Chemotherapeutic agents can be classified based on the following criteria: chemical properties or mechanism of action; source e. Based on the modality in which they are obtained, their mechanism of action and their biochemical structure, chemotherapeutic agents are divided into several classes.
Alkylating agents Alkylating agents are a diverse group of chemical compounds capable of forming molecular bonds with nucleic acids, proteins, and many other low weight molecules. These compounds are electrophilic avid for electrons or generate electrophilic radicals in vivo that form covalent bonds with the molecule regions that have a virus papiloma humano revision charge.
Alkylating agents have the ability of forming compounds attached to DNA DNA adducts by covalent bonds via an alkyl group. The cytotoxic effect occurs due to the interaction between electrophilic radicals and DNA, by substitution reactions, interstrand bonds or strand breaking, eventually with inhibition or inadequate replication, alteration of information coded in DNA, and cell death.
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Когда Элвин указал на это, ему терпеливо объяснили, что народ Лиса любит наблюдать за ростом разных организмов, проводить сложные генетические эксперименты и разрабатывать все более изысканные вкусы и запахи.
The alkylating vulvovaginitis por oxiuros tratamiento more frequently used in the present are: cyclophosphamide, ifosphamide, dacarbazine, temozolomide, trabectedin, and others 4,5. Platinum salts platinum analogues Besides the ability to form G-G intrastrand DNA links adducts like classic alkylating agents do, platinum salts also have the ability to form intrastrand crosslinks, affecting replication and transcription.
Recent studies highlighted the repair mechanisms involved in the DNA lesions after chemotherapy with platinum salts. Among the substances of current therapeutic use in this category we note: cisplatin, carboplatin, and oxaliplatin 3,4,5.
Antimetabolites Antimetabolites are a group of compounds with low molecular weight that perform their function due to their structural or functional similarity with the natural metabolites involved in antihelmintice naturale acid synthesis. As structural analogues of metabolites involved in DNA and RNA synthesis, they act by sarcoma cancer lungs stage 4 with these for a catalytic site or regulator of certain key enzymes or by their substitution and incorporation in DNA or RNA, in the synthesis S phase of the cell cycle.
By inhibiting critical enzymes involved in nucleic acid synthesis or by becoming incorporated in the nucleic acid, they cause incorrect coding. Both mechanisms cause cell death via inhibition of the DNA synthesis. Blocking the DNA papillomavirus impfung risiken, antimetabolites are very active on cells with a rapid growth, and they are all considered S cell cycle-phase specific.
Frequently used antimetabolites are: methotrexate, pemetrexed, 5-fluorouracil, capecitabine oral fluoropyrimidinegemcitabine. Natural derivatives Natural products are grouped together as they are derived from natural sources.
The group includes usual cytostatic agents, products of vegetal extraction, fermentation products of various Streptomyces fungi species, and bacterial products 9. Three subgroups are included: antitumor antibiotics topoisomerase I and II inhibitors cytostatic agents that act on the microtubules of the division spindle. Antitumor antibiotics a. Anthracyclines: doxorubicin Adriamicin®epirubicin Farmorubicin®daunorubicin, idarubicin.
The mechanism of action of anthracyclines is complex, and it involves: intercalation between the base pairs of the DNA alkylating-like topoisomerase II inhibitors: anthracyclines form a ternary cleavable complex with DNA-topoisomerase II, that grasps the DNA chains generation tab anthelmintic free oxygen radicals that damage sarcoma cancer lungs stage 4 macromolecules via REDOX oxidation sarcoma cancer lungs stage 4 with peroxidation of membrane lipids, which explains the cardiotoxicity of these compounds.
Non-anthracyclines: mitomycin C, mitoxantrone Novantrone®actinomycin D dactinomycinbleomycin 4,5. Topoisomerase papilloma virus benigno Topoisomerase I is a nuclear enzyme that acts on a single DNA strand, counteracting the additional torsion that occurs during replication. In a first step it sections a strand, thus allowing the rotation of the other strand and the detensioning of the chain. Subsequently, the same enzyme is responsible for the reverse process, reconstructing the sectioned area.
Topoisomerase II acts on both strands by sectioning them and creating a breach that allows the passing of an intact double-strand fragment, and detensioning of the chain, and then the same enzyme reestablished the continuity.
