics is its negative effect on the bone marrow, and therefore on the entire hematopoietic system. At long-term use, which is usually required during therapy oncological neoplasms, and with autoimmune processes, even the development of leukemia is possible.
But even if blood cancer can be avoided, changes in blood composition will inevitably affect the functioning of all systems. If blood viscosity increases, the kidneys suffer, since a large load is placed on the membranes of the glomeruli, as a result of which they can be damaged.
When taking cytostatics, you should be prepared for permanent feeling unwell. Patients who have undergone a course of treatment with drugs of this group constantly report a feeling of weakness, drowsiness, and inability to concentrate on a task. Common complaints include headache, which is constantly present and is difficult to eliminate with analgesics.
During treatment, women usually experience menstrual irregularities and the inability to conceive a child.
Disorders digestive system manifest themselves in the form of nausea and diarrhea. This often becomes the reason for a person’s natural desire to limit their diet and reduce the amount of food they eat, which, in turn, leads to anorexia.
Not hazardous to health, but unpleasant consequence Taking cytostatics causes hair loss on the head and body. After stopping the course, hair growth usually resumes.
Based on this, it can be emphasized that the answer to the question of what cytostatics are, contains information not only about the benefits of this type of drug, but also about high risk for health and well-being during its use.
Rules for taking cytostatics
It is important to understand that a cytostatic has a direct effect on the activity of the immune system, inhibiting it. Therefore, during the course a person becomes susceptible to any infection.
In order to prevent infection, it is necessary to follow all safety measures: do not appear in places large cluster people, wear protective gauze bandage and use local antiviral protection ( oxolinic ointment), avoid hypothermia. If a respiratory infection does occur, you should immediately consult a doctor.
How to reduce side effects?
Modern medicine makes it possible to minimize the severity of side effects that occur while taking cytostatics. Special preparations, blocking vomiting reflex in the brain, make it possible to maintain normal well-being and performance during treatment.
As a rule, the tablet is taken early in the morning, after which it is recommended to increase the drinking regime to 2 liters of water per day. Cytostatics are predominantly excreted by the kidneys, so their particles can settle on the tissues of the bladder, causing irritant effect. A large number of drinking fluids and frequent emptying of the bladder makes it possible to reduce the severity of side effect cytostatics on the bladder. It is especially important to empty your bladder thoroughly before going to bed.
Examinations during treatment
Taking cytostatics requires regular examination of the body. At least once a month, the patient must undergo tests showing the effectiveness of the kidneys, liver, and hematopoietic system:
- clinical blood test;
- biochemical blood test for creatinine, ALT and AST levels;
- complete urine analysis;
- CRP indicator.
Thus, knowing everything up-to-date information about why cytostatics are needed, what they are, what types of drugs there are and how to take them correctly, you can count on a favorable prognosis for the treatment of oncological and autoimmune diseases.
