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Current Medicinal Chemistry, 2011, 18, 1509-1514 1509
Exploring Old Drugs for the Treatment of Hematological Malignancies
F. Gan#,1,2, B. Cao#,1, D. Wu1, Z. Chen1, T. Hou*,3 and X. Mao*,1,4 1Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, China 2Department of Pharmacy, The First Hospital, Xianning University, Xianning, China 3Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, China 4Department of Pharmacology, School of Pharmacy, Soochow University, Suzhou, China Abstract: Drug discovery is costly and time-consuming, but it will become easier and simpler if a drug could be developed from an old
one with well-documented investigations associated with pharmacology, pharmacokinetics, toxicology and clinical safety. In terms of
hematological malignancies, several successful drugs have been discovered and developed from old ones such as arsenic trioxide for
acute promyelocytic leukemia and thalidomide for multiple myeloma. In this review, we discussed the latest advancement in exploring
old drugs for the treatment of hematological malignancies.
Keywords: Drug repositioning, drug discovery, old drug, hematological malignancy.
1. INTRODUCTION
patent agreement, such as ampicillin; ii) those drugs withdrawn from the market due to its latent toxicity, such as thalidomide; iii) Drug discovery is a complicated systemic engineering requiring ancient drugs. This kind of drugs are traditional in most Eastern or investment of capital, human resources, and various technology African countries and have been used for hundreds of years or expertise. More importantly, it requires strict adherence to regula- longer but not scientifically developed in modern era; iv) to a cer- tions on testing and manufacturing standards, thus, development of tain extent, old drugs should also include those candidates aborted a novel drug is time-consuming and costly. According to a recent during the evaluation because of its efficacy or safety issues; v) analysis of 68 approved drugs, it takes an average of 10 to 15 years currently, most researchers also regard those on-patent drugs as old and US$ 800 million to bring a single drug from bench to patient’s drug resources because of its established safety evaluation and po- bedside [1]. By further analysis, the cost is steadily increased tential application for new indications. mainly due to the low successful rate and the high expenses in the safety evaluation and clinical trials. It would also expand the re- 3. OLD DRUGS ARE HOPES OF HEMATOLOGICAL MA-
sources for postmarketing safety surveillance to $29.3 million [2]. LIGNANCIES
For fiscal year 2008, it would be nearly $400 million, accounting for more than 40% of FDA resources for drug regulation [2]. To con- Reviewing the history of the drug discovery, especially in the trol the escalating high cost and increase the ebbing marketing rate application of old drugs, one can find that most successful cases are in the R & D of new drugs, scientists have incepted various strate- found in hematological malignancies (Table 1), and these drugs
gies and developed advanced technologies, of which re-evaluation include arsenic trioxide for acute promyelocytic leukemia (APL) [6, of old drugs has emerged as the most rapid and most efficient way 7], dexamethasone and prednisolone for multiple myeloma (MM) [3, 4]. As we have known that almost all drugs used in human ther- [8, 9], and thalidomide for MM [10, 11], chronic lymphoid leuke- apy possess more than one kind of acting targets and display major mia (CLL) [12] and mantle cell lymphoma (MCL) [13]. In addition, and/or minor actions thus bringing one or several pharmacological several other old drugs also display potential activity in the treat- side effects in addition to their main activity [5]. In some cases, ment of leukemia and myeloma and have been currently evaluated such “side” effects are therapeutic for other diseases. To extend at preclinical or clinical settings (Table 1).
such old drugs, a new term “ Drug repositioning” or “Drug repur-posing” has emerged and new uses for old drugs has raised great 3.1. Arsenic Trioxide
interest among drug scientists and clinicians [5]. Actually some old drugs have been developed for new indications, such as aspirin for Arsenic trioxide has been used for the treatment of cancers and stroke, sildenafil (Viagra) for erection dysfunction and other disorders for more than 500 years in China [14]. In Western methotrexate for rheumatoid arthritis (Table 1). In this review, we
countries, arsenic derivatives were once used for syphilis treatment discussed latest advancement in repositioning old drugs for hemato- [14]. However, arsenic exposure induces cardiovascular diseases, logical malignancies and the discovery strategies. developmental abnormalities, neurological and neurobehavioral disorders, diabetes, hearing loss, hematological disorders, and vari- 2. WHAT IS AN OLD DRUG?
