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-j
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
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Catalogue of Type Mineral Specimens Yafsoanite Kim AA, Zayakina NV, Lavrentev YuG: ZVMO,(1982) 111, 118-121 Russia - Yakutiya-SW - Central Aldan - Kuranakh gold deposit Yakhontovite Postnikova VP, Isipursky SI, Sidorenko GA, