lI.Two Hundred Years of Drug Discoveries 25 FIGURE 1.24 Jean-Francois Borel individuals in the medical and ommunity spent the nex ean-Francois Borel.(Figure 1.24)who worked for FIGURE 123 George Hitchings and Gertrude Elion Sandoz Pharmaceuticals(Basel,Switzerland).He discov. and Gertrude Elion(Wellcome Research,Tuckahoe,USA) “h (Figure 1.23)pioneered the design of immunosuppressant uted to the discovery and characterization of the biol ical demonstrating also anticancer activity.4 The corticoster profile of what will become a revolutionary drug.its use in T adi.com was isolated from the quently used as immunosunn ants in yarious clinical sit Borel discov red that unlike immunosu sants tha acted indiscriminately,thiscompound selectively suppressed the T-cells of the immune system.Excited by these charac sup des the n luction and rele press inflammatory responses through release of adenosine of IL-2 by Thelper white blood cells.Secondly.it inhibits they suppress immune responses by inducing the apoptosis sion on both T-helper and T-cytotoxic cytes andn ng the synt ite duction thus leading to a dec se in the purine synthesis.47 Often,their mechanisms of action were activated lymphocyte.In addition,these compounds have established long after their discovery.For inst ance,gluco ecently bee n found to block signaling pathways triggered expre 148 for nte by ant contr ell rapamy period"of the 1950s and 1960s when corti ids wen also induces moposed to prevent organ reiection in renal transplantation T-lymphoc es mofeil reduces the prolif harmacology helped Isurgery to enter a new era of opti eration of T-cell by inhibiting purine synthesis and by it sm, nproving a monophosp e after the first heart of activ T-Iymp transplant performed in Cape Town in 1967 by Christiaan (globulines)deplete circulating lymph while selective
II. Two Hundred Years of Drug Discoveries 25 and Gertrude Elion (Wellcome Research, Tuckahoe, USA) ( Figure 1.23 ) pioneered the design of immunosuppressants demonstrating also anticancer activity. 144 The corticosteroids were used in 1948 by Kendall and Hench and gave the spectacular demonstration of their successful use in patients with Rheumatoid Arthritis (RA). They were subsequently used as immunosuppressants in various clinical situations. Among immunosuppressants described, a nitrogen mustard-like 145 , cyclophosphamide, alkylates DNA bases and preferentially suppresses immune responses mediated by -lymphocytes. Methotrexate and its polyglutamate derivatives suppress infl ammatory responses through release of adenosine; they suppress immune responses by inducing the apoptosis of activated T-lymphocytes and inhibiting the synthesis of both purines and pyrimidines. 146 Azathioprine, studied by Roy Calne (Cambridge, UK), inhibits several enzymes of purine synthesis. 147 Often, their mechanisms of action were established long after their discovery. For instance, glucocorticoids inhibit the expression of genes coding for interleukin-2 (IL-2) and other mediators. 148 After the “ heroic period ” of the 1950s and 1960s when corticosteroids were proposed to prevent organ rejection in renal transplantation, pharmacology helped surgery to enter a new era of optimism, characterized by improving allograft survival rates. Revolutionary methods of rejection treatment have been responsible for this new era 149 few years after the fi rst heart transplant performed in Cape Town in 1967 by Christiaan Barnard. A few determined individuals in the medical and research community spent the next two decades attempting to solve the organ rejection puzzle. One of these scientists was Jean-Francois Borel, ( Figure 1.24 ) who worked for Sandoz Pharmaceuticals (Basel, Switzerland). He discovered the immunosuppressant agent that ultimately moved transplantation from the realm of curiosity into routine therapy. Both J. Borel and H. Stähelin markedly contributed to the discovery and characterization of the biological profi le of what will become a revolutionary drug. 150 In its subsequent exploitation, Borel played the leading role 151 . He chose to examine a compound that was isolated from the soil fungus Tolypocladium infl atum Gams. Borel discovered that, unlike immunosuppressants that acted indiscriminately, this compound selectively suppressed the T-cells of the immune system. Excited by these characteristics, Borel continued his study and, in 1973, purifi ed the compound called cyclosporine. 