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'''Hóa trị liệu''' ([[tiếng Anh]]: '''Chemotherapy'''; viết tắt '''chemo''') là một phương pháp điều trị [[ung thư]] sử dụng một hoặc nhiều thuốc kháng ung thư - gây độc tế bào. Đây là một phần của [[phác đồ]] trị liệu ung thư chuẩn. Hóa trị liệu có thể trị khỏi hẳn ung thư hoặc giảm bớt và kéo dài sự sống cho bệnh nhân. Hóa trị liệu thường phối hợp với các phương pháp điều trị ung thư khác, như [[xạ trị]], [[phẫu thuật]], [[nhiệt trị]]. Các thuốc hóa trị cũng được sử dụng điều trị các bệnh khác, như [[viêm cứng khớp đốt sống]], [[bệnh đa xơ cứng]], [[bệnh Crohn]], [[bệnh vẩy nến]], [[psoriatic arthritis]], [[systemic lupus erythematosus]], [[viêm khớp dạng thấp]], và [[bệnh xơ cứng bì]].
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Các thuốc hóa trị liệu tiêu diệt các tế bào sinh truỏng nhanh, đây là đặc tính điển hình của tế bào ung thư. Nhưng cũng vì vậy các thuốc này cũng gây hại đến các tế bào bình thường có chu kỳ sinh trưởng nhanh như: tế bào ở [[tủy xương]], [[hệ tiêu hóa]], [[nang tóc]]. Do đó gây ra các phản ứng phụ như: [[suy tủy]] (giảm sản xuất các tế bào máu), [[viêm niêm mạc]] (viêm trên đường tiêu hóa), và [[rụng tóc]].
{{chính|Lịch sử hóa trị liệu ung thư}}
[[File:Sidney Farber nci-vol-1926-300.jpg|thumb|150px|[[Sidney Farber]] được xem là cha đẻ của hóa trị ung thư hiện đại.]]
Thuốc đầu tiên được sử dụng điều trị ung thư vào đầu thế kỷ 20, mặc dù ban đầu nó không được sửu dụng cho mục đích này. [[khí mustard]] được sử dụng như là vũ khí [[hoá học]] trong [[thế chiến thứ I]] và được khám phá có khả năng chống [[tạo huyết]].<ref>{{cite journal |author=Krumbhaar EB |title=tole of the blood and the bone marrow in certain forms of gas poisoning |journal=JAMA |volume=72 |pages=39–41 |year=1919 |doi=10.1001/jama.1919.26110010018009f }}</ref> Một hợp chất cấu trúc tương tự là [[nitrogen mustards]] được nghiên cứu thêm trong [[chiến tranh thế giới thứ II]] tại đại học Yale University.<ref name="gilman">{{cite journal |author=Gilman A |title=The initial clinical trial of nitrogen mustard|journal=Am. J. Surg. |volume=105 |pages=574–8 |year=1963 |month=May |pmid=13947966 |doi=10.1016/0002-9610(63)90232-0|issue=5 }}</ref> chúng tiêu diệt các tế bào phát triển nhanh như tế bào bạch cầu,do đó nó có tác dụng tương tự trên tế bào ung thư.Do đó, tháng 12 năm 1942, một số bệnh nhân mắc [[lymphomas]] (ung thư tế bào máu) đưa thuốc vào cơ thể qua tĩnh mạch.<ref name="gilman" /> Their improvement, although temporary, was remarkable.<ref>{{cite journal | author =Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ, Gilman A, McLennan MT. | title = Nitrogen mustard therapy | journal = JAMA| volume = 132 | issue = 3 |pages = 126–132 | year = 1946 | doi = 10.1001/jama.1946.02870380008004 }}</ref><ref>{{cite journal | author =Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ, Gilman A, McLennan MT. | title = Landmark article Sept. 21, 1946: Nitrogen mustard therapy. Use of methyl-bis(beta-chloroethyl)amine hydrochloride and tris(beta-chloroethyl)amine hydrochloride for Hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. By Louis S. Goodman, Maxwell M. Wintrobe, William Dameshek, Morton J. Goodman, Alfred Gilman and Margaret T. McLennan| journal = JAMA|volume = 251 | issue = 17 | pages = 2255–61 | year = 1984 | pmid=6368885 | doi=10.1001/jama.251.17.2255}}</ref> Đồng thời, during a military operation in World War II, following a German [[Air raid on Bari|air raid]] on the Italian harbour of Bari, several hundred people were accidentally exposed to mustard gas, which had been transported there by the [[Allies of World War II|Allied forces]] to prepare for possible retaliation in the event of German use of chemical warfare. The survivors were later found to have very low white blood cell counts.