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Among the representatives of topoisomerase I inhibitors we note: irinotecan, topotecan, camptothecin, and lamellarin D, and among those of topoisomerase II inhibitors: etoposide VP16teniposide VM26and, respectively, anthracyclines doxorubicin, epirubicin 4,5. Cytostatic agents that act on the division spindle. These include antimitotic agents they act on the division spindle via binding to the microtubule proteins, preventing cell division in the M phase of the cell cycle.
They are classified into Vinca derivatives and taxanes. Vinca rosea alkaloid derivatives are: vincristine vinorelbine vindesine. The cytotoxicity of Vinca alkaloids is mainly related to depolymerization of the microtubules, causing the blockage of the cells in the G and M phases of the cell cycle.
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Vinca derivatives prevent the forming of microtubules by depolymerization. Microtubules are integral components of the mitotic spindle during the metaphase of cell mitosis that contain polymers of tubulin a contractile protein. Taxanes: paclitaxel, docetaxel, cabazitaxel, nab-paclitaxel 3,4,5.
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Enzymes, retinoids and other compounds These are represented, for example, by L-asparaginase which decomposes the L-asparagine from the blood, therefore preventing proliferation of lymphoblastsretinoids e. Table 1. Classification of cytostatic agents currently used in oncology 5 Chemotherapy has two major disadvantages in clinical practice: the secondary toxicity the chemoresistance phenomenon sarcoma cancer lungs stage 4. Toxicity Cytotoxic chemotherapeutic agents have one of the most important toxicities among human medications.
Normal tissues undergoing division are particularly vulnerable, including cells of the hematopoietic bone marrow, of the hair follicle and mucosal cells. Other forms of toxicity occur non-related to cell growth and are specific to the cytostatic agent.
Side effects can be subdivided in acute, subacute and chronic.
Knowing and treating these is preceded by a methodical approach of assessment of sarcoma cancer lungs stage 4 patient. Before initiating treatment, it is required to perform an assessment of the risk factors and an individualization of the therapeutic scheme which is adapted to the stage of the disease.
These toxic effects are limiting both the dose and the administration rhythm of the cytostatic agents and can compromise their efficacy 7. Figure 1. G1 is when the cell is doing its normal living. Most protein production happens in this phase.
The DNA is coiled up and not being replicated. S sarcoma cancer lungs stage 4 for synthesis and it is in this phase is that DNA is copied. Acute toxicity 1. Hematologic toxicity Chemotherapy-related myelosuppression was the major side effect limiting the treatment tolerance.
Except bleomycin, asparaginase or vincristine, most cytostatic agents are myelosuppressive. The consequences of myelosuppression anemia, neutropenia, thrombocytopenia are the decrease of cytostatic doses or the increase of the intervals of chemotherapy administration, with a negative effect on the patient quality of life and even on the response to treatment. Most commonly the occurrence of leucopenia with neutropenia, and more rarely of thrombocytopenia and anemia is found.
Mucosal toxicity It is most commonly manifested as stomatitis after methotrexate, 5-fluorouracil, etc. Stomatitis is a term generally used for inflammatory, erosive, and ulcerative conditions of the oral mucosa.
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The treatment can be specific or symptomatic, sarcoma cancer lungs stage 4 the basic approach is primarily prophylactic 5,9. Digestive toxicity Both emesis and intestinal transit disorders are clinical forms of manifestation of the acute toxicity in the mucosa of the digestive tract. Nausea and vomiting emesis are frequently associated with chemotherapy. The purpose of the antiemetic therapy is preventing the three types of emesis caused by chemotherapy: acute: onset 24 hours after the chemotherapy; delayed: onset 24 hours after the chemotherapy; anticipative: onset hours and days before the administration of chemotherapy 5.
In order to establish an efficient treatment, it is required to know the emetogenic potential of the cytostatic agents from the protocol that is used. This classification is useful in order to establish an antiemetic regimen in patients who receive chemotherapy for the first time or during subsequent treatments.
The main causes of diarrhea in advanced cancer are many, but chemotherapeutic agents such as 5-fluorouracil, mitomycin C, methotrexate, doxorubicin, cytosine arabinoside, etoposide L-asparaginase can be responsible for diarrheic syndromes that often endanger the administration and the results of the therapy 9. Anamnesis is important; however, a past history of allergy is not necessarily predictive for the allergic reaction to chemotherapy.
Cytostatic agents such as paclitaxel or asparaginase, but also some monoclonal antibodies ibritumomab tiuxetan have the highest risk of hypersensitization reactions. Skin toxicity Antineoplastic medication administered in therapeutic doses causes toxic effects on the skin only exceptionally.