152 Cyclosporine is active in two ways. First, it impedes the production and release of IL-2 by T-helper white blood cells. Secondly, it inhibits IL-2 receptor expression on both T-helper and T-cytotoxic white blood cells. Tacrolimus and cyclosporine, known as calcineurin inhibitors, act on the IL-2 by inhibiting its production thus leading to a decrease in the proliferation of the activated lymphocyte. In addition, these compounds have recently been found to block signaling pathways triggered by antigen recognition in T-cells. 153 In contrast, rapamycin inhibits kinases required for cell cycling and responds to IL-2. Rapamycin also induces apoptosis of activated T-lymphocytes. Mycophenolate mofetil reduces the proliferation of T-cell by inhibiting purine synthesis and by its action on inosine monophosphate dehydrogenase, thereby depleting guanosine nucleotides and inducing apoptosis of activated T-lymphocytes. 154 Antilymphocyte antibodies (globulines) deplete circulating lymphocytes while selective FIGURE 1.23 George Hitchings and Gertrude Elion . FIGURE 1.24 Jean-François Borel . Ch01-P374194.indd 25 h01-P374194.indd 25 5/29/2008 5:42:14 PM /29/2008 5:42:14 PM
■26 CHAPTERI A History of Drug Discovery monoclonal antibodies are directed against IL-2 receptor hiTt的ciethcte,tprmirferianofarctatedTces the otent and verse agents vtion cascade.thmnma ffects.thus improving graft and patient survival rates. E.Contribution of chemists to the fight against cancer 1.Drugs against the cancer cell Chemistry has had a major role in the discovery and of the mustard family of FIGURE 1.25 Catharanthus roseus agents in the first half of the 20th century.The application of medicinal chemistry to sulfur mustard gas led to agents today.The change of a sulf (a)Nitrogen mustards (b)Vinca alkaloids,taxans and other plant anticancer drugs alkyl a anti riethylamine was the prototype first studied by pharma- s with inter cologists from Yale University (USA).Louis S.Goodman. cancer properties might still appear through chance in the Maxwell Win robe am Dar future,especially from natural products. Second,synthetic used tos ds discovere results obtained in patients treated for Hodgkin's disease PP lymphosarcoma,and leukemia by this first nitrogen mus- tard.Indeed,in the first two disorders,dramatic improve expressed from woody night ade (Solanum dulcamara mpressive prop to treat t ors and constant success in hematological malignancies where han 1.600 obtained when Vin the leaves of the subtropical plant Catharanthus roseus (L) P ased in 19/0 the response (Figure 1.25)Madagas car periwinkle,were reputed amon vith therapy combining mec hamine. uperior to that sly reported with the use of sin ndole alkaloids vinblastine and vincristine which are a complete remission defined as the complete disappear mor eukemias,and c cers as s cell cervical ar fosfamide were further deve ess differ y in uc ASTA pharmaceuticals (Bielefeld,Germany).Brock and tumors that they affect and in their toxic properties.From his team synthesized and screened moe than 1,000 cand the use of Podophyllum in ancient China,a lot of plant main effe rivatives are being used in cancerc chemo
26 CHAPTER 1 A History of Drug Discovery monoclonal antibodies are directed against IL-2 receptor thus reducing the rate of proliferation of activated T-cells. With the availability of such potent and diverse agents it is now possible to develop multi drug regimens that can depress the immune system at the different steps of the activation cascade, with minimal side effects, thus improving graft and patient survival rates. 155 E . Contribution of chemists to the fi ght against cancer 1 . Drugs against the cancer cell Chemistry has had a major role in the discovery and development of most new anticancer drugs, and some of these are still relevant to drug discovery today. The dawning of cancer chemotherapy is generally accepted to have been the serendipitous discovery of the mustard family of agents in the fi rst half of the 20th century. The application of medicinal chemistry to sulfur mustard gas led to agents that are still clinically useful today. The change of a sulfur atom in favor of a nitrogen one transformed the worse war weapon into a benefi cial drug active against cancer. (a) Nitrogen mustards Thus, the fi rst agents were nitrogen mustards (halogenated alkyl amine hydrochlorides) among which 2-2 -2 -trichlotriethylamine was the prototype fi rst studied by pharmacologists from Yale University (USA). Louis S. Goodman, Maxwell M. Wintrobe, William Dameshek, Morton Goodman, Alfred Gilman, and Margaret McLennan 156 performed in 1943 but only presented in 1946, the salutary results obtained in patients treated for Hodgkin’s disease, lymphosarcoma, and leukemia by this fi rst nitrogen mustard. Indeed, in the fi rst two disorders, dramatic improvement has been observed in an impressive proportion of terminal and so-called radiation resistant cases. First constant success in hematological malignancies where obtained when Vincent T. De Vita, Arthur A. Serpick, and Paul P. Carbone (NCI) increased in 1970 the response rate with “ MOPP ” therapy combining mechlorethamine, vincristine, procarbazine, and prednisone. This protocol was superior to that previously reported with the use of single drugs with 35 of 43, or 81% of the patients achieving a complete remission, defi ned as the complete disappearance of all tumor and return to normal performance status. 