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An '''antineoplastic''' is a medicine used to treat cancer. The category is the largest in pharmacology, both by the number of medicines it contains and by the range of mechanisms by which they act, and includes the classical cytotoxic chemotherapies that kill dividing cells without regard for which tissue they belong to, the endocrine therapies that block the hormonal signal driving a hormone-responsive cancer, the targeted small molecules and monoclonal antibodies that inhibit specific oncogenic pathways, and the immunotherapies that disinhibit or redirect the patient's own immune response against the tumour. The category overlaps substantially with [[:Category:Immunosuppressants|immunosuppressants]] at the cytotoxic boundary, with [[:Category:Sex_hormones|sex hormones]] in the endocrine indications, and with the [[:Category:Biologics|biologics]] across the immunotherapy and antibody classes.

The pharmacological history begins, as so much of twentieth-century medicine does, with an accident of war. On the night of 2 December 1943 the Luftwaffe bombed the harbour of [[wikipedia:Bari|Bari]] in southern Italy and destroyed the SS ''[[wikipedia:John Harvey (Liberty ship)|John Harvey]]'', a Liberty ship carrying a secret cargo of two thousand mustard-gas bombs intended for retaliation if the German army used chemical weapons. The mustard agent leached into the harbour water and the oil slick covering it; over a thousand servicemen and Italian civilians were exposed, and several hundred died. The medical officer dispatched to investigate, [[wikipedia:Stewart Francis Alexander|Stewart Francis Alexander]] of the U.S. Army Chemical Warfare Service, noted at autopsy that the victims had specifically depleted lymphoid tissue and bone marrow.<ref name="alexander1947">Alexander SF. Medical report on the Bari Harbor mustard casualties. ''Military Surgeon''. 1947 Sep;101(1):1-17.</ref> Alexander's classified report reached the pharmacologists [[wikipedia:Louis S. Goodman|Louis Goodman]] and [[wikipedia:Alfred Gilman Sr.|Alfred Gilman]] at Yale, who had separately been studying the related sulphur mustards. They reasoned that a selective lymphocyte killer might be useful in the lymphoid malignancies. On 27 August 1942, a year before Bari, they had treated a patient with terminal non-Hodgkin lymphoma with the nitrogen mustard mechlorethamine; the lymph nodes melted away within days, recurred within months, and the remission could be obtained again with a second course. The work was declassified after the war, published in 1946, and is conventionally taken as the beginning of medical oncology.<ref name="goodman1946">Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ, Gilman A, McLennan MT. 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. ''JAMA''. 1946 Sep 21;132(3):126-132. PMID 20990490.</ref>

The second key observation came from Boston. The pathologist [[wikipedia:Sidney Farber|Sidney Farber]] at the Children's Hospital, who had spent the 1930s as the autopsy pathologist for all children dying of acute lymphoblastic leukemia in the city, hypothesised that folic acid, which had recently been shown to promote bone-marrow proliferation in nutritional megaloblastic anemia, might be exactly what the leukemic cells were using to grow; an antagonist of folate might therefore arrest them. He persuaded the Indian biochemist [[wikipedia:Yellapragada Subbarow|Yellapragada Subbarow]] at Lederle Laboratories to synthesize folate analogues, and in November 1947 he administered [[wikipedia:Aminopterin|aminopterin]] to sixteen children with ALL. Ten produced temporary haematological remission, the first the disease had ever shown. Aminopterin was succeeded by the better-tolerated [[Methotrexate|methotrexate]], and the principle that a single medicine could produce remission in a previously uniformly fatal cancer was established.<ref name="farber1948">Farber S, Diamond LK, Mercer RD, Sylvester RF Jr, Wolff JA. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). ''New England Journal of Medicine''. 1948 Jun 3;238(23):787-793. PMID 18860765.</ref> Methotrexate also produced the first complete and durable cure of a metastatic solid cancer, in [[wikipedia:Min Chiu Li|Min Chiu Li]] and [[wikipedia:Roy Hertz|Roy Hertz]]'s 1956 treatment of choriocarcinoma at the National Cancer Institute.

The cytotoxic era expanded along structural-class lines. The fluorinated pyrimidine [[wikipedia:5-fluorouracil|5-fluorouracil (5-FU)]] was synthesised by [[wikipedia:Charles Heidelberger|Charles Heidelberger]] at the University of Wisconsin in 1957 on the rational hypothesis that tumour cells incorporated uracil faster than normal cells; [[Fluorouracil|5-FU]] became and remains the backbone of colorectal-cancer chemotherapy. The platinum complex [[wikipedia:Cisplatin|cisplatin]], discovered through [[wikipedia:Barnett Rosenberg|Barnett Rosenberg]]'s 1965 observation at Michigan State University that bacterial cells did not divide near a platinum electrode in his electromagnetic-field experiments, was approved in 1978 and converted metastatic testicular cancer from uniformly fatal to over 90 percent curable.<ref name="rosenberg1969">Rosenberg B, Vancamp L, Trosko JE, Mansour VH. Platinum compounds: a new class of potent antitumour agents. ''Nature''. 1969 Apr 26;222(5191):385-386. PMID 5782119.</ref> The natural-product chemotherapies followed: the vinca alkaloids vincristine and vinblastine (Eli Lilly, 1958-1963, from ''Catharanthus roseus''); the anthracycline doxorubicin (Farmitalia, 1969, from ''Streptomyces peucetius''); the epipodophyllotoxin etoposide; the taxanes paclitaxel (extracted from the bark of the Pacific yew tree by Wall and Wani in 1971, brought to clinical use by [[wikipedia:Susan Horwitz|Susan Horwitz]]'s mechanistic work, approved 1992) and docetaxel; and the topoisomerase inhibitors irinotecan and topotecan.

