Doi:10.1016/s0305-7372(03)00116-6

CANCER TREATMENT REVIEWS 2003; 29: 515–523doi:10.1016/S0305-7372(03)00116-6 Classification of anticancer drugs—a newsystem based on therapeutic targets Enrique Espinosa, Pilar Zamora, Jaime Feliu andManuel Gonza´lez Baro´n Servicio de Oncologı´a Me´dica, Hospital La Paz, Madrid, Spain The arrival of a great number of new antineoplastic agents has made it necessary to reclassify all of them. Anticancer drugsmay act at different levels: cancer cells, endothelium, extracellular matrix, the immune system or host cells. The tumour cellcan be targeted at the DNA, RNA or protein level. Most classical chemotherapeutic agents interact with tumour DNA,whereas monoclonal antibodies and small molecules are directed against proteins. The endothelium and extracellular matrixmay be affected also by specific antibodies and small molecules.
2003 Elsevier Ltd. All rights reserved.
Key words: Antineoplastic drugs; chemotherapy; classification; monoclonal antibodies; new drugs; small molecules.
therapy. A global view is important to remember the drugs and their mechanism of action and also forteaching purposes. On the other hand, multidrug Most patients with advanced solid tumours still die regimens usually include drugs belonging to differ- of their disease. For this reason, new effective drugs ent groups to increase efficacy and decrease toxicity, are needed and, in fact, new agents appear every at least whenever classical chemotherapy is con- few months. The last years have witnessed the ap- pearance of a great number of anticancer drugs, We hereby propose a new drug classification many of which cannot be included in a simple based on the kind of target. Drugs may be directed at classification. Classically, anticancer drugs were tumour cells or other elements involved in carcino- grouped as chemotherapy, hormonal therapy and genesis, i.e., the endothelium and extracellular ma- immunotherapy. Chemotherapy included a number trix, and the immune system. Potential host cells a families defined by both their chemical structure such as the bone may also be targeted. Table 2 shows and mechanism of action: alkylating agents, antibi- all these groups. The target may be located at the otics, antimetabolites, topoisomerase I and II inhib- DNA, RNA or protein level. In general, chemother- itors, mitosis inhibitors, platinum compounds and apy acts at the DNA level in tumour cells, whereas others (Table 1). However, the group ‘‘others’’ has monoclonal antibodies and small molecules interact expanded so much that this classification is no with proteins, either in the tumour cells or in other elements. Antisense oligonucleotides are the main A drug classification serves two main objectives: the achievement of a comprehensive view of the It is beyond our scope to describe the mechanism available drugs and the design of combination of action of every drug in detail. In some cases, theprecise mechanism is still uncertain. Besides, someof the compounds we shall mention may not go Correspondence to: Enrique Espinosa, Servicio de OncologııaMedica, Hospital La Paz, Po de la Castellana, 261-28046 Madrid, beyond phase III trials. We would like to offer a useful tool to classify both available and forthcoming 0305-7372/$ - see front matter C 2003 ELSEVIER LTD. ALL RIGHTS RESERVED.
Classical classification of anticancer drugs The drugs may act on DNA either by breaking the helix itself, interfering with DNA-related proteins, or modifying the expression of specific genes. Most classical anticancer agents have one of these mech- anism of action, and new drugs are being incorpo- rated every year (Tables 3a and 3b).
Anti-estrogensAnti-androgensLH–RH analogsAnti-aromatase agents Alkylating agents were the first compounds identi- fied to be useful in cancer. They form a variety ofinterstrand cross-links called adducts, that alterDNA structure or function. The most common site ofalkylation is the N-7 position of guanine, but it anticancer drugs, even when a global classification varies depending on the family of drugs. Alkylators might have some exceptions or could be very sche- belong to one of several families: nitrogen mustards, matic in some instances. We have restricted the in- nitrosoureas, triazenes, platinum compounds and clusion of new compounds to those under clinical Non-specificDNA break: chemotherapyDNA-related proteins: chemotherapySpecificHormonal therapy, retinoidsInterferon aGene therapy Membrane receptorsExtracellular domain: MoAbIntracellular domain: small moleculesCytoplasmIntracellular pathways: small moleculesTubulin: chemotherapy * In this group, antisense therapy might also be developed in the future.