157 Cyclophosphamide and the related alkylating agent ifosfamide were further developed by Norbert Brock for ASTA pharmaceuticals (Bielefeld, Germany). Brock and his team synthesized and screened more than 1,000 candidate oxazaphosphorine compounds. 158 The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard which is only formed in cells with low levels of aldehyde deshydrogenase. Phosphoramide mustard forms DNA cross links between and within DNA strands at guanine N-7 positions, leading to cell death. (b) Vinca alkaloids, taxans and other plant anticancer drugs Although “ serendipity ” is not a reliable source of new anticancer-drug leads, more molecules with interesting anticancer properties might still appear through chance in the future, especially from natural products. Second, synthetic chemistry has been used to modify drug leads discovered in plant material – the so-called semi-synthetic approach. A lot of anticancer drugs have been extracted from plants. 159 Eighteen centuries ago, Galen proposed the juice expressed from woody nightshade ( Solanum dulcamara ) to treat tumors and warts, which has been demonstrated to exert anti-infl ammatory properties. 160 In the recent decades, more than 1,600 genera have been examined. 161 Extracts of the leaves of the subtropical plant Catharanthus roseus (L.), ( Figure 1.25 ) Madagascar periwinkle, were reputed among ethnobotanists to be useful in the treatment of diabetes. The attempt to verify the antidiabetic properties of the extracts led instead to the discovery and isolation of two complex indole alkaloids, vinblastine and vincristine, which are used in the clinical treatment of a variety of lymphomas, leukemias, and cancers as small cell lung or cervical and breast cancer. 162 The two alkaloids, although structurally almost identical, nevertheless differ markedly in the type of tumors that they affect and in their toxic properties. From the use of Podophyllum in ancient China, a lot of plant derivatives are being used in cancer chemotherapy: two glycosides were extracted to prepare podophyllotoxin, and subsequently two semi-synthetic derivatives, etoposide and FIGURE 1.25 Catharanthus roseus . Ch01-P374194.indd 26 h01-P374194.indd 26 5/29/2008 5:42:20 PM /29/2008 5:42:20 PM
Il.Two Hundred Years of Drug Discoveries 27 sopened,US President Richarc the" with ar dollars of new funding.This may explain why,in the fol- lowing years,many new compounds with antineoplasti n plants. Among them.the pyr alate botu from Chinese tree br pectrum anticancer and clinical studies.If the parent alkaloid is inactive.the esters harringtonine and homoharringtonine obtained Ceph and M ing to Hagop M SA). tumors or leukemias. The most enthusiastic reports conce the diterpenoid paclitaxe (from Taxus revifolia and FIGURE 1.26 Pierre Potier 20ch7 had v.This tree was known as a toxic plant for animals and difficult conversion of 10-DAB into paclitaxel,in 1988 humans for centuries Monroe E.Wall and Mansukh C with only four steps with an overall yield being 35%,still Re search In Park (Chapel Hill. commercia the D he yew of Mo covery and de f ant Pharmacology,Albert Einstein College of Medicine (New a paclitaxel semi-synthetic analog.docetaxel (Taxotere). York) sugg sted that paclitaxel's mechanism of actior by Pierre Potier et al.represent significant advances in was different from that of any previou ptients with a varicty of malignanci xel and a sin indi fibroblast cells in the G2 and M phases of the cell c cate that important biological and clinical differences exist It has been suggested that Taxol exerted its activity by between the two compounds.Although the mechanism by of the microtubule skeleto which they disrupt mitosis and cell replication is unique a lot of soli here are sma paclitaxel from the vew bark was quite diffcult three tree the affinity of the two com for 1g of drug (one cure of chemotherapy).This difficulty differences may explain the lack of complete cross-resistance encouraged the pursuit of semi-synthetic production. d between docetaxel and paclitaxe in immedia synthetic anticancer drugs a hroad research pr ram to evaluate alternative sourcin options and their commercial feasibility.7 The prospe (c)Antimetabolites finding a solution to the paclitaxel supply problem through using a n ring taxa way in which has generated anticar was p ed by Pierre Potie e1.26 in the Institur cell lines des Naturelles (Gif-sur-Yvette up a series of screening programs that invited chemists early 1980s that a naturally from around the world to submit their novel compounds ning the pachta 10-d ety against a range of in vitro tum and wa ntained in the ne edle of the abun by Ge head of the dant english yew (Taxus baccata).potier succeeded in the
