Doxorubicin

Doxorubicin (INN, AAN, BAN, USAN)
Systematic (IUPAC) name
(7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
Clinical data
Pronunciation /ˌdɒksəˈruːbᵻsɪn/
Trade names Adriamycin, Doxil, Caelyx, Myocet
AHFS/Drugs.com monograph
MedlinePlus a682221
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Legal status
Routes of
administration		 Intravenous, intravesical
Pharmacokinetic data
Bioavailability 5% (Oral)
Protein binding 75%[1]
Metabolism Hepatic
Biological half-life Triphasic; 12 minutes, 3.3 hours, 30 hours. Mean: 1-3 hours[1][2]
Excretion Urine (5-12%), faeces (40-50%)[1]
Identifiers
CAS Number 23214-92-8 YesY
ATC code L01DB01
PubChem CID 31703
IUPHAR/BPS 7069
DrugBank DB00997 YesY
ChemSpider 29400 YesY
UNII 80168379AG YesY
KEGG D03899 YesY
ChEBI CHEBI:28748 YesY
ChEMBL CHEMBL53463 N
Chemical data
Formula C27H29NO11
Molar mass 543.52 g/mol
 NYesY (what is this?)  (verify)

Doxorubicin, sold under the trade names Adriamycin among others, is a medication used in cancer chemotherapy. It is derived by chemical semisynthesis from a bacterial species.[2] It is an anthracycline antitumor antibiotic (note: in this context, this does not mean it is used to treat bacterial infections) closely related to the natural product daunomycin and like all anthracyclines, it works by intercalating DNA, with the most serious adverse effect being life-threatening heart damage. It is commonly used in the treatment of a wide range of cancers, including hematological malignancies (blood cancers, like leukaemia and lymphoma), many types of carcinoma (solid tumours) and soft tissue sarcomas.[3] It is often used in combination chemotherapy as a component of various chemotherapy regimens.

Common adverse effects of doxorubicin include hair loss (seen in most of those treated with the drug), myelosuppression (a compromised ability of the body's bone marrow to produce new blood cells), nausea and vomiting (which are seen in roughly 30-90% of people treated with the drug), oral mucositis, oesophagitis, diarrhoea, skin reactions (including hand-foot syndrome) and localised swelling and redness along the vein in which the drug is delivered.[2][4] Less common, yet serious reactions include hypersensitivity reactions (including anaphylaxis), radiation recall, heart damage and liver dysfunction.[4] Some people experience red discoloration of their urine, sometimes for up to 1 to 2 days after treatment.[5]

It is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.[6] The drug is administered intravenously, as the hydrochloride salt.[2] Doxorubicin is photosensitive, and containers are often covered by an aluminum bag and/or brown wax paper to prevent light from affecting it.[2] Doxorubicin is also available in liposome-encapsulated forms as Doxil (pegylated form), Myocet (nonpegylated form), and Caelyx, although these forms must also be given by intravenous injection.[2]

Medical use

Doxorubicin is commonly used to treat some leukemias and Hodgkin's lymphoma, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue sarcoma, multiple myeloma, and others.[2][4] Commonly used doxorubicin-containing regimens are AC (Adriamycin, cyclophosphamide), TAC (Taxotere, AC), ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), BEACOPP, CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) and FAC (5-fluorouracil, adriamycin, cyclophosphamide).[2]

Doxil (see below) is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after platinum-based chemotherapy, or for the treatment of AIDS-related Kaposi's sarcoma.[7]