The endocrine treatments of hormone-responsive cancers are an old strand of the same story. [[wikipedia:George Beatson|George Beatson]] in 1896 in Glasgow had performed an oophorectomy on a young woman with advanced breast cancer and observed regression, anticipating by sixty years the development of the antiestrogen [[Tamoxifen|tamoxifen]] (originally a failed contraceptive at ICI, repurposed for breast cancer by [[wikipedia:V. Craig Jordan|Craig Jordan]] in the 1970s, approved in 1977 and the foundation of modern adjuvant therapy for hormone-receptor-positive breast cancer). The aromatase inhibitor [[Anastrozole|anastrozole]] (Zeneca, 1995) and its successors letrozole and exemestane replaced ovarian estrogen synthesis in postmenopausal women; the [[:Category:Antiandrogens|antiandrogens]] and gonadotropin-releasing hormone agonists treated prostate cancer by analogous androgen ablation. The retinoid [[Tretinoin|tretinoin]] (all-trans retinoic acid), originally a topical dermatologic agent, was used by Wang Zhen-yi in Shanghai in 1986 to induce differentiation of acute promyelocytic leukemia cells; the cure rate for APL is now above 90 percent, by a non-cytotoxic mechanism.

The targeted-therapy era began with the molecular dissection of a single leukemia. In 1960 [[wikipedia:Peter Nowell|Peter Nowell]] and [[wikipedia:David Hungerford|David Hungerford]] in Philadelphia identified an abnormal small chromosome (the Philadelphia chromosome) in patients with chronic myeloid leukemia; in 1973 [[wikipedia:Janet Rowley|Janet Rowley]] in Chicago showed it was a translocation between chromosomes 9 and 22; in the 1980s the translocation was shown to produce the BCR-ABL fusion gene encoding a constitutively active tyrosine kinase. The pharmacologist [[wikipedia:Brian Druker|Brian Druker]] at Oregon Health Sciences University, working with chemists at Ciba-Geigy on a screening project that had run a decade, identified the small molecule that became [[wikipedia:Imatinib|imatinib]] as a selective inhibitor of the BCR-ABL kinase. The Phase I trial in 1998 produced complete haematological response in essentially every chronic-phase patient; imatinib was approved in 2001 and the survival of CML approached that of an age-matched normal population.<ref name="druker2001">Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. ''New England Journal of Medicine''. 2001 Apr 5;344(14):1031-1037. PMID 11287972.</ref> The class of [[wikipedia:Tyrosine kinase inhibitor|tyrosine kinase inhibitors]] now contains more than fifty approved medicines acting on the EGFR (gefitinib, erlotinib, osimertinib), HER2 (lapatinib, tucatinib), VEGFR (sorafenib, sunitinib, pazopanib), BRAF (vemurafenib, dabrafenib), MEK, ALK, ROS1, BTK, JAK, CDK4/6, PARP, and FGFR pathways, each tied to specific molecular subsets of specific cancers.

The immunotherapy revolution is the most recent chapter. [[wikipedia:James P. Allison|James Allison]] at Berkeley and [[wikipedia:Tasuku Honjo|Tasuku Honjo]] in Kyoto independently showed in the 1990s that T-cell activation was held in check by inhibitory receptors (CTLA-4 and PD-1 respectively), and that blocking these "checkpoints" with monoclonal antibodies could release a latent antitumour response. The CTLA-4 antibody [[wikipedia:Ipilimumab|ipilimumab]] (Bristol-Myers Squibb, 2011) and the PD-1 antibodies [[wikipedia:Pembrolizumab|pembrolizumab]] (Merck, 2014) and [[wikipedia:Nivolumab|nivolumab]] (BMS, 2014) produced durable remissions in melanoma, then in lung cancer, then in two dozen other diagnoses, and converted some metastatic cancers from uniformly fatal to long-term-survivable conditions. Allison and Honjo shared the 2018 Nobel Prize. Chimeric antigen receptor T-cell therapy (CAR-T), in which a patient's own T cells are engineered ex vivo to express a receptor against a tumour antigen and re-infused, was approved in 2017 (tisagenlecleucel) for paediatric acute lymphoblastic leukemia and is being extended to lymphomas, myeloma, and a growing list of indications.