ous types of cancers [15]. Due to toxic side effects of long-term heroic-dose of oral arsenic in most patients, and with the advent of Generally, an old drug should be “of age”, but latest concepts in modern radiotherapy and chemotherapy, the arsenic treatment for old drug repositioning indicate that an old drug sometimes is not CML was abandoned in Western medicine. But in China, the study very “old”. An old drug could be defined as the following catego- on arsenic trioxide has never stopped. In 1971, they started a large ries: i) off-patent drugs. These kinds of drugs have been used for a scale clinical trial in more than 1000 cases of different types of certain period and become generic and are not protected by the cancers by i.v. administration of arsenic trioxide [16]. Therapeutic effects were observed in several cancer types, including CML, lym- *Address correspondence to these authors at the Institute of Functional Nano & Soft phoma, esophageal cancer, and particularly APL. The preliminary Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional result in APL was reported in 1992 [16]. They found that a prepara- Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China; Tel: +86 tion containing arsenic with a trace amount of mercury chloride was (512) 65882039; Fax: +86 (512) 65882846; E-mail: [email protected] Laboratory of Targeted Anti-leukemia Drug Discovery, Cyrus Tang Hematology Center, Soochow University, 199 Ren Ai Road, Room703-507, Suzhou Industrial Park, cal complete remission (CR) up to 84% without major toxic side Suzhou, Jiangsu 215123, China; Tel: +86 (512) 65880877 ext 507; Fax: +86 (512) effects [16]. Moreover, 28% of the patients survived more than 10 65882123; E-mail: [email protected] years [16, 17]. Following this study, a small scale clinical trial was #These authors contributed equally to this study. 0929-8673/11 $58.00+.00
2011 Bentham Science Publishers Ltd.
1510 Current Medicinal Chemistry, 2011 Vol. 18, No. 10
Gan et al.
Old Drugs Were Developed for Hematological Malignancies
Drugs Original
Indications* New
Indications**
Notes and refs.
Blood cancers, mainly for Acute Promyelocytic Leukemia Leukemia, Mantle cell lymphoma, and Myeloma Multiple Myeloma and other Plasma Cell Neoplasm *indicates those diseases the drugs were originally designed for. **includes those indications approved by FDA or those potential applications. held in USA, and 11 of the 12 patients studied achieved complete genesis [32, 33]. Therefore thalidomide was immediately with- remission after treatment that lasted from 12 to 39 days [18]. Stud- drawn from market in 1961. Research on thalidomide slowed down ies on the mechanism of action indicated that arsenic trioxide pre- in the 1960s, but never stopped. Several lines of mechanisms of sents dual activities (induction of apoptosis and differentiation) on teratogenesis were proposed including angiogenesis inhibition [32, APL cells in vivo and in vitro [19]. Apoptosis induced by arsenic 34], free radical-mediated oxidative DNA damage [35], and inhibi- trioxide is associated with the insult of mitochondrial and the acti- tion on IGF1 and FGF2 expression [34, 36]. All these molecular vation of caspases. The differentiation of APL cells is closely re- events are associated with cancer development. Thalidomide was lated to the modulation of PML-RAR, the key protein in leu- first tested as a single agent for the treatment of multiple myeloma kemogenesis [20]. Recent studies indicate thioredoxin reductase is a in 1999 for its anti-angiogenesis activity [33], followed by a series target of arsenic trioxide [21]. Arsenic trioxide was approved by the of successful multicenter clinical trials which ensured thalidomide US FDA for acute promyelocytic leukemia [22] and is used as one was approved by the FDA. Thalidomide analogues such as le- nalidomide were also developed and are more powerful, but with fewer side effects [37]. Thalidomide and lenalidomide are now used as a first line therapy for multiple myeloma. The discovery of tha- 3.2. Glucocorticoids
lidomide was believed as a breakthrough in the therapy of multiple Dexamethasone was first synthesized in late 1950s and imme- myeloma in the last 30 years. Thalidomide has also been evaluated diately became a new star in the corticosteroid family. In addition in a number of other hematological disorders, including AML [38, to its general application in the inflammatory and autoimmune dis- 39], myelofibrosis with myeloid metaplasia and MDS, and some eases, dexamethasone is also used to protect patients from the side- effects of chemotherapeutical agents. In 1972, one group found that cells of a cloned myeloma line from a Balb/c mouse bearing spe- 4. DISCOVERY STRATEGIES FOR DRUG REPOSITION-