Liposomal formulations

There is a pegylated (polyethylene glycol coated) liposome-encapsulated form of doxorubicin, sold as Doxil. It was developed to treat Kaposi's sarcoma, an AIDS-related cancer that causes lesions to grow under the skin, in the lining of the mouth, nose and throat, or in other organs. The polyethylene glycol coating results in preferential concentration of doxorubicin in the skin. However, this also results in a side effect called palmar plantar erythrodysesthesia (PPE), more commonly known as hand-foot syndrome. Following administration of this form of doxorubicin, small amounts of the drug can leak from capillaries in the palms of the hands and soles of the feet. The result of this leakage is redness, tenderness, and peeling of the skin that can be uncomfortable and even painful. In clinical testing at 50 mg/m2 dosing every 4 weeks, half of people developed hand-foot syndrome. The rate of this side effect limits the dose of this formulation that can be given as compared with plain doxorubicin in the same treatment regimen, thereby limiting potential substitution. Substitution would be desirable because liposome-encapsulated doxorubicin is less cardiotoxic than unencapsulated doxorubicin. This form is also approved by the FDA for treatment of ovarian cancer and multiple myeloma.[8][9]

A non-pegylated liposomal doxorubicin, called Myocet, is approved in Europe and Canada for treatment of metastatic breast cancer in combination with cyclophosphamide, but has not been approved by the FDA for use in the United States. Unlike Doxil, the Myocet liposome does not have a polyethylene glycol coating, and therefore does not result in the same rate of hand-foot syndrome. The minimization of this side effect may allow for one for one substitution with doxorubicin in the same treatment regimen, thereby improving safety with no loss of efficacy. Like Doxil, the liposomal encapsulation of the doxorubicin limits the cardiotoxicity. In theory, by limiting the cardiotoxicity of doxorubicin through liposomal encapsulation, it can be used safely in concurrent combination with other cardiotoxic chemotherapy drugs, such as trastuzumab. There is an FDA black box warning that trastuzumab cannot be used in concurrent combination with doxorubicin, only in sequential combination. Though concurrent combination of trastuzumab and doxorubicin in clinical studies found superior tumor response, the combination resulted in unacceptable cardiotoxicity, including risk of cardiac failure manifesting as congestive heart failure (CHF). Published phase II study results have shown that Myocet, trastuzumab, and paclitaxel can safely be used concurrently without the cardiac risk, as measured by reduction in LVEF function, while still achieving superior tumor response. This finding is the basis for the ongoing phase III trial for FDA approval.[8]

Adverse effects

The most dangerous side effect of doxorubicin is cardiomyopathy, leading to congestive heart failure. The rate of cardiomyopathy is dependent on its cumulative dose, with an incidence about 4% when the dose of doxorubicin is 500–550 mg/m², 18% when the dose is 551–600 mg/m² and 36% when the dose exceeds 600 mg/m².[10] There are several ways in which doxorubicin is believed to cause cardiomyopathy, including oxidative stress, downregulation of genes for contractile proteins, and p53 mediated apoptosis.[10] The drug dexrazoxane is used to mitigate doxorubicin's cardiotoxicity.

Another common and potentially fatal complication of doxorubicin is typhlitis, an acute life-threatening infection of the bowel.[11]

Additionally, some patients may develop PPE, characterized by skin eruptions on the palms of the hand or soles of the feet, swelling, pain, and erythema.[7]

Due to these side effects and its red color, doxorubicin has earned the nickname "red devil"[12] or "red death."[13]

Chemotherapy can cause reactivation of hepatitis B, and doxorubicin-containing regimens are no exception.[14][15]

Doxorubicin and several chemotherapeutic drugs (including cyclophosphamide) cause dyspigmentation. Other groups of drugs that cause this problem include antimalarials, amiodarone, heavy metals (but not iron), tetracyclines, and antipsychotics.[16]

Biosynthesis

Doxorubicin (DXR) is a 14-hydroxylated version of daunorubicin, the immediate precursor of DXR in its biosynthetic pathway. Daunorubicin is more abundantly found as a natural product because it is produced by a number of different wild type strains of Streptomyces. In contrast, only one known non-wild type species, Streptomyces peucetius subspecies cesius ATCC 27952, was initially found to be capable of producing the more widely used doxorubicin.[17] This strain was created by Arcamone et al. in 1969 by mutating a strain producing daunorubicin, but not DXR, at least in detectable quantities.[18] Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of genetic modifications, other strains of Streptomyces can produce doxorubicin.[19] His group has also cloned many of the genes required for DXR production, although not all of them have been fully characterized. In 1996, Strohl's group discovered, isolated and characterized dox A, the gene encoding the enzyme that converts daunorubicin into DXR.[20] By 1999, they produced recombinant dox A, a cytochrome P450 oxidase, and found that it catalyzes multiple steps in DXR biosynthesis, including steps leading to daunorubicin.[21] This was significant because it became clear that all daunorubicin-producing strains have the necessary genes to produce DXR, the much more therapeutically important of the two. Hutchinson's group went on to develop methods to improve the yield of DXR, from the fermentation process used in its commercial production, not only by introducing dox A encoding plasmids, but also by introducing mutations to deactivate enzymes that shunt DXR precursors to less useful products, for example baumycin-like glycosides.[17] Some triple mutants, that also over-expressed dox A, were able to double the yield of DXR. This is of more than academic interest, because at that time DXR cost about $1.37 million per kg and current production in 1999 was 225 kg per annum.[22] More efficient production techniques have brought the price down to $1.1 million per kg for the nonliposomal formulation. Although DXR can be produced semi-synthetically from daunorubicin, the process involves electrophilic bromination and multiple steps, and the yield is poor.[23] Since daunorubicin is produced by fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively.

Mechanism of action

Diagram of two doxorubicin molecules intercalating DNA, from PDB: 1D12​.[24]

Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis.[3][25][26] This inhibits the progression of the enzyme topoisomerase II, which relaxes supercoils in DNA for transcription.[27] Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication.[3] It may also increase quinone type free radical production, hence contributing to its cytotoxicity.[4]

The planar aromatic chromophore portion of the molecule intercalates between two base pairs of the DNA, while the six-membered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to the intercalation site, as evidenced by several crystal structures.[24][28]

By intercalation, doxorubicin can also induce histone eviction from transcriptionally active chromatin.[29][30] As a result, DNA damage response, epigenome and transcriptome are deregulated in doxorubicin-exposed cells.[29]

History

In the 1950s, an Italian research company, Farmitalia Research Laboratories, began an organized effort to find anticancer compounds from soil-based microbes. A soil sample was isolated from the area surrounding the Castel del Monte, a 13th-century castle. A new strain of Streptomyces peucetius, which produced a red pigment, was isolated, and an antibiotic from this bacterium was effective against tumors in mice. Since a group of French researchers discovered the same compound at about the same time, the two teams named the compound daunorubicin, combining the name Dauni, a pre-Roman tribe that occupied the area of Italy where the compound was isolated, with the French word for ruby, rubis, describing the color.[31] Clinical trials began in the 1960s, and the drug was successful in treating acute leukemia and lymphoma. However, by 1967, it was recognized that daunorubicin could produce fatal cardiac toxicity.[32]

Researchers at Farmitalia soon discovered that changes in biological activity could be made by minor changes in the structure of the compound. A strain of Streptomyces was mutated using N-nitroso-N-methyl urethane, and this new strain produced a different, red-colored antibiotic. They named this new compound Adriamycin, after the Adriatic Sea, and the name was later changed to doxorubicin to conform to the established naming convention.[18] Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. It also showed a higher therapeutic index, yet the cardiotoxicity remained.[33]

Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Subsequent research has led to many other anthracycline antibiotics, or analogs, and there are now over 2,000 known analogs of doxorubicin. By 1991, 553 of them had been evaluated in the screening program at the National Cancer Institute (NCI).[31] In 2016 GPX-150 was granted Orphan Drug designation by US FDA.[34]

Society and culture

Names

It is also known as hydroxydaunorubicin and hydroxydaunomycin.

It is sold under a number of different brand names, including Adriamycin PFS, Adriamycin RDF, or Rubex.[2]

Shortage

As of February 2014, Doxil was available in limited supply.[35] In 2011, Doxil became available only in very limited supply due to production problems with the third-party manufacturer. Johnson & Johnson (JNJ), through its subsidiary Janssen Products, LP, had been receiving its Doxil supply from contract manufacturer Ben Venue Laboratories (located in Bedford, Ohio), a unit of Boehringer Ingelheim GmbH of Germany.[36] The problems began when Ben Venue temporarily shut down their manufacturing facility due to quality control issues.[37]

In February 2012, to address the Doxil shortage, the US Food and Drug Administration (FDA) allowed for the temporary importation of Lipodox, which contains the same active ingredient as Doxil and is made by Sun Pharma Global FZE (Sun), a subsidiary of India's Sun Pharmaceutical Industries Ltd.[38] The agency said it intends to continue allowing the importation of Lipodox until Sun has made enough generic Doxil to meet demand.[39]

The FDA approved the first generic version of Doxil, made by Sun, in February 2013. It will be available in 20 milligram and 50 milligram vials.[40]

Research

Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt-positive lymphomas in mice.[41]

Recent animal research coupling a murine monoclonal antibody with doxorubicin has created an immunoconjugate that was able to eliminate HIV-1 infection in mice. Current treatment with antiretroviral therapy (ART) still leaves pockets of HIV within the host. The immunoconjugate could potentially provide a complementary treatment to ART to eradicate antigen-expressing T cells.[42]

Antimalarial activity

There is some evidence for antimalarial activity for doxorubicin and similar compounds. In 2009, a compound similar in structure to doxorubicin was found to inhibit plasmepsin II, an enzyme unique to the malarial parasite Plasmodium falciparum.[43] The pharmaceutical company GlaxoSmithKline (GSK) later identified doxorubicin in a set of compounds that inhibit parasite growth [44]

