Hóa trị liệu

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bệnh nhân được điều trị ung thư vú hóa trị liệu bằng docetaxel. găng tay và túi lạnh được đặt trên tay để giảm đau ở móng tay

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.


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.

Các thuốc kháng ung thư thế hệ mới (ví dụ, các kháng thể đơn dòng) không gây độc tế bào ở tế bào thường, chúng tác động đến mục tiêu là các protein bất thường và cần thiết cho phát triển của các tế bào ung thư. Such treatments are thường được xem trị liệu đích (khác với các hóa trị liệu cũ) và thường được sử dụng đi kèm với các phương pháp điều trị truyền thống trong pháp đồ điều trị ung thư.

Hóa trị liệu có thể sử dụng một thuốc/ lần (đơn hóa trị liệu) hoặc nhiều thuốc/ lần (Hóa trị liệu kết hợp hoặc đa hóa trị liệu). Hóa trị liệu sử dụng thuốc có thể chuyển thành dạng có hoạt tính gây độc tế bào dưới ánh sáng còn được gọi là quang hóa trị liệu.

Lịch sử[sửa | sửa mã nguồn]

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.[1] 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.[2] 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.[2] Their improvement, although temporary, was remarkable.[3][4] Đồng thời, during a military operation in World War II, following a German air raid on the Italian harbour of Bari, several hundred people were accidentally exposed to mustard gas, which had been transported there by the 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.[5] 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.[6]

Phân loại[sửa | sửa mã nguồn]

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.[7]

Alkylating[sửa | sửa mã nguồn]

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.[8] They are so named because of their ability to alkylate nhiều phân tử, bao gồm protein, RNADNA. This ability to bind covalently to DNA via their alkyl group is the primary cause for their anti-cancer effects.[9] 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.[7][10] 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.[11]

The subtypes of alkylating agents are the nitrogen mustards, nitrosoureas, tetrazines, aziridines, cisplatins 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.[9][10] They impair cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules.[12] Non-classical alkylating agents include procarbazine and hexamethylmelamine.[9][10]

Anti-metabolites[sửa | sửa mã nguồn]

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 groups.
Bài chi tiết: Antimetabolite

Anti-metabolites 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 nucleotides; a molecule comprising a nucleobase, a sugar and a phosphate group. The nucleobases are divided into purines (guanine and adenine) and pyrimidines (cytosine, thymine and uracil). Anti-metabolites resemble either nucleobases or nucleosides (a nucleotide without the phosphate group), but have altered chemical groups.[13] 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 anti-folates, fluoropyrimidines, deoxynucleoside analogues and thiopurines.[9][13]

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.[14][15] 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.[16] 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.[14] Capecitabine is a prodrug of 5-fluorouracil that is broken down in cells to produce the active drug.[17] The deoxynucleoside analogues include cytarabine, gemcitabine, decitabine, Vidaza, fludarabine, nelarabine, cladribine, clofarabine and pentostatin. The thiopurines include thioguanine and mercaptopurine.[9][13]

Anti-microtubule agents[sửa | sửa mã nguồn]

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.[18] Microtubules are dynamic structures, which means that they are permanently in a state of assembly and disassembly. Vinca alkaloids and taxanes 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).[9][19] Also, these drugs can affect blood vessel growth; an essential process that tumours utilise in order to grow and metastasise.[19]

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.[19] These drugs are cell cycle specific. They bind to the tubulin molecules in S-phase and provent proper microtubule formation required for M-phase.[11]

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.[19]

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.[20][21]

Topoisomerase inhibitors[sửa | sửa mã nguồn]

Topoisomerase I and II Inhibitors

Topoisomerase inhibitors 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 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 replication or translation. Inhibition of topoisomerase I or II interferes with both of these processes.[22][23]

Two topoisomerase I inhibitors, irinotecan and topotecan, are semi-synthetically derived from camptothecin, which is obtained from the Chinese ornamental tree Camptotheca acuminata.[11] 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, 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.[24]

Cytotoxic antibiotics[sửa | sửa mã nguồn]

The cytotoxic antibiotics are a varied group of drugs that have various mechanisms of action. The group includes the anthracyclines 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.[25] Actinomycin is a complex molecule that intercalates DNA and prevents RNA synthesis.[26] Bleomycin, a glycopeptide isolated from Streptomyces verticillus, also intercalates DNA, but produces free radicals that damage DNA. This occurs when bleomycin binds to a metal ion, becomes chemically reduced and reacts with oxygen.[27][28] Mitomycin is a cytotoxic antibiotic with the ability to alkylate DNA.[29]

Tham khảo[sửa | sửa mã nguồn]