II. Two Hundred Years of Drug Discoveries 27 teniposide. 163 As the 1970s opened, US President Richard Nixon established the National Cancer Program, popularly known as the “ war on cancer, ” with an initial half-billion dollars of new funding. This may explain why, in the following years, many new compounds with antineoplastic properties were isolated in plants. Among them, the pyridocarbazole alkaloids ellipticine and 9-methoxyellipticine from Ochrosia elliptica , intercalate between the base pairs of DNA. 164 Camptothecin and its derivatives, alkaloids from Chinese tree Camptotheca acuminata , showed a broad-spectrum anticancer activity. 9-Aminocamptothecin gave birth to topotecan and irinotecan. 165 Alkaloids from Cephalotaxus species were isolated for experimental and clinical studies. If the parent alkaloid is inactive, the esters harringtonine and homoharringtonine obtained from Cephalotaxus harringtonia , according to Hagop M. Kantarjian and Moshe Talpaz, (M. D. Anderson Cancer Center, Houston, USA), give new hopes in the cure of solid tumors or leukemias. 166 The most enthusiastic reports concern the diterpenoids paclitaxel, Taxol® (from Taxus brevifolia ) and docetaxel, Taxotere® (from Taxus baccata ) having unique tri- or tetracyclic 20 carbon skeletons extracted from the bark of yew. This tree was known as a toxic plant for animals and humans for centuries. 167 Monroe E. Wall and Mansukh C. Wani, at the Research Triangle Park (Chapel Hill, USA), identifi ed the active principle of the yew tree in 1971. 168 In 1979, Susan Horwitz of the Department of Molecular Pharmacology, Albert Einstein College of Medicine (New York) suggested that paclitaxel’s mechanism of action was different from that of any previously known cytotoxic agent. She observed an increase in the mitotic index of P388 cells and an inhibition of human HeLa and mouse fi broblast cells in the G2 and M phases of the cell cycle. 169 It has been suggested that Taxol exerted its activity by preventing depolymerization of the microtubule skeleton. Clinical use of paclitaxel includes a lot of solid tumors with best results in ovarian and breast cancers. Extraction of paclitaxel from the yew bark was quite diffi cult: three trees for 1 g of drug (one cure of chemotherapy). This diffi culty encouraged the pursuit of semi-synthetic production. The strategy included immediately increasing the amount of paclitaxel derived from yew bark and establishing a broad research program to evaluate alternative sourcing options and their commercial feasibility. 170 The prospects for fi nding a solution to the paclitaxel supply problem through semi-synthesis using a naturally occurring taxan as a starting material, were considerable. This approach was pioneered by Pierre Potier ( Figure 1.26 in the Institut de Chimie des Substances Naturelles (Gif-sur-Yvette, France). 171 He found in the early 1980s that a naturally occurring taxan containing the paclitaxel core, 10-deacetylbaccatin III, was 20 times more abundant than paclitaxel and was primarily contained in the needles of the abundant English Yew ( Taxus baccata ). Potier succeeded in the diffi cult conversion of 10-DAB into paclitaxel, in 1988, with only four steps with an overall yield being 35%, still signifi cantly less than needed for an effi cient commercial process. 172 The discovery and development of the taxans class of antitumor compounds, involved the discovery of a paclitaxel semi-synthetic analog, docetaxel (Taxotere®), by Pierre Potier et al. , represent signifi cant advances in the treatment of patients with a variety of malignancies. Although paclitaxel and docetaxel have a similar chemical root, extensive research and clinical experience indicate that important biological and clinical differences exist between the two compounds. Although the mechanism by which they disrupt mitosis and cell replication is unique, there are small but important differences in the formation of the stable, non-functional microtubule bundles and in the affi nity of the two compounds for binding sites. 