See also

References

  1. 1 2 3 "(doxorubicin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 15 April 2014.
  2. 1 2 3 4 5 6 7 8 9 Brayfield, A, ed. (19 December 2013). "Doxorubicin". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 15 April 2014.
  3. 1 2 3 Tacar, O; Sriamornsak, P; Dass, CR (February 2013). "Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems.". The Journal of Pharmacy and Pharmacology 65 (2): 157–70. doi:10.1111/j.2042-7158.2012.01567.x. PMID 23278683.
  4. 1 2 3 4 Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  5. ↑ "Doxorubicin: MedlinePlus Drug Information". www.nlm.nih.gov. Retrieved 2016-02-01.
  6. ↑ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
  7. 1 2 "DOXIL Product Information." Ortho Biotech Products, L.P. Retrieved on April 19, 2007. Archived September 21, 2007 at the Wayback Machine
  8. 1 2 "Liposomal doxorubicin (Caelyx, Myocet)". Macmillan Cancer Support. April 1, 2009. Retrieved 2009-11-27.
  9. ↑ "Doxorubicin liposomal". Chemocare. Cleveland Clinic. Retrieved 2009-11-27.
  10. 1 2 Chaterjee, Kanu; Jianqing Zhang; Norman Honbo; Joel S. Karliner (January 2010). "Doxorubicin Cardiomyopathy". Cardiology 115 (2): 155–162. doi:10.1159/000265166. PMC 2848530. PMID 20016174. Retrieved 22 January 2014.
  11. ↑ Kaczmarek A, Brinkman BM, Heyndrickx L, Vandenabeele P, Krysko DV J (2012). "Severity of doxorubicin-induced small intestinal mucositis is regulated by the TLR-2 and TLR-9 pathways.". J Pathol. 226 (4): 598–608. doi:10.1002/path.3009. PMID 21960132.
  12. ↑ Bloch, Richard; Bloch, Annette. "25 Most Asked Questions". Fighting Cancer. R. A. Bloch Cancer Foundation. Archived from the original on June 26, 2007. Retrieved 2007-06-28.
  13. ↑ Groopman, Jerome E. (2007). How Doctors Think. Boston: Houghton Mifflin. p. 49. ISBN 0-618-61003-0.
  14. ↑ Yeo W, Lam KC, Zee B, et al. (November 2004). "Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy". Ann Oncol 15 (11): 1661–6. doi:10.1093/annonc/mdh430. PMID 15520068.
  15. ↑ Dillon R, Hirschfield GM, Allison ME, Rege KP (2008). "Fatal reactivation of hepatitis B after chemotherapy for lymphoma". BMJ 337: a423. doi:10.1136/bmj.39490.680498.BE. PMID 18595895.
  16. ↑ http://www.nejm.org/image-challenge?ci=09012011&query=TOC
  17. 1 2 Lomovskaya N, Otten SL, Doi-Katayama Y, et al. (1999). "Doxorubicin overproduction in Streptomyces peucetius: cloning and characterization of the dnrU ketoreductase and dnrV genes and the doxA cytochrome P-450 hydroxylase gene". J. Bacteriol. 181 (1): 305–18. PMC 103563. PMID 9864344.
  18. 1 2 Arcamone F, Cassinelli G, Fantini G, et al. (1969). "Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius". Biotechnol Bioeng 11 (6): 1101–10. doi:10.1002/bit.260110607. PMID 5365804.
  19. ↑ Grimm A, Madduri K, Ali A, Hutchinson CR (1994). "Characterization of the Streptomyces peucetius ATCC 29050 genes encoding doxorubicin polyketide synthase". Gene 151 (1–2): 1–10. doi:10.1016/0378-1119(94)90625-4. PMID 7828855.
  20. ↑ Dickens ML, Strohl WR (1996). "Isolation and characterization of a gene from Streptomyces sp. strain C5 that confers the ability to convert daunomycin to doxorubicin on Streptomyces lividans TK24". J. Bacteriol. 178 (11): 3389–95. PMC 178102. PMID 8655530.
  21. ↑ Walczak RJ, Dickens ML, Priestley ND, Strohl WR (1999). "Purification, properties, and characterization of recombinant Streptomyces sp. strain C5 DoxA, a cytochrome P-450 catalyzing multiple steps in doxorubicin biosynthesis". J. Bacteriol. 181 (1): 298–304. PMC 103562. PMID 9864343.
  22. ↑ Hutchinson CR, Colombo AL (1999). "Genetic engineering of doxorubicin production in Streptomyces peucetius: a review". J. Ind. Microbiol. Biotechnol. 23 (1): 647–52. doi:10.1038/sj.jim.2900673. PMID 10455495.
  23. ↑ Lown JW (1993). "Anthracycline and anthraquinone anticancer agents: current status and recent developments". Pharmacol. Ther. 60 (2): 185–214. doi:10.1016/0163-7258(93)90006-Y. PMID 8022857.