<ref>Faguet, p. 71</ref> Sau chiến tranh thế giới thứ II was over and the reports declassified, the experiences converged and led researchers to look for other substances that might have similar effects against cancer. The first chemotherapy drug to be developed from this line of research was [[mustine]]. Since then, many other drugs have been developed to treat cancer, and drug development has exploded into a multibillion-dollar industry, although the principles and limitations of chemotherapy discovered by the early researchers still apply.<ref>{{cite journal | author =Joensuu H. | title = Systemic chemotherapy for cancer: from weapon to treatment| journal = Lancet Oncol.| volume = 9| issue = 3 | page = 304 | year = 2008| pmid=18308256 | doi = 10.1016/S1470-2045(08)70075-5}}</ref>
==Phân loại==
[[File:Cross-linked DNA by nitrogen mustard.png|thumb|left| Hai DNA base that are liên kết chéo bởi nitrogen mustard . Different nitrogen mustards will have different chemical groups (R). Nitrogen mustards most commonly alkylate the N7 nitrogen of guanine (as shown here) but other phân tử được alkylate hóa.<ref name =Siddik/>]] ▼
▲[[File:Cross-linked DNA by nitrogen mustard.png|thumb|left| Hai DNA base that are liên kết chéo bởi nitrogen mustard. Different nitrogen mustards will have different chemical groups (R). Nitrogen mustards most commonly alkylate the N7 nitrogen of guanine (as shown here) but other phân tử được alkylate hóa.<ref name =Siddik/>]]
===Alkylating===
{{chính|Thuốc chống ung thư Alkylating}}
Alkylating là nhóm hóa trị liệu đầu tiên còn được sử dụng. Nguồn gốc là dẫn chất từ [[khí mustard]] sử dụng trong chiến tranh, hiện nay có nhiều loại alkylating được sử dụng.<ref name=Corrie/> They are so named because of their ability to [[alkylation|alkylate]] nhiều phân tử, bao gồm [[protein]], [[RNA]] và [[DNA]]. This ability to bind [[covalent bond|covalently]] to DNA via their [[alkyl group]] is the primary cause for their anti-cancer effects.<ref name=lind>{{cite journal|last=Lind M.J.|title=Principles of cytotoxic chemotherapy|journal=Medicine|year=2008|volume=36|issue=1|pages=19–23|doi=10.1016/j.mpmed.2007.10.003|first1=M.J.}}</ref> DNA is made of two strands and the molecules may either bind twice to one strand of DNA (intrastrand crosslink) or may bind once to both strands (interstrand crosslink). If the cell tries to replicate crosslinked DNA during [[cell division]], or tries to repair it, the DNA strands can break. This leads to a form of programmed cell death called [[apoptosis]].<ref name =Siddik>{{chú thích sách|last=Siddik ZH|title=Mechanisms of Action of Cancer Chemotherapeutic Agents: DNA-Interactive Alkylating Agents and Antitumour Platinum-Based Drugs|year=2005|publisher=John Wiley & Sons, Ltd|doi=10.1002/0470025077.chap84b}}</ref><ref name="pmid19002790"/> Alkylating agents will work at any point in the cell cycle and thus are known as cell cycle-independent drugs. For this reason the effect on the cell is dose dependent; the fraction of cells that die is directly proportional to the dose of drug.<ref name="pmid14508075"/>