173 These differences may explain the lack of complete cross-resistance observed between docetaxel and paclitaxel in clinical studies. 174 Besides natural products, synthetic anticancer drugs fl ourished in various directions. (c) Antimetabolites A third way in which chemistry has generated anticancer-drug was conducted through screening programs using cancer cell lines in vitro . In the 1950s, the NCI set up a series of screening programs that invited chemists from around the world to submit their novel compounds for screening against a range of in vitro tumor cell lines. Antimetabolites interest in cancer treatment had been discovered by George Hitchings, head of the department of biochemistry at Burroughs Wellcome, and Gertrude Elion, FIGURE 1.26 Pierre Potier . Ch01-P374194.indd 27 h01-P374194.indd 27 5/29/2008 5:42:21 PM /29/2008 5:42:21 PM
■28 CHAPTER I A History of Drug Discovery utilizing what today is termed"rational drug design."They methodi ally here they could see cel During the a number of effective drugs to treat a variety of ilnesses. including leukemia,malaria.herpes.and gout.They began amining the nucl acids.pan ay purin ine ed the ks.Th without the presence of certain purines,and set to work on antimetabolite compounds which locked up enzymes nec yfor the inc nto nud ney synt thwo subs ved to be effective treatments for leukemia.a blood malignancy characterized by a great .due t ourine molecule thereb creating 6-mercap IGURE 1.27 Barnett Rosenberg. o treat leukemia.After this success,Elion and Hitchings nber o itional drugs using the EC. ess the imr This latter dis 6 breast.lung and other cancers.they pose a risk of cardi ioanewdhgzathiopneimpnemdnw9 otoxicity and therefore.they are typically used in limited organ The team body's loped allop doses.Doxorubici nd t al inf tions.With Howard Schaeffer.Elion was also at the origin (e)Platinum anticancer drugs acy he irax which interferes with n pro pes vir rug ch Cisplatin was disco ously in 1965 for 30 ney,a fe (Michigan State University.USA)were studying the effect viral resistance.Hitchings and Elion won the Nobel Prize of an electric current on E.coli. n Physiology or Medicine in 1988 for their disc It was found that cell division was inhibited by the portant pri or uctio mmine-c um fron de ted that it ssed antitumor activitv. (d)Anticancer antibiotics In 1972.the NCI introduced cisplatin into clinical trials list am ong th main anti a ma ei the treatme est Di Ma central platinum atom surrounded by two chloride atoms an the prototypical member in the anthracyclines antitumor two molecules of ammonia moieties.The antitumor activity ntibioti Adriamy 4-hydroxy de been she n to be much greate when the chloride an 01967 The effects.these drugs have been widely used as dose-limited due to its ability to form DNA adducts.The drug is able chemotherapeutic agents for the treatment of human solid to enter the cell freely in its neutral form,yet once in the since their discovery Thes ell the chlori ions are displaced to aquated r (New
28 CHAPTER 1 A History of Drug Discovery utilizing what today is termed “ rational drug design. ” They methodically investigated areas where they could see cellular and molecular targets for the development of useful drugs. During their long collaboration, they produced a number of effective drugs to treat a variety of illnesses, including leukemia, malaria, herpes, and gout. They began examining the nucleic acids, particularly purines, including adenine and guanine, two of DNA’s building blocks. They discovered that bacteria could not produce nucleic acids without the presence of certain purines, and set to work on antimetabolite compounds which locked up enzymes necessary for the incorporation of these purines into nucleic acids. 175 They synthesized two substances, diaminopurine and thioguanine, which the enzymes apparently latched onto instead of adenine and guanine. These new substances proved to be effective treatments for leukemia, a blood malignancy characterized by a great increase in white blood cells count, due to the activity of oncogenes. Later, Elion substituted an oxygen atom with a sulfur atom on a purine molecule, thereby creating 6-mercaptopurine used to treat leukemia. After this success, Elion and Hitchings developed a number of additional drugs using the same principle. Later, these related drugs were found to not only interfere with the multiplication of white blood cells, but also suppress the immune system. This latter discovery led to a new drug, azathioprine (Imuran®), and a new application – organ transplants. 