  24. 1 2 Frederick CA, Williams LD, Ughetto G, et al. (March 1990). "Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin". Biochemistry 29 (10): 2538–49. doi:10.1021/bi00462a016. PMID 2334681. Crystal structure is available for download as a PDB file.
  25. ↑ Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Gewirtz DA (April 1994). "Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells". Mol Pharmacol 45 (4): 649–56. PMID 8183243.
  26. ↑ Momparler RL, Karon M, Siegel SE, Avila F (August 1976). "Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells". Cancer Res 36 (8): 2891–5. PMID 1277199.
  27. ↑ Pommier, Y; Leo, E; Zhang, H; Marchand, C (May 2010). "DNA topoisomerases and their poisoning by anticancer and antibacterial drugs.". Chemistry & Biology 17 (5): 421–33. doi:10.1016/j.chembiol.2010.04.012. PMID 20534341.
  28. ↑ Pigram WJ, Fuller W, Hamilton LD (January 1972). "Stereochemistry of intercalation: interaction of daunomycin with DNA". Nature New Biol 235 (53): 17–9. doi:10.1038/newbio235017a0. PMID 4502404.
  29. 1 2 Pang B, Qiao X, Janssen L, Velds A, Groothuis T, Kerkhoven R, Nieuwland M, Ovaa H, Rottenberg S, van Tellingen O, Janssen J, Huijgens P, Zwart W, Neefjes J (2013). "Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin". Nature Communications 4 (5): 1908. doi:10.1038/ncomms2921. PMID 23715267.
  30. ↑ Pang B, de Jong J, Qiao X, Wessels LF, Neefjes J (2015). "Chemical profiling of the genome with anti-cancer drugs defines target specificities". Nature Chemical Biology 11 (7): 472. doi:10.1038/nchembio.1811. PMID 25961671.
  31. 1 2 Weiss RB (December 1992). "The anthracyclines: will we ever find a better doxorubicin?". Seminars in Oncology 19 (6): 670–86. PMID 1462166.
  32. ↑ Tan C, Tasaka H, Yu KP, Murphy ML, Karnofsky DA (March 1967). "Daunomycin, an antitumor antibiotic, in the treatment of neoplastic disease. Clinical evaluation with special reference to childhood leukemia". Cancer 20 (3): 333–53. doi:10.1002/1097-0142(1967)20:3<333::AID-CNCR2820200302>3.0.CO;2-K. PMID 4290058.
  33. ↑ Di Marco A, Gaetani M, Scarpinato B (February 1969). "Adriamycin (NSC-123,127): a new antibiotic with antitumor activity". Cancer Chemother Rep 53 (1): 33–7. PMID 5772652.
  34. ↑ Investigational Sarcoma Drug GPX-150 Gets Orphan Drug Designation. 2016
  35. ↑ "Drug Shortages, doxorubicin". US Food and Drug Administration. Retrieved 2014-02-22.
  36. ↑ Peter Loftus (2011-07-21). "J&J is Short of Cancer Drug Doxil". Wall Street Journal.
  37. ↑ "Ben Venue Laboratories – Voluntary Shutdown". US Food and Drug Administration. 2011-11-30. Retrieved 2014-02-22.
  38. ↑ Harris, Gardiner (2012-02-21). "Shipments From Abroad to Help Ease Shortage of Two Cancer Drugs". New York Times. Retrieved 2014-02-22.
  39. ↑ Yukhananov, Anna (2012-02-21). "FDA acts to stem shortages of two cancer drugs". Reuters. Retrieved 2014-02-22.
  40. ↑ "FDA NEWS RELEASE". US Food and Drug Administration. 2013-02-04. Retrieved 2014-02-22.
  41. ↑ Wendel H, De Stanchina E, Fridman J, Malina A, Ray S, Kogan S, Cordon-Cardo C, Pelletier J, Lowe S (2004). "Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy". Nature 428 (6980): 332–7. doi:10.1038/nature02369. PMID 15029198.
  42. ↑ Johansson S, Goldenberg D, Griffiths G, Wahren B, Hinkula J (2006). "Elimination of HIV-1 infection by treatment with a doxorubicin-conjugated anti-envelope antibody". AIDS 20 (15): 1911–1915. doi:10.1097/01.aids.0000247111.58961.60. PMID 16988511.
  43. ↑ Friedman R, Caflisch A (2009). "Discovery of Plasmepsin Inhibitors by Fragment-Based Docking and Consensus Scoring". ChemMedChem 4 (8): 1317–26. doi:10.1002/cmdc.200900078. PMID 19472268.
  44. ↑ Gamo F-J; et al. (2010). "Thousands of chemical starting points for antimalarial lead identification". Nature 465 (7296): 305–310. doi:10.1038/nature09107. PMID 20485427.

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