cific cytoplasmic glucocorticoid receptors could be killed by dex- amethasone [23]. Further studies indicated that dexamethasone-induced myeloma cell death are associated with both apoptotic and With the success of old drugs in the treatment of several dis- autophagy signals [24]. For example, dexamethasone induced cyto- eases, scientists are becoming more and more interested in drug chrome C-dependent and independent apoptosis [25] by changing repositioning. Recently, several papers have been published in the conformation of Bax and Bim [26]. Recent studied indicated highly-ranked journals to call for drug discovery from the old ones that autophagy is a novel pathway induced by dexamethasone [27]. [3, 4, 41-43]. They not only called for the reformation in the law The caspase inhibitor Z-VAD-fmk inhibited apoptosis but not auto- system thus paving the road that allows old drugs used in valuable phagy in Dexamethasone-treated cells [27]. Following the first new ways [43], but also developed new strategies for the reposition- report, more and more investigations have demonstrated that dex- ing of old drugs. Generally speaking, those strategies could be clas- amethasone is very effective to myeloma cancer cells alone or in combination with other drugs, such as doxorubicin, vincristine and even most recent drugs such as thalidomide and Bortezomib [28]. 4.1. Serendipity
Dexamethasone is now the backbone in the prescription of multiple myeloma treatment. Recently, dexamethasone was introduced to the Based on the mechanistic understanding, some physicians would try their applications in some off-labeled diseases. Legally, treatment of chronic lymphoid leukemia [29, 30] and relapsed lym- off-label use is the practice of prescribing pharmaceuticals for an phoma [31]. Our recent study demonstrated that not only dex-amethasone and prednisolone, but all other glucocorticoids display unapproved indication and it is empirical and sometimes leads to great discovery. The best example is the application of thalidomide anti-myeloma activity for cells bearing c-maf and cyclin D2 [58]. in leprosy [44]. As stated earlier in this paper, thalidomide was developed as a sleeping drug for morning sickness during preg- 3.3. Thalidomide
nancy, and was withdrawn from the market in 1961 due to its tera- Thalidomide was originally developed in the 1950s for the togenicity. However, 3 years later, Dr. Jacob Sheskin, Professor at treatment of pregnancy-associated morning sickness and was first the Hebrew University of Jerusalem at Hadassah University Hospi- marketed in 1957 as a "wonder drug" for insomnia, coughs, colds tal, administered thalidomide to a critically ill patient with erythema and headaches because its sedative-hypnotic effects. However, nodosum leprosum in an attempt to relieve his pain in spite of the thalidomide was soon found to be associated with malformation. In ban. To his surprise, thalidomide was effective in control of the the late 1950s and early 1960s, more than 10,000 children in 46 symptoms of this disorder. The result was followed by more favor- countries were born with deformities such as phocomelia as a con- able experiences and then by a clinical trial [44,45]. Mechanisti- sequence of thalidomide use associated with its inhibition on angio- cally, thalidomide cures leprosy by inhibiting tumor necrosis factor Old Drugs for Blood Cancer Therapy
Current Medicinal Chemistry, 2011 Vol. 18, No. 10 1511
alpha [46-48]. The FDA has since approved the drug's use in the antagonists dichloroisoprenaline (DCI) and pronethalol [52] (Fig. treatment of erythema nodosum leprosum. Thalomid, as the drug is 1a). DCI is a non-selective blocker for the 1-adrenergic and 2-
commercially known, sold over $300 million per year in United adrenergic receptors, but it has low potency. Pronethalol was a promising clinical candidate with similar structure to DCI but showed carcinogenicity in mice. However, the insertion of a 4.2. Exploration of the Side Activities
methoxy bridge into the arylethanolamine structure of pronethalol
(Fig. 1a) will increase the potency of the compound and eliminate