The contemporary pharmacopoeia of antineoplastic medicines numbers in the high hundreds. The clinical organisation of cancer therapy has shifted, over thirty years, from a tissue-of-origin classification (a "lung cancer regimen") toward a molecular classification (an "EGFR-mutant non-small-cell lung cancer regimen"), so that an individual patient's treatment is now determined by tumour genomic and immunohistochemical profile in addition to its anatomic origin. The category includes both the few medicines that cure a previously fatal cancer (curative chemotherapy of acute lymphoblastic leukemia, of Hodgkin lymphoma, of choriocarcinoma, of testicular germ-cell tumour; targeted therapy of chronic myeloid leukemia; immunotherapy of melanoma) and the much larger number that prolong life by months or years in incurable disease. The toxicity profile is correspondingly enormous and is dominated, in the cytotoxic agents, by myelosuppression, mucositis, alopecia, infertility, and second-malignancy risk; in the targeted agents, by class- and target-specific effects (the dermatologic toxicity of EGFR inhibitors, the hypertension of VEGF inhibitors, the QT prolongation of multiple kinase inhibitors); and in the immunotherapies, by autoimmune phenomena ranging from rash and hypothyroidism to severe colitis, hepatitis, pneumonitis, and an unpredictable list of organ-specific autoimmune syndromes.

== Classes indexed ==

By mechanism (selected):

* '''Cytotoxic chemotherapies''':
** Alkylating agents (nitrogen mustards, oxazaphosphorines, platinums): mechlorethamine, cyclophosphamide, ifosfamide, melphalan, bendamustine, [[wikipedia:Cisplatin|cisplatin]], carboplatin, oxaliplatin
** [[:Category:Antimetabolites|Antimetabolites]] (folate, purine, pyrimidine analogues): [[Methotrexate|methotrexate]], pemetrexed, [[Fluorouracil|5-fluorouracil]] and capecitabine, gemcitabine, cytarabine, [[wikipedia:Mercaptopurine|6-mercaptopurine]], [[wikipedia:Fludarabine|fludarabine]]
** Anthracyclines: doxorubicin, daunorubicin, epirubicin, idarubicin
** Vinca alkaloids and taxanes: vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, cabazitaxel
** Topoisomerase inhibitors: etoposide, irinotecan, topotecan
* '''Endocrine therapy''' (also indexed under [[:Category:Endocrine_therapy|endocrine therapy]] and [[:Category:Sex_hormones|sex hormones]]):
** Selective estrogen-receptor modulators: [[Tamoxifen|tamoxifen]], raloxifene
** [[:Category:Aromatase_inhibitors|Aromatase inhibitors]]: [[Anastrozole|anastrozole]], letrozole, exemestane
** [[:Category:Antiandrogens|Antiandrogens]] and GnRH agents (for prostate cancer)
* '''Targeted small molecules''': the tyrosine kinase inhibitors imatinib, dasatinib, nilotinib (BCR-ABL); erlotinib, gefitinib, osimertinib (EGFR); the BRAF inhibitors vemurafenib, dabrafenib; the BTK inhibitors ibrutinib, acalabrutinib; the CDK4/6 inhibitors palbociclib, ribociclib, abemaciclib; the PARP inhibitors olaparib, niraparib, rucaparib; many others
* '''Monoclonal antibodies''' (also indexed under [[:Category:Monoclonal_antibodies|monoclonal antibodies]] and [[:Category:Biologics|biologics]]): rituximab (CD20), trastuzumab (HER2), bevacizumab (VEGF), cetuximab (EGFR), the immune-checkpoint antibodies [[wikipedia:Ipilimumab|ipilimumab]], [[wikipedia:Pembrolizumab|pembrolizumab]], [[wikipedia:Nivolumab|nivolumab]], atezolizumab, durvalumab
* '''Cellular and other immunotherapies''': CAR-T cell products tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene; bispecific T-cell engagers blinatumomab, teclistamab
* '''Differentiating agents''': [[Tretinoin|tretinoin (all-trans retinoic acid)]] for acute promyelocytic leukemia, arsenic trioxide
* '''Radiopharmaceuticals''' (radiolabelled medicines for targeted radiotherapy): iodine-131, lutetium-177 dotatate, lutetium-177 PSMA, radium-223

== Notes on scope ==

The boundary of this category is "medicine prescribed primarily to treat a malignant neoplasm." Medicines whose principal indication is autoimmune disease (the immunosuppressants, the biologics for rheumatoid arthritis and inflammatory bowel disease) are collected under [[:Category:Immunosuppressants|immunosuppressants]] and are cross-indexed here when they are also approved for an oncologic indication (methotrexate, cyclophosphamide). Supportive-care medicines used in the management of chemotherapy side effects (the [[:Category:5-HT3_antagonists|5-HT3 antagonists]] for nausea, [[wikipedia:Filgrastim|filgrastim]] for neutropenia, the bone-targeted [[:Category:Bisphosphonates|bisphosphonates]] for skeletal events) are not antineoplastics but are critical to the safe use of the category and are listed under their primary class. The radiologic and surgical treatments of cancer are not medicines and are not listed here. Hormonal contraceptives are not antineoplastics and are listed under [[:Category:Hormonal_contraceptives|hormonal contraceptives]].

== About these pages ==

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.

== References ==

<references/>

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Category:Antineoplastics - Revision history

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