176 The team also developed allopurinol, a drug successful in reducing the body’s production of uric acid, thereby treating gout, pyrimethamine, used to treat malaria, and trimethoprim used to treat bacterial infections. With Howard Schaeffer, Elion was also at the origin of acyclovir, marketed as Zovirax® which interferes with the replication process of the herpes virus, 177 drug characterized by a radical antiviral effi ciency, a fair inocuity and, despite an extensive use for 30 years, very few cases of viral resistance. Hitchings and Elion won the Nobel Prize in Physiology or Medicine in 1988 for their discoveries of “ important principles for drug treatment, ” which constituted the groundwork for rational drug design. (d) Anticancer antibiotics Anthracyclines may be listed among the main anticancer drugs. Daunomycin (also called daunorubicin) was isolated from Streptomyces peucetius in 1962 by Aurelio Di Marco from Farmitalia (Milan, Italy). 178 With adriamycin it is the prototypical member in the anthracyclines antitumor antibiotic family. Adriamycin (a 14-hydroxy derivative of daunorubicin) was isolated from the same microorganism, in 1967. Despite their severe cardiotoxicity and other side effects, these drugs have been widely used as dose-limited chemotherapeutic agents for the treatment of human solid cancers or leukemias since their discovery. 179 These antibiotics contain a quinone chromophore and an aminoglycoside sugar. Their antineoplastic activity has been mainly attributed to a strong interaction with DNA in the target cells. 180 While anthracyclines can be very effective against breast, lung and other cancers, they pose a risk of cardiotoxicity and therefore, they are typically used in limited doses. Doxorubicin and Epirubicin are commonly used in combination with other chemotherapy drugs to help decrease the risk of side effects. 181 (e) Platinum anticancer drugs Cisplatin was discovered serendipitously in 1965 while Barnett Rosenberg ( Figure 1.27 ) and Loretta Van Camp (Michigan State University, USA) were studying the effect of an electric current on E. coli . It was found that cell division was inhibited by the production of cis -diammine-dichloroplatinum from the platinum electrodes rather than by the method expected 182 ( Figure 1.28 ). Further studies on the drug indicated that it possessed antitumor activity. In 1972, the NCI introduced cisplatin into clinical trials. It now has a major role in the treatment of testicular, ovarian, head and neck, bladder, esophageal, and small cell lung cancers. Cisplatin is a square planar compound containing a central platinum atom surrounded by two chloride atoms and two molecules of ammonia moieties. The antitumor activity has been shown to be much greater when the chloride and ammonia moieties are in the cis confi guration as opposed to the trans confi guration. The cytotoxicity of cisplatin is due to its ability to form DNA adducts. 183 The drug is able to enter the cell freely in its neutral form, yet once in the cell the chloride ions are displaced to allow the formation of a more reactive, aquated compound. In 1975, Memorial Sloan-Kettering Cancer Center (New York) initiated trials FIGURE 1.27 Barnett Rosenberg . Ch01-P374194.indd 28 h01-P374194.indd 28 5/29/2008 5:42:22 PM /29/2008 5:42:22 PM
lI.Two Hundred Years of Drug Discoveries nticacompany Roche.It is a newat a am through covalent adducts with DNA inducing apoptosis 2.A new generation of anticancer drugs leads following the discovery of a new target:for example. the specific identification of a cancer-related gene from the dimensiona structure of a target.obtained using-ray stallography.can lead to the rational design of specific ibitor molecules that target functionally important parts f the structure.It is to be considered that mo er antican cer drugs targeting molecular aberrations that are specific to tumor cells.Whether this goal will be attained for common man ave become e shed is esp ftur a ents signifies a paradigm shift in cancer therapy with less reliance on drugs that non-discriminately kill tumor and host cells.Two examples may illustrate this purpose. (a)Protein tyrosine kinases(TKs) TKs are enzymes that catalyze the transfer of phosphate FIGURE 1.28 Effect of the electric current transmitted through plati num electrodes on E coli culture function and motility Tks were larsely ignored in drus of development because of a paucity of evidence for a causa alone ive role in human cancer and concerns about drug specif of the BCR-ABL in the testicular cancer studies.but they were favorable was successfully used in chronic myeloid leukemia.1 Studies using cisplatin alone and in combination withadri First results with imatinib were obtained by Ciba Company in1996 TKs are now regarded as excellent targets fo cisplatin-as wellas resistance asainst it.there has been a need for the development of analogs which are just as potent but not as toxic.Several cisplatin analogs were consi e Ib)Antiangiogenic agents to the parent or the 10g agents may target angiogenesis.Dung 1-cyclobutane-dicarboxylato)platinum (ID).or carboplatin vessels was the most interesting. com This neovascularization plays both beneficial and damaging between oles in the organism. Vascular endothelial growth factor inia Co VEGF) and lohr 1980s.5ne the most impor Broomhead (Camberra.Australia)9 and developed by