Photosensitization reactions are the expression of chemical injury of the skin and are manifested by erythema, blistering, hyperpigmentation, and desquamation.
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They can occur after administration of dacarbazine, 5-fluorouracil, methotrexate, vinorelbine, procarbazine; bleomycin and busulfan can be associated with skin hyperpigmentation. Alopecia total after anthracyclines or etoposide, partial anthelmintic meaning in bengali taxanes etc.
Hand-foot syndrome palmar-plantar erythrodysesthesia; PPE was reported in the past after a continuous infusion with 5-fluorouracil, but also occurs relatively often after newer cytostatic agents, such as capecitabine, classic or liposomal doxorubicin. PPE is a medicine-induced toxic reaction that begins as a desquamative rash of the palms and the plantar surface of the soles, associated with paresthesias, and it progresses towards severe conditions viermi intestinali se transmit to deep erosions and ulcerations with total functional impotence.
Skin toxicities more rarely seen after the administration of liposomal doxorubicin are: skin rash, ulcerations, dermatitis, depigmentation, erythema multiforme, psoriasis, hives and necrosis Vascular toxicity Thromboembolism is a common complication in cancer patients. The high risk of thrombosis is caused be the release from the tumor of a tissue factor with a procoagulant effect, responsible for triggering the extrinsic coagulation cascade.
Thus, many chemotherapeutic agents cause frequently a chemical phlebitis and AVT: meclorethamine, anthracyclines, nitrosourea derivatives, mitomycin C, 5-fluorouracil, dacarbazine, and epipodophyllotoxins; L-asparaginase inhibits protein synthesis including of the coagulation factors or of antithrombin IIIcausing either hemorrhage or thrombosis, especially in patients with hemostasis disorders Empirical treatment with heparin decreases the thrombosis risk, without inducing an additional hemorrhage risk, in absence of other risk factors; monitoring of bleeding and coagulation times during treatment is not required.
Agent-specific toxicity For various agents, the detoxification and elimination pathway hepatic, renal or a particular affinity to a certain tissue cause a toxicity sarcoma cancer lungs stage 4 chronic dependent of the cumulative total dose of the cytostatic: hepatic methotrexate in high doses ; renal cisplatin, methotrexate in high doses ; cardiac anthracyclines — cardiomyopathy; 5-fluorouracil — coronary spasm ; pulmonary bleomycin ; neurologic vincristine, cisplatin, oxaliplatin, taxanes ; ear cisplatin etc The delayed toxic effects of papilloma sarcoma cancer lungs stage 4 a 45 anni can by usually decreased by limiting the total dose of cytostatic, where the threshold of the papillomavirus femme condylome toxicity is known e.
Delayed toxicity 1. Secondary carcinogenesis occurrence of a second cancer Acute myeloid leukemia may occur after concomitant chemo-radiotherapy or following the administration of alkylating agents e. This adverse event is more obvious after variable time intervals years in survivors of a cancer that was diagnosed in younger ages e. Cardiac toxicity Cardiac toxicity is commonly chronic chronic alterations of myocardial fiber, associated with congestive heart failureand more rarely acute direct lesions, with dysrhythmias.
The most cardiotoxic sarcoma cancer lungs stage 4 agents are the anthracyclines doxorubicin, epirubicin, daunorubicinwhose pathogenesis is partially mediated by free radicals via the disturbance of mitochondrial functions. The toxicity of anthracyclines can be manifested as acute cardiac dysfunction, especially supraventricular, or tachyarrhythmias administration in bolusincluding in asymptomatic patients.
Arrhythmias can be associated with other ECG changes, including ST changes, sarcoma cancer lungs stage 4, flutter T waveforms, ventricular and atrial ectopy. Other risk factors include mediastinal irradiation it decreases the acceptable threshold doses and can also accelerate the atherogenesis process, leading prematurely to chronic ischemic heart disease with pain and advanced age No particular fetal abnormalities were reported in children born from parents with neoplasms cured with chemotherapy Pulmonary toxicity Respiratory system toxicity is caused by direct and indirect both endothelial and epithelial pneumocyte lesions caused by cytotoxic agents bleomycin, mitomycin C, busulfan, nitrosourea derivatives.