The subtypes of alkylating agents are the [[nitrogen mustard]]s, [[nitrosoureas]], [[tetrazine]]s, [[aziridine]]s, [[cisplatin]]s and derivatives, and non-classical alkylating agents. Nitrogen mustards include [[mechlorethamine]], [[cyclophosphamide]], [[melphalan]], [[chlorambucil]], [[ifosfamide]] and [[busulfan]]. Nitrosoureas include [[N-Nitroso-N-methylurea]] (MNU), [[carmustine]] (BCNU), [[lomustine]] (CCNU) and [[semustine]] (MeCCNU), [[fotemustine]] and [[streptozotocin]]. Tetrazines include [[dacarbazine]], [[mitozolomide]] and [[temozolomide]]. Aziridines include [[thiotepa]], [[mytomycin]] and diaziquone (AZQ). Cisplatin and derivatives include [[cisplatin]], [[carboplatin]] and [[oxaliplatin]].<ref name=lind/><ref name="pmid19002790">{{cite journal |author=Damia G, D'Incalci M |title=Mechanisms of resistance to alkylating agents |journal=Cytotechnology |volume=27 |issue=1–3 |pages=165–73 |year=1998 |month=September |pmid=19002790 |pmc=3449574 |doi=10.1023/A:1008060720608 |url=}}</ref> They impair cell function by forming [[covalent bond]]s with the [[amino group|amino]], [[carboxyl group|carboxyl]], [[sulfhydryl group|sulfhydryl]], and [[phosphate group]]s in biologically important molecules.<ref name=takimoto>Takimoto CH, Calvo E.[http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628 "Principles of Oncologic Pharmacotherapy"] in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) [http://www.cancernetwork.com/cancer-management-11/ Cancer Management: A Multidisciplinary Approach]. 11 ed. 2008.</ref> Non-classical alkylating agents include [[procarbazine]] and hexamethylmelamine.<ref name=lind/><ref name="pmid19002790"/>
===Anti-metabolites===
[[File:Deoxcytidine, Gemcitidine and Decitabine.png|thumb|Deoxcytidine (left) and two anti-metabolite drugs (centre and right); [[Gemcitabine]] and [[Decitabine]]. The drugs are very similar but they have subtle differences in their [[chemical group]]s.]]
{{chính|Antimetabolite}}
[[Anti-metabolite]]s are a group of molecules that impede DNA and RNA synthesis. Many of them have a similar structure to the building blocks of DNA and RNA. The building blocks are [[nucleotide]]s; a molecule comprising a [[nucleobase]], a sugar and a [[phosphate group]]. The nucleobases are divided into [[purine]]s ([[guanine]] and [[adenine]]) and [[pyrimidine]]s ([[cytosine]], [[thymine]] and [[uracil]]). Anti-metabolites resemble either nucleobases or nucleosides (a nucleotide without the phosphate group), but have altered [[chemical group]]s.<ref name="pmid19476376">{{cite journal |author=Parker WB |title=Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer |journal=Chem. Rev. |volume=109 |issue=7 |pages=2880–93 |year=2009 |month=July |pmid=19476376 |pmc=2827868 |doi=10.1021/cr900028p |url=}}</ref> These drugs exert their effect by either blocking the enzymes required for DNA synthesis or becoming incorporated into DNA or RNA. By inhibiting the enzymes involved in DNA synthesis, they prevent mitosis because the DNA cannot duplicate itself. Also, after misincorperation of the molecules into DNA, [[DNA damage]] can occur and programmed cell death ([[apoptosis]]) is induced. Unlike alkylating agents, anti-metabolites are cell cycle dependent. This means that they only work during a specific part of the cell cycle, in this case [[S-phase]] (the DNA synthesis phase). For this reason, at a certain dose, the effect plateaus and proportionally no more cell death occurs with increased doses. Subtypes of the anti-metabolites are the [[antifolate|anti-folate]]s, fluoropyrimidines, deoxynucleoside analogues and [[thiopurine]]s.<ref name=lind/><ref name="pmid19476376"/>