MoAb, monoclonal antibodies and MMPs, metalloproteinases.
C L A S S I F I C A T I O N O F A N T I C A N C E R D R U G S Drugs directed against tumour DNA: chemotherapy Cyclophosphamide, ifosfamide, melphalan, chlorambucil, bendamustine Anthracyclines: doxorubicin, epirubicin, idarubicin, mitoxantrone Fluoropyrimidines (5FU, ftorafur, capecitabine) and raltitrexed Adenosine analogs: deoxycoformycin, cladribine Topo, topoisomerase; DHFR, dihydrofolic reductase; TS, thymidilate synthase; FTRG, formyltransferase ribonucleotide glycinamide;RR, ribonucleotide reductase; £, inhibition.
Drugs directed against tumour DNA: modifiers of specific genes Union to specific receptors, transcriptional Antiestrogens: tamoxifen, fulvestrantAntiandrogens: flutamide, There are some new experimental agents among the alkylators, such as bendamustine or tira- compound, has activity in lymphomas (2–4). Tira- Topoisomerase I and II inhibitors, antimetabolites pazamine is activated in hypoxic cells and en- and ecteinascidin could be grouped together as hances the cytotoxicity of radiation, cisplatin and drugs directed at protein–DNA complexes, because the taxanes (5,6). It has been used for the treatment they do not bind directly to DNA (1).
of non-small cell lung cancer and head and neck The anthracyclines (doxorubicin and their analogs epirubicin and idarubicin) inhibit topoisomerase II Some antibiotics also belong to the group of al- and form free radicals. Mitoxantrone, although kylators: bleomycin and mitomycin C. The anthra- synthetic, can be regarded as an anthracycline. The cyclines have a different mechanism of action and main epipodophillotoxin, etoposide, also inhibits Topoisomerase I transiently breaks a single strand specific genes does not mean that this activity is re- of DNA during DNA replication, thereby reducing torsional strain. Inhibitors of this enzyme derive Gene therapy also targets specific genes, but in from camptothecin. This family has grown rapidly this case the mechanism of action differs substan- in recent years. In addition to topotecan and irino- tially from that of the hormones. Genes are intro- tecan, new experimental agents could join the family duced in vectors to either repair or block specific in the near future, for instance rubitecan (7,8), lur- On the other hand, antimetabolites interfere with enzymes that contribute to DNA synthesis. In this group we have antifolates, fluoropyrimidines, ral-titrexed, cytarabine, gemcitabine, and adenosineanalogs A number of anticancer drugs such as the fluoro- Pemetrexed has recently been incorporated to the pyrimidines and platinum compounds interfere clinic. This drug shows activity in non-small cell with RNA synthesis. However, they mainly act by lung cancer, breast cancer, mesothelioma and head binding to DNA. The major representatives in this and neck tumours (13–15). Table 3a indicates the group are antisense oligonucleotides. These mole- target enzyme for each antimetabolite.
cules are directed against specific mRNAs. The A marine derivative, ecteinascidin or ET-743, has mRNAs of bcl-2, myb, p53, mdm2, Her-2 and a unique mechanism of action. Formerly thought to methyltransferase-1 have been targeted with these be an alkylator, recent investigations have shown oligonucleotides (19–25). The synthesis of antisense that it blocks transcriptional factors—such as TC- oligonucleotides is complex and improved methods NER or Sp1—and seems to affect RNA polymerase to deliver the compound in the target are needed II-mediated gene transcription (16). Ecteinascidin (25–27). These problems are delaying the develop- has been used in patients with refractory sarcomas ment of antisense therapy. Another drug in this group is angiozyme, which blocks the mRNA of thevascular endothelial growth factor (28,29).