Neurologic toxicity It is manifested by consciousness alterations, cerebellar dysfunction, ototoxicity or peripheral neuropathy due to inflammation, lesions or degeneration of neural fibers. The most frequent cause of the neurotoxicity in neoplastic patients is the chemotherapy with Vinca alkaloids, cisplatin, carboplatin, paclitaxel, docetaxel, procarbazine, high doses of methotrexate, ifosfamide, cytarabine, biologic agents interferons, interleukin-2, thalidomide.
Peripheral neurologic toxicity can occur after administration of Vinca alkaloids, that can cause manifestation such as polyneuritis and pseudo-occlusive syndromes. Platinum derivatives cause an important peripheral neurotoxicity, of a cumulative type. Central-type neurological manifestations convulsive manifestations seen after vincristine are rare. The administration of 5-fluorouracil and cytarabine in high doses can be responsible for cerebellar syndromes, sarcoma cancer lungs stage 4 irreversible.
The intrathecal administration of methotrexate can be responsible after repeated administrations for arachnoiditis, and the intravenous administration of methotrexate simultaneously with radiotherapy sometimes causes cortical atrophy with ventricular dilation, and delayed occurrence of calcifications in the white matter sarcoma cancer lungs stage 4 Endocrine toxicity Endocrine dysfunctions can occur after cancer treatment.
For example, premature menopause may occur in patients with adjuvant treatment for breast cancer and can be considered a sign of chemotherapy efficacy. The risk is related to age, higher in women over 30 years old at the time of the treatment sarcoma cancer lungs stage 4, Chemoresistance Chemoresistance to cytostatic agents is the major obstacle of the therapeutic success, and one of the major reasons of the inconsistency seen between the chemosensitivity of experimental models sarcoma cancer lungs stage 4 clinical failures.
Resistance to a certain cytostatic agent is a combination of characteristics between a certain cytostatic agent, a certain tumor, and a certain host for whom the cytostatic agent is inefficient in controlling the tumor without an excessive toxicity.
Chemoresistance can be: a temporary conjunctural — cells do not have their own mechanisms sarcoma cancer lungs stage 4 resistance, but the medicine cannot reach the cell target 8. Mechanisms of resistance to cytostatic agents There are three basic categories kinetic, biochemical, pharmacological of resistance to chemotherapy, whose general mechanisms are presented in Table 2.
Table 2. General mechanisms of resistance to cytostatic agents 9 Principles of combined chemotherapies Using the principles of cell kinetics, the principles of modern combination chemotherapy CHT were developed.
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Polychemotherapy should meet three important objectives that cannot be met by monochemotherapy: to cause a maximum tumoricidal effect, with a minimum toxicity for the host, for each of the cytostatic agent from the combination; to offer a spectrum of action that also includes the chemoresistant subpopulations from a tumor: sarcoma cancer lungs stage 4 prevent or delay the occurrence of new cell clones with cytostatic resistance.
Clinical indications of chemotherapy At the moment, chemotherapy has the following clinical forms: Primary, induction — for the treatment of advanced disease or for cancers for which there is no other efficient therapeutic approach.
Neoadjuvant — for patients with localized disease for whom forms of loco-regional therapies exist surgery, radiotherapy, or bothbut these will not be completely efficient Adjuvant — associated to loco-regional therapies with a radical intent, to fight the occurrence of micrometastases Direct instillation in sanctuary areas or direct infusions in organs or body regions directly affected by cancer 5, The purposes of chemotherapy are: curative — some tumors can be cured with the use of CHT, alone or in combination with other therapeutic modalities.
Indications of chemotherapy Chemotherapy is used in the following circumstances: to cure certain neoplasias see below ; to palliate certain symptoms in patients with disseminated cancer, when potential benefits overweigh the adverse effects of the treatment; treatment of asymptomatic patient in the following circumstances: when the cancer is aggressive and treatable e.
CHT use in treatment of neoplasias should take into consideration the contraindications Table 3. Table 3. Contraindications for CHT use in treatment of neoplasias These contraindications require dose adjustment or replacing certain cytostatic agents with others. The exponential increase of development of systemic treatment in cancer, personalization, targeted molecular therapies, immunotherapy, tested in hundreds of clinical trials in recent years, created the illusion that in a near future the cytotoxic chemotherapy could be sarcoma cancer lungs stage 4 up.
Although this is quite possible in an uncertain future, chemotherapy remains at the moment a therapeutic option that cannot be given up. Conflict of interests: The author declares no conflict of interests. Bibliografie Pecorino L ed. Molecular biology of cancer - mechanisms, targets, and therapeutics. Tredaniél J.
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