The anti-folates include [[methotrexate]] and [[pemetrexed]]. Methotrexate inhibits [[dihydrofolate reductase]] (DHFR), an enzyme that regenerates [[tetrahydrofolate]] from [[dihydrofolate]]. When the enzyme is inhibited by methotrexate, the cellular levels of folate coenzymes diminish. These are required for [[thymidylate]] and purine production, which are both essential for DNA synthesis and cell division.<ref name="isbn0-443-07101-2">Wood, p. 11</ref><ref name="isbn0-470-09254-8"/> Pemetrexed is another anti-metabolite that affects purine and pyrimidine production, and therefore also inhibits DNA synthesis. It primarily inhibits the enzyme [[thymidylate synthase]], but also has effects on DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase and [[glycinamide ribonucleotide formyltransferase]].<ref name="pmid15217974">{{cite journal |author=Adjei AA |title=Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent |journal=Clin. Cancer Res. |volume=10 |issue=12 Pt 2 |pages=4276s–4280s |year=2004 |month=June |pmid=15217974 |doi=10.1158/1078-0432.CCR-040010 |url=}}</ref> The fluoropyrimidines include [[fluorouracil]] and [[capecitabine]]. Fluorouracil is a nucleobase analogue that is metabolised in cells to form at least two active products; 5-fluourouridine monophosphate (FUMP) and 5-fluoro-2'-deoxyuridine 5'-phosphate (fdUMP). FUMP becomes incorporated into RNA and fdUMP inhibits the enzyme thymidylate synthase; both of which lead to cell death.<ref name="isbn0-443-07101-2"/> Capecitabine is a [[prodrug]] of 5-fluorouracil that is broken down in cells to produce the active drug.<ref name="pmid12515569">{{cite journal |author=Wagstaff AJ, Ibbotson T, Goa KL |title=Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer |journal=Drugs |volume=63 |issue=2 |pages=217–36 |year=2003 |pmid=12515569 |doi= 10.2165/00003495-200363020-00009|url=}}</ref> The deoxynucleoside analogues include [[cytarabine]], [[gemcitabine]], [[decitabine]], [[Vidaza]], [[fludarabine]], [[nelarabine]], [[cladribine]], [[clofarabine]] and [[pentostatin]]. The thiopurines include [[thioguanine]] and [[mercaptopurine]].<ref name=lind/><ref name="pmid19476376"/>
===Anti-microtubule agents===
[[File:Microtubules and alkaloids.png|thumb|left|Vinca alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. Both mechanisms cause defective mitosis.]]
Anti-microtubule agents are [[plant]]-derived chemicals that block cell division by preventing [[microtubule]] function. Microtubules are an important cellular structure composed of two proteins; [[α-tubulin]] and [[β-tubulin]]. They are hollow rod shaped structures that are required for cell division, among other cellular functions.<ref name="pmid1687171">{{cite journal |author=Rowinsky EK, Donehower RC |title=The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics |journal=Pharmacol. Ther. |volume=52 |issue=1 |pages=35–84 |year=1991 |month=October |pmid=1687171 |doi= 10.1016/0163-7258(91)90086-2|url=}}</ref> Microtubules are dynamic structures, which means that they are permanently in a state of assembly and disassembly. [[Vinca alkaloid]]s and [[taxane]]s are the two main groups of anti-microtubule agents, and although both of these groups of drugs cause microtubule disfunction, their mechanisms of action are completely opposite. The vinca alkaloids prevent the formation of the microtubules, whereas the taxanes prevent the microtubule disassembly. By doing so, they prevent the cancer cells from completing mitosis. Following this, cell cycle arrest occurs, which induces programed cell death ([[apoptosis]]).<ref name=lind/><ref name="pmid20577942"/> Also, these drugs can affect blood vessel growth; an essential process that tumours utilise in order to grow and metastasise.<ref name="pmid20577942">{{cite journal |author=Yue QX, Liu X, Guo DA |title=Microtubule-binding natural products for cancer therapy |journal=Planta Med. |volume=76 |issue=11 |pages=1037–43 |year=2010 |month=August |pmid=20577942 |doi=10.1055/s-0030-1250073 |url=}}</ref>