II. Two Hundred Years of Drug Discoveries 29 of cisplatin alone and later in combination with cyclophosphamide and/or adriamycin in patients with urothelial tract cancer. The results were not as positive as those seen in the testicular cancer studies, but they were favorable. 184 Studies using cisplatin alone and in combination with adriamycin to fi ght ovarian cancer done by Holland gave substantial improvements. 185 Due to the extreme toxicity of cisplatin, as well as resistance against it, there has been a need for the development of analogs which are just as potent, but not as toxic. Several cisplatin analogs were considered as viable alternatives to the parent drug in terms of their toxicities, antitumor properties, and potential biochemical selectivity but it has been concluded that diamine(1, 1-cyclobutane-dicarboxylato)platinum (II), or carboplatin, was the most interesting. 186 From that time a lot of comparisons were performed between cisplatin and carboplatin. 187 Triplatin tetranitrate was discovered by Nicholas Farrell (Virginia Commonwealth University) 188 and John Broomhead (Camberra, Australia) 189 and developed by Swiss pharmaceutical company Roche. It is a new platinum anticancer drug, result of a trinuclear platinum coordination complex with chloride and amine ligands. It is active through covalent adducts with DNA inducing apoptosis. 2 . A new generation of anticancer drugs The fourth, and most recent, application of chemistry in anticancer drugs conception has been to generate drug leads following the discovery of a new target; for example, the specifi c identifi cation of a cancer-related gene from the sequence of the human genome. Such targets can be proteins, enzymes, or nucleic acids. Knowledge of the threedimensional structure of a target, obtained using X-ray crystallography, can lead to the rational design of specifi c inhibitor molecules that target functionally important parts of the structure. It is to be considered that most drugs that have been discovered through screening are highly toxic agents, whereas most efforts are now to discover anticancer drugs targeting molecular aberrations that are specifi c to tumor cells. Whether this goal will be attained for common human solid cancers that have become established is still unclear, in view of the widespread misregulation of signaling pathways. The emergence of tumor-specifi c, molecularly targeted agents signifi es a paradigm shift in cancer therapy, with less reliance on drugs that non-discriminately kill tumor and host cells. Two examples may illustrate this purpose. (a) Protein tyrosine kinases (TKs) TKs are enzymes that catalyze the transfer of phosphate from adenosine triphosphate (ATP) to tyrosine residues in proteins. The human genome contains about 90 TKs regulating cellular proliferation, survival, differentiation, function, and motility. TKs were largely ignored in drug development because of a paucity of evidence for a causative role in human cancer and concerns about drug specifi - city and toxicity. The knowledge of their importance was evident. Imatinib mesylate, an inhibitor of the BCR–ABL was successfully used in chronic myeloid leukemia. 190 First results with imatinib were obtained by Ciba Company in 1996. 191 TKs are now regarded as excellent targets for cancer chemotherapy, but reality lies somewhere between the extremes of triumph and tribulation. 192 (b) Antiangiogenic agents Antiangiogenic agents may target angiogenesis. During cancer cell proliferation, tumor growth is accompanied by the formation of new blood capillaries from preexisting vessels. This neovascularization plays both benefi cial and damaging roles in the organism. Vascular endothelial growth factor (VEGF) identifi ed in the 1980s, is one of the most important pro-angiogenic factors involved in tumor angiogenesis. VEGF increases vascular permeability, which might FIGURE 1.28 Effect of the electric current transmitted through platinum electrodes on E. coli culture. Ch01-P374194.indd 29 h01-P374194.indd 29 5/29/2008 5:42:22 PM /29/2008 5:42:22 PM