Almost all drugs present one or more pharmacological side ef- the carcinogenicity being found with pronethalol in animal models fects because they can act on more than one target molecules or [52]. Similar efforts have brought newer and more selective beta- organs. However, these side effects are possibly important in differ- blockers (such as nebivolol) in the treatment of hypertension [71]. ent clinical settings and could lead to a therapeutic outcome to an-other disorder. The best example is the discovery of sildenafil. Sild- Based on thalidomide, several derivatives were successfully synthesized such as lenalidomide and pomalidomide (Fig. 1b). This
enafil was originally designed for the treatment of angina pectoris secondary generation of thalidomide has been fully developed and and hypertension. However, when it was applied for clinical trials for patients of angina, it displayed no positive return. In contrast, displays more powerful therapeutic efficacy but less toxicity than thalidomide [53]. Of them, lenalidomide was approved for clinic continuous penile erection was noticed in patients. Then it was earlier than thalidomide by FDA. In our exploration of clioquinol, moved to the treatment of erection dysfunction (ED) [70] and achieved a great success. Thalidomide in the treatment of MM is we designed and tested a series of clioquinol analogs and found that
5-amino-8-hydroxyquinoline (5AHQ, Fig. 1c) is more potent and
another good example. As we stated earlier, thalidomide is terato- effective in inhibiting proteasomal activity than clioquinol. Further genic by inhibiting VEGF signaling thus disrupting angiogenesis during the formation of limbs[30,31]. Angiogenesis is proposed as studies suggested that 5AHQ overcomes bortezomib-resistance and induces cell apoptosis synergistically with bortezomib [69]. an important factor in myeloma development because increased bone marrow vascularity and angiogenesis-associated signals of IL-6, VEGF, FGFR are frequently seen in myeloma [49]. Thus tha- 4.5. High Throughput Screening
lidomide was challenged for myeloma treatment in a clinical trial in The above-discussed four strategies have led to the successful 1999 using its antiangiogenic activity [33]. It turned out great re- discovery of some drugs in the past decades. However, with the mission after myeloma administration which finally led to the wide advancement in the genomics, proteomics, and informatics technol- application in myeloma. Currently, French Prestwick chemical ogy, scientists are able to manipulate a large set of compounds si- company developed a protocol called SOSA approach (Selective multaneously to develop a novel drug from old ones. There are Optimization of Side Activities) [50]. The objective of SOSA is to several collections of old drugs available from commercial and proceed to a reversal of affinities, such that the identified side effect public sectors, including (1) LoPac Library (Sigma-Aldrich), which becomes the principal activity and vice versa. Prestwick has docu- contains 1280 well-documented pharmacologically-active com- mented an array of off-patent drugs for novel drug discovery. We pounds (most of them are off-patent drugs); (2) Prestwick chemical have screened this library and found several compounds for poten- library from French Prestwick Chemical Co., which is composed of 1120 off-patent medicines (>85% are clinical pharmaceutics); (3) Spectrum Collection (MicroSource Discovery Systems, Inc.), con- 4.3. Development of Ancient or Traditional Drugs Using Mod-
taining 2000 biologically active and structurally diverse compounds ern Approaches
including known drugs; (4) NIH Brain Bioactive Compound Col-lection, a large collection of available medications including CNS Ancient or traditional drugs are a great heritage of human be- ings and have been long used in some countries. However, evalu- or CNS-like active compounds. These libraries have paved a solid base for the identification of novel indications by means of high ated under the modern standards, those old drugs are not safe throughput screening which includes two basic strategies: enough or don’t display high efficacy thus being abandoned. The best example is arsenic trioxide as stated earlier. Another example Phenotype-based, or end-point, screening. In this strategy, is harringtonine (HT). Harringtonine is a cephalotaxus alkaloid an aliquot of each old drug is added to