Vinca alkaloids are derived from the [[Madagascar periwinkle]], ''Catharanthus roseus'' (formerly known as ''Vinca rosea''). They bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules. The original vinca alkaloids are completely natural chemicals, which include; [[vincristine]] and [[vinblastine]]. Following the success of these drugs, semi-synthetic vinca alkaloids were produced; [[vinorelbine]], [[vindesine]] and [[vinflunine]].<ref name="pmid20577942"/> These drugs are [[cell cycle]] specific. They bind to the tubulin molecules in [[S-phase]] and provent proper microtubule formation required for [[M-phase]].<ref name="pmid14508075"/>
Taxanes are natural and semi-synthetic drugs. The first drug of their class, [[paclitaxel]], was originally extracted from the [[Pacific Yew]] tree, ''Taxus brevifolia''. Now this drug and another in this class, [[docetaxel]], are produced semi-synthetically from a chemical found in the bark of another Yew tree; ''[[Taxus baccata]]''. These drugs promote microtubule stability, preventing their disassembly. Paclitaxel prevents the cell cycle at the boundary of G2-M, whereas docetaxel exerts its effect during [[S-phase]]. Taxanes present difficulties in formulation as medicines because they are poorly soluble in water.<ref name="pmid20577942"/>
[[Podophyllotoxin]] is an anti-neoplastic [[lignan]] primarily obtained from the [[American Mayapple]] (''Podophyllum peltatum'') and [[Himalayan Mayapple]] (''Podophyllum hexandrum'' or ''Podophyllum emodi''). It has anti-microtubule activity, and its mechanism is similar to that of vinca alkaloids in that they bind to tubulin, inhibiting microtubule formation. Podophyllotoxin is used to produce two other drugs with different mechanisms of action; [[etoposide]] and [[teniposide]].<ref name="pmid9562603">{{cite journal |author=Damayanthi Y, Lown JW |title=Podophyllotoxins: current status and recent developments |journal=Curr. Med. Chem. |volume=5 |issue=3 |pages=205–52 |year=1998 |month=June |pmid=9562603 |doi= |url=}}</ref><ref>{{cite journal|last=Liu YQ, Yang L, Tian X|title=Podophyllotoxin: current perspectives|journal=Curr Bioactive Compounds|year=2007|volume=3|issue=1|pages=37–66|doi=10.1016/j.jallcom.2006.06.070|first1=Cong|first2=Wei|first3=Zhengnan|first4=Zhong|first5=Qibo|first6=Yu|first7=Wenhui|first8=Ming|first9=Zhuhong|first10=Guodong|first11=Guangheng}}</ref>
===Topoisomerase inhibitors===
[[File:Topoisomerase Inhibitor.JPG|thumb|Topoisomerase I and II Inhibitors]]
[[Topoisomerase inhibitor]]s are drugs that affect the activity of two enzymes; [[topoisomerase I]] and [[topoisomerase II]]. When the DNA double stranded helix is unwound, during DNA replication or [[translation (biology)|translation]] for example, the adjacent unopened DNA winds tighter (supercoils), like opening the middle of a twisted rope. The stress caused by this effect is in part aided by the topoisomerase enzymes. They produce single or double strand breaks into DNA, reducing the tension in the DNA strand. This allows the normal unwinding of DNA to occur during [[DNA replication|replication]] or [[translation (biology)|translation]]. Inhibition of topoisomerase I or II interferes with both of these processes.<ref>{{chú thích sách|last=Lodish H, Berk A, Zipursky SL, et al.|title=Molecular Cell Biology. 4th edition. The Role of Topoisomerases in DNA Replication|year=2000|publisher=New York: W. H. Freeman|url=http://www.ncbi.nlm.nih.gov/books/NBK21703/}}</ref><ref name="pmid12351817">{{cite journal |author=Goodsell DS |title=The molecular perspective: DNA topoisomerases |journal=Stem Cells |volume=20 |issue=5 |pages=470–1 |year=2002 |pmid=12351817 |doi=10.1634/stemcells.20-5-470 |url=}}</ref>