The classical representatives in this group are hor- monal agents. Steroids, antihormones and retinoidsshare a common mechanism of action because they In the last decade, a great number of compounds modify the expression of specific genes (Table 3b).
have joined this group, mainly monoclonal anti- Steroid hormones, such as glucocorticoids, bind to bodies and small molecules. They are all very spe- receptor proteins in the cytoplasm or nucleus to cific and their effect is cytostatic rather than form a hormone–receptor complex. This complex cytotoxic. They can bind to membrane receptors or has the capacity to activate regulatory sequences in DNA. Antioestrogens and antiandrogens block re-ceptors of oestrogens and androgens, respectively.
These receptors are ligand-regulated transcriptionfactors located in the nucleus. The antiaromatase agents anastrozole, letrozole and exemestane act inthe cytoplasm, mainly in tumour cells but also in Two groups may be distinguished: monoclonal an- tibodies and small molecules. The former block the LH–RH analogs bind to a specific membrane re- extracellular domain of the receptor, whereas the ceptor linked to a G protein in the hypothalamus.
latter cross the membrane and inhibit the intracel- However, the ultimate effect takes place in the tu- lular domain, usually a tyrosin-kinase (Table 4). The mour cell, and for this reason the analogs should be term ‘‘small molecule’’ may be misleading, because grouped together with the other hormones (Table 2).
classical chemotherapy compounds are also small in The antitumour activity of interferon a appears to size, but it allows the distinction with monoclonal be due to a combination of direct antiproliferative as well as indirect immune-mediated effects. It has also The first antitumour antibodies were directed antiangiogenic effects mediated through interferon against lymphoid antigens, such as CD20 and CD52.
gamma (18). Thus, this drug may appear in several Some of them combine the antibody with an isotope groups in our classification. Activity over some to increase efficacy (30–34). These highly active C L A S S I F I C A T I O N O F A N T I C A N C E R D R U G S Drugs directed against the membrane receptors of one of the most active drugs in chronic myeloidleukaemia and in gastrointestinal stromal tumours.
Other drugs are aimed at the ras or the phosphati- compounds have expanded the possibilities of dyl-inositol pathways, as well as the proteasome and treatment in patients with refractory lymphomas the cyclin-dependent kinases. With few exceptions, and are now being evaluated in first- line therapy.
these agents are now in the first steps of clinical New antibodies are under investigation at this mo- development. Table 5A includes some of them.
ment: the anti-CD33 gemtuzumab and the anti-CD22 Ras is activated by farnesyl transferase. Once ac- tivated, the ras protein activates raf and MEK.
The main antibodies for carcinomas are trast- Farnesyl-transferase inhibitors act as false metabo- uzumab (37,38) and cetuximab (39,40). Trastuzumab lites of this enzyme, for instance, lonafarnib and is available for the treatment of Her-2 positive breasttumours, either alone or in combination with che-motherapy, and new possible indications are being Drugs acting in the cytoplasm of the tumour cell studied. On the other hand, an anti-MUC antibody (A) Inhibitors of intracellular pathways in tumour cells could be used in the future as a vaccine in patients Small molecules bind to receptors of the epider- mal growth factor family. Some of them are specific for EGFR (Her-1), such as gefitinib (ZD-1839) (42–43) or OSI- 774 (44). Gefitinib is the only member of the group that has been tested in phase III trials so far. Itobtains responses as single agent in non-small cell lung cancer and head and neck tumours. PKI-166 inhibits both Her-1 and Her-2 (45). CI-1033 is an ir- reversible inhibitor of all the epidermal growth fac- Cyclin-dependent kinasesFlavopiridol, CYC-202 A number of metabolic pathways carry proliferationsignals to the nucleus. Although we shall comment on them separately, all of them are interrelated.
These pathways are activated by growth factors and a few of them have been targeted with specific drugs. Figure 1 shows a scheme of the pathways that are being used in cancer therapeutics. The better known drug in this group is imatinib, which inhibits the tyrosine kinase of bcr/abl and c-kit (47,48). It is R115,777 (49,50). There are also inhibitors of raf Drugs directed against the endothelium and the (BAY 43-9006) and MEK (CI-1040) (51,52).