blood cancer cells of from the evergreen tree Cephalotaxus harringtonia K. Koch var interest. After a defined period of incubation, cell viability harringtonia present in China [51]. Seeds of this genus of conifers is evaluated. Those drugs with ability to induce cancer cell were part of the Traditional Chinese Medicine (TCM) since 1400s but are toxic to humans [51]. To improve its application, Chinese Molecule-targeted screening. In this strategy, we first take investigators applied modern analytic methods and isolated four advantage of cancer genomics and proteomic advancements alkaloids including homoharringtonine (HHT) which display sig- and choose one or two molecules as the screening targets nificant antitumour activity. Clinical trials were performed in the for novel indications of old drugs. Most of blood cancer U.S. using continuous infusion schedules of 3-7 mg/m2 daily for 5- cells are featured with chromosomal aberrations, such as 7 days initially, and later lower dose schedules of 2.5 mg/m2 daily translocation, deletion, and insertion, which lead to novel for 7-14 days. Results in solid tumors were negative. However, fusion genes or dysregulated genes. Best examples are the encouraging results were reported in patients with AML, myelo- BCR/ABL fusion gene due to the reciprocal translocation dysplastic syndrome, APL, and CML [51]. Currently, HHT has denoted as t(9;22)(q34;q11) in chronic myelogenous leu- been widely used for leukemia in China. And new semisynthetic kemia and the PML/RAR
fusion gene due to the transloca- preparations and HHT derivatives that bypass multidrug resistance tion denoted as t(15;17)(q22;q12) in acute promyelocytic may improve the efficacy and toxicity profiles, and broaden the leukemia. Drug discovery targeting these cancer-specific genes will be molecular mechanism-oriented and, more im-portantly, because the molecules are usually cancer- 4.4. Structural Modification
specific, those drugs are less toxic and more effective in the treatment of blood cancer patients. We have applied this Similar compounds with the same core structure theoretically strategy to screen three small off-patent libraries and found share the similar biological and pharmacological activity. The struc-tural modification can improve drug efficacy and decrease the tox- that old drugs such as clioquinol [54] and cyproheptadine [55] show potential for the treatment of leukemia and mye- icity of a lead candidate. Propranolol, the first successful non- selective beta blocker, was derived from the early -adrenergic 1512 Current Medicinal Chemistry, 2011 Vol. 18, No. 10
Gan et al.
Fig. (1). Drug discovery by structural modification. a, Propranolol was derived from the early
-adrenergic antagonists dichloroisoprenaline (DCI) and
pronethalol. The insertion of a methoxy bridge (*) into the arylethanolamine structure of pronethalol increases the potency of the compound and apparently
eliminates the carcinogenicity found with pronethalol in animal models. b, More potent lenalidomide and pomalidomide are derived from thalidomide by
adding amino group. c. 5-amino-8-hydroxyquinoline was developed from clioquinol by replacing the chloride with amino at position 5 and removing the io-
dine.
5. OUR EXPERIENCE
breast and prostate cancer apoptosis in the presence of copper [65, 66]. In our effort to seek inhibitors of cyclin D2 transactivators, we Multiple myeloma is an incurable plasma cell malignancy fea- found that clioquinol could significantly decrease D-cyclins at both tured with various chromosomal translocations and dysregulated protein and mRNA levels. Mechanistically, Clioquinol-induced genes such as D-cyclins and c-maf. At least one of the 3 cyclin Ds cancer cell apoptosis is associated with its inhibition on proteaso- (CCND1, CCND2 and CCND3) is dysregulated in any MM cells mal activity [54, 66]. Further investigations suggested that clioqui- [56]. Cyclin D2, along with its transcription factor c-maf, was re- nol alone can induce cell apoptosis of leukemia or myeloma cells ported in more than 50% of MM cell lines and patient samples, and and can delay tumor growth in leukemia cell xenografted mice, is an indicator of poor prognosis [57, 58]. D-cyclins coordinate with which is different from solid tumors such as breast and prostate cyclin-dependent kinase 4 or 6 (CDK4/6) to phosphorylate the tu- cancer xenografts [54]. This kind of apoptosis induction is critical mor