Two topoisomerase I inhibitors, [[irinotecan]] and [[topotecan]], are semi-synthetically derived from [[camptothecin]], which is obtained from the Chinese ornamental tree ''[[Camptotheca acuminata]]''.<ref name="pmid14508075"/> Drugs that target topoisomerase II can be divided into two groups. The topoisomerase II poisons cause increased levels enzymes bound to DNA. This prevents DNA replication and [[translation (biology)|translation]], causes DNA strand breaks, and leads to programmed cell death ([[apoptosis]]). These agents include [[etoposide]], [[doxorubicin]], [[mitoxantrone]] and [[teniposide]]. The second group, catalytic inhibitors, are drugs that block the activity of topoisomerase II, and therefore prevent DNA synthesis and translation because the DNA cannot unwind properly. This group includes [[novobiocin]], merbarone, and [[aclarubicin]], which also have other significant mechanisms of action.<ref name="pmid19377506">{{cite journal |author=Nitiss JL |title=Targeting DNA topoisomerase II in cancer chemotherapy |journal=Nature Reviews Cancer |volume=9 |issue=5 |pages=338–50 |year=2009 |month=May |pmid=19377506 |pmc=2748742 |doi=10.1038/nrc2607 |url=}}</ref>
===Cytotoxic antibiotics===
The cytotoxic antibiotics are a varied group of drugs that have various mechanisms of action. The group includes the [[anthracycline]]s and other drugs including [[actinomycin]], [[bleomycin]], [[plicamycin]] and [[mitomycin]]. [[Doxorubicin]] and [[daunorubicin]] were the first two anthracyclines, and were obtained from the [[bacterium]] ''[[Streptomyces peucetius]]''. Derivatives of these compounds include [[epirubicin]] and [[idarubicin]]. Other clinically used drugs in the anthracyline group are [[pirarubicin]], [[aclarubicin]] and [[mitoxantrone]]. The mechanisms of anthracyclines include [[DNA intercalation]] (molecules insert between the two strands of DNA), generation of highly reactive [[free radicals]] that damage intercellular molecules and topoisomerase inhibition.<ref name="pmid15169927">{{cite journal |author=Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L |title=Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity |journal=Pharmacol. Rev. |volume=56 |issue=2 |pages=185–229 |year=2004 |month=June |pmid=15169927 |doi=10.1124/pr.56.2.6 |url=}}</ref> Actinomycin is a complex molecule that intercalates DNA and prevents [[RNA synthesis]].<ref name="pmid2410919">{{cite journal |author=Sobell HM |title=Actinomycin and DNA transcription |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=82 |issue=16 |pages=5328–31 |year=1985 |month=August |pmid=2410919 |pmc=390561 |doi= 10.1073/pnas.82.16.5328|url=}}</ref> Bleomycin, a [[glycopeptide]] isolated from ''Streptomyces verticillus'', also intercalates DNA, but produces [[free radical]]s that damage DNA. This occurs when bleomycin binds to a [[metal ion]], becomes [[reduction (chemistry)|chemically reduced]] and reacts with [[oxygen]].<ref name="pmid1384141">{{cite journal |author=Dorr RT |title=Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics |journal=Semin. Oncol. |volume=19 |issue=2 Suppl 5 |pages=3–8 |year=1992 |month=April |pmid=1384141 |doi= |url=}}</ref><ref name="isbn0-470-09254-8 3">Airley, p. 87</ref> Mitomycin is a cytotoxic antibiotic with the ability to alkylate DNA.<ref name="pmid2131038">{{cite journal |author=Verweij J, Pinedo HM |title=Mitomycin C: mechanism of action, usefulness and limitations |journal=Anticancer Drugs |volume=1 |issue=1 |pages=5–13 |year=1990 |month=October |pmid=2131038 |doi= 10.1097/00001813-199010000-00002|url=}}</ref>
== Tham khảo ==
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