The phosphatidyl-inositol pathway starts with the serin threonine PI-3K, which is connected with mTOR through PKB/Akt. MTOR controls apoptosis and is related to the balance between cellular ca- tabolism and anabolism. Specific drugs in this pathway are rapamycin derivatives such as CCI-779, which inhibits mTOR (53). PI-3K is also connectedwith protein-kinase C, a family of enzymes that ac- tivate the transcription factor NF-jB. Protein-kinase C is inhibited by bryostatin (54,55) and PKC-412 (56).
The proteasome—a group of enzymes that de- grade proteins—is inhibited by PS-341 (57,58). On the other hand, the chaperones exert the oppositefunction, i.e., they protect proteins from degrada-tion. Geldanamycin derivatives such as 17-AAG in-crease the degradation of one of the main chaperones, heat shock protein 90 (59,60).
Finally, flavopiridol and CYC-202 (a roscovitine The main endothelial growth factors—vascular en- derivative) inhibit cyclin-dependent kinases (61,62).
dothelial growth factor (VEGF)and basic fibroblast The staurosporin compound UCN-01 inhibits CDK-2 growth factor (bFGF)—are inhibited by thalido- mide (68,69). Another inhibitor specific for VEGF iscarboxyamido-triazole (70,71). Interferon a also re-duces VEGF synthesis in tumour cells, but this effectseems to be mediated through interferon gamma (18,72,73). Cyclo-oxygenase 2 may stimulate endo-thelial growth, hence one of the possible mecha- Tubulin contributes to the maintenance of cell shape, nisms of action of COX-2 inhibitors (74,75).
intracellular transport and mitosis, so drugs inter- With regard to VEGF receptors, the monoclonal fering with tubulin are grouped here in the present antibody bevacizumab binds to all of these receptors classification. The vinca alkaloids bind to specific (70,76,77). SU-5416 is a small molecule binding to the sites on tubulin and prevent polymerization of tu- tyrosine kinase of VEGFR-1 and VEGFR-2 (70,78). It bulin dimers, thereby disrupting the formation of also binds to platelet derived growth factor receptor microtubules. The taxanes have a different binding and c-kit. Clinical trials with SU-5416 in haemato- site and stabilize microtubules: this unusual stability logical malignancies and colorectal cancer have been inhibits the normal reorganization of the microtu- initiated. Another small molecule, SU-6668, binds to bule network. Oral formulations of taxanes will VEGFR, bFGFR and platelet derived growth factor improve convenience if they prove to be as active as the parent drugs (65). The epothilones are a new Finally, combretastatin inhibits the mitotic spin- group of tubulin-stabilizing agents. Preclinical dle in the endothelium and induces apoptosis studies have shown promising activity of these compounds, but the results of phase II and III clin-ical trials are not still available (66,67). Table 5Bshows all these drugs.
Activation of MMPs in tumours facilitates invasionand is an essential step in angiogenesis. MMPs may also stimulate the release of VEGF, bFGF and insulin growth factor. A number of MMP inhibitors arecurrently under clinical investigation (83). Most of Compounds directed against the endothelium in- them are synthetic inhibitors of the enzyme activity, hibit either endothelial growth factors or the recep- such as marimastat (84–86), prinomastat or BAY 12- tors of such factors. On the other hand, most drugs 9566 (83). Tetracycline derivatives such as neovastat acting in the extracellular matrix inhibit metallo- also down regulate the production, inhibit the acti- proteinases (MMPs). They all have antiangiogenic vation and increase the degradation of MMPs C L A S S I F I C A T I O N O F A N T I C A N C E R D R U G S Apart from MMPs, other elements of the extra- 7. Giovanella BC, Stehlin JS, Hinz HR, Kozielski AJ, Harris NJ, cellular matrix could be targeted as a form of anti- Vardeman DM. Preclinical evaluation of the anticancer cancer therapy, for instance, integrin, endothelin and (Rubitecan). Int J Oncol 2002; 20(1): 81–88.
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