suppressor pRb thus activating transcription factor E2F and for the treatment because if clioquinol-induced cancer cell death is enabling cell cycle progress to S phase from G1 phase [59]. Thus dependent on copper addition and it will add additional toxicity to inhibition of cyclin D could arrest MM cells in G1 phase and in- patients due to the accumulative toxicity of copper. Our clioquinol duce cell apoptosis [59]. Based on this hypothesis, we designed a has been approved by Health Canada for clinical trial in the treat- high throughput screening system using cyclin D2 promoter-driven ment of refractory and/or relapse acute myelogenous leukemia. firefly luciferase as a reporter and screened old drug libraries LO-PAC, Prestwick and Spectrum [58]. Through this screen, we identi- 5.2. Cyproheptadine
fied the off-patented drugs clioquinol [54] and cyproheptadine [55] as potential therapeutics for both myeloma and leukemia, and we Cyproheptadine is a typical antihistamine/anticholinergic and also found natural products such as pristimerin [60] and kinetin antiserotonergic agent. It acts as a 5-HT2 receptor antagonist and riboside [61] for the treatment of blood cancers. also blocks calcium channels. Cyproheptadine is mostly used to treat allergic reactions such as hay fever and also used to treat 5.1. Clioquinol
nightmares and manage serotonin syndrome and is also used to treat unintentional weight loss in patients with cancer [67], but it has Clioquinol is an antifungal and antiprotozoal drug developed in never been reported for its proapoptotic or anti-cancer activity. In 1930s and was very effective in anti-infective, intestinal our efforts to look for the inhibitors of cyclin D transactivation by a antiamebic, and vaginal trichomonacide and soon was marketed high throughput screening, we found that cyproheptadine is able to worldwide. However, clioquinol was suspected to be highly associ- inhibit all 3 types of cyclin Ds in all the tested leukemia and mye- ated with subacute myelo-optic neuropathy (SMON) between 1957 loma cell lines by inhibiting several transcription factors such as and 1970 [62]. It has thus been restricted or discontinued in some AP-2 [55]. Further studies indicated that cyproheptadine can shrink countries. Recently, clioquinol was revitalized as a novel agent in tumors of AML and myeloma xenografted mice models [55]. Re- the treatment of Alzhemier’s Disease [63] and Huntington’s Dis- cent study indicated that cyproheptadine can also synergizes with ease [64]. In 2005, it was reported to be a potential drug to induce Bortezomib in the treatment of mantal cell lymphoma by inhibiting Old Drugs for Blood Cancer Therapy
Current Medicinal Chemistry, 2011 Vol. 18, No. 10 1513
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6. CONCLUSIONS
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Grander, D.; Kharaziha, P.; Laane, E.; Pokrovskaja, K.; Panaretakis, T. Autophagy as the main means of cytotoxicity by glucocorticoids in hemato- ACKNOWLEDGEMENTS
logical malignancies. Autophagy, 2009, 5, 1198-1200.
Chauhan, D.; Pandey, P.; Ogata, A.; Teoh, G.; Krett, N.; Halgren, R.; Rosen, The authors thank Dr. Aaron D. Schimmer at Ontario Cancer S.; Kufe, D.; Kharbanda, S.; Anderson, K. Cytochrome c-dependent and - Institute, Princess Margaret Hospital, University Health Network, independent induction of apoptosis in multiple myeloma cells. J. Biol. Toronto, Canada, for his critical discussion. This project was sup- Chem., 1997, 272, 29995-29997.
Lopez-Royuela, N.; Balsas, P.; Galan-Malo, P.; Anel, A.; Marzo, I.; Naval, J. ported by Jiangsu Provincial Natural Science Foundation (Grant Bim is the key mediator of glucocorticoid-induced apoptosis and of its poten- No. BK2010218), by the National Basic Research Program (“973” tiation by rapamycin in human myeloma cells. Biochim. Biophys. Acta., Program, Grants No. 2011CB933501, and 2011CB933503), by 2010, 1803,311-322.
Suzhou City Science and Technology Program (Social Develop- Swerdlow, S.; McColl, K.; Rong, Y.; Lam, M.; Gupta, A.; Distelhorst, C.W. Apoptosis inhibition by Bcl-2 gives way to autophagy in glucocorticoid- ment Project, Grant No. SS201033), and by National Natural Sci- treated lymphocytes. Autophagy, 2008, 4, 612-620.
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Received: December 15, 2010
Revised: March 05, 2011
Accepted: March 06, 2011

Source: http://cadd.suda.edu.cn/Group/papers/review10.pdf