  1. ^ Krumbhaar EB (1919). “tole of the blood and the bone marrow in certain forms of gas poisoning”. JAMA 72: 39–41. doi:10.1001/jama.1919.26110010018009f. 
  2. ^ a ă Gilman A (May năm 1963). “The initial clinical trial of nitrogen mustard”. Am. J. Surg. 105 (5): 574–8. doi:10.1016/0002-9610(63)90232-0. PMID 13947966. 
  3. ^ Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ, Gilman A, McLennan MT. (1946). “Nitrogen mustard therapy”. JAMA 132 (3): 126–132. doi:10.1001/jama.1946.02870380008004. 
  4. ^ Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ, Gilman A, McLennan MT. (1984). “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”. JAMA 251 (17): 2255–61. doi:10.1001/jama.251.17.2255. PMID 6368885. 
  5. ^ Faguet, p. 71
  6. ^ Joensuu H. (2008). “Systemic chemotherapy for cancer: from weapon to treatment”. Lancet Oncol. 9 (3): 304. doi:10.1016/S1470-2045(08)70075-5. PMID 18308256. 
  7. ^ a ă Siddik ZH (2005). Mechanisms of Action of Cancer Chemotherapeutic Agents: DNA-Interactive Alkylating Agents and Antitumour Platinum-Based Drugs. John Wiley & Sons, Ltd. doi:10.1002/0470025077.chap84b. 
  8. ^ Lỗi chú thích: Thẻ <ref> sai; không có nội dung trong thẻ ref có tên Corrie
  9. ^ a ă â b c d Lind M.J., M.J. (2008). “Principles of cytotoxic chemotherapy”. Medicine 36 (1): 19–23. doi:10.1016/j.mpmed.2007.10.003. 
  10. ^ a ă â Damia G, D'Incalci M (September năm 1998). “Mechanisms of resistance to alkylating agents”. Cytotechnology 27 (1–3): 165–73. doi:10.1023/A:1008060720608. PMC 3449574. PMID 19002790. 
  11. ^ Lỗi chú thích: Thẻ <ref> sai; không có nội dung trong thẻ ref có tên pmid14508075
  12. ^ Takimoto CH, Calvo E."Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
  13. ^ a ă â Parker WB (July năm 2009). “Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer”. Chem. Rev. 109 (7): 2880–93. doi:10.1021/cr900028p. PMC 2827868. PMID 19476376. 
  14. ^ a ă Wood, p. 11
  15. ^ Lỗi chú thích: Thẻ <ref> sai; không có nội dung trong thẻ ref có tên isbn0-470-09254-8
  16. ^ Adjei AA (June năm 2004). “Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent”. Clin. Cancer Res. 10 (12 Pt 2): 4276s–4280s. doi:10.1158/1078-0432.CCR-040010. PMID 15217974. 
  17. ^ Wagstaff AJ, Ibbotson T, Goa KL (2003). “Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer”. Drugs 63 (2): 217–36. doi:10.2165/00003495-200363020-00009. PMID 12515569. 
  18. ^ Rowinsky EK, Donehower RC (October năm 1991). “The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics”. Pharmacol. Ther. 52 (1): 35–84. doi:10.1016/0163-7258(91)90086-2. PMID 1687171. 
  19. ^ a ă â b Yue QX, Liu X, Guo DA (August năm 2010). “Microtubule-binding natural products for cancer therapy”. Planta Med. 76 (11): 1037–43. doi:10.1055/s-0030-1250073. PMID 20577942. 
  20. ^ Damayanthi Y, Lown JW (June năm 1998). “Podophyllotoxins: current status and recent developments”. Curr. Med. Chem. 5 (3): 205–52. PMID 9562603. 
  21. ^ Liu YQ, Yang L, Tian X, Cong (2007). “Podophyllotoxin: current perspectives”. Curr Bioactive Compounds 3 (1): 37–66. doi:10.1016/j.jallcom.2006.06.070. 
  22. ^ Lodish H, Berk A, Zipursky SL, et al. (2000). Molecular Cell Biology. 4th edition. The Role of Topoisomerases in DNA Replication. New York: W. H. Freeman. 
  23. ^ Goodsell DS (2002). “The molecular perspective: DNA topoisomerases”. Stem Cells 20 (5): 470–1. doi:10.1634/stemcells.20-5-470. PMID 12351817. 
  24. ^ Nitiss JL (May năm 2009). “Targeting DNA topoisomerase II in cancer chemotherapy”. Nature Reviews Cancer 9 (5): 338–50. doi:10.1038/nrc2607. PMC 2748742. PMID 19377506. 
  25. ^ Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (June năm 2004). “Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity”. Pharmacol. Rev. 56 (2): 185–229. doi:10.1124/pr.56.2.6. PMID 15169927. 
  26. ^ Sobell HM (August năm 1985). “Actinomycin and DNA transcription”. Proc. Natl. Acad. Sci. U.S.A. 82 (16): 5328–31. doi:10.1073/pnas.82.16.5328. PMC 390561. PMID 2410919. 
  27. ^ Dorr RT (April năm 1992). “Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics”. Semin. Oncol. 19 (2 Suppl 5): 3–8. PMID 1384141. 
  28. ^ Airley, p. 87
  29. ^ Verweij J, Pinedo HM (October năm 1990). “Mitomycin C: mechanism of action, usefulness and limitations”. Anticancer Drugs 1 (1): 5–13. doi:10.1097/00001813-199010000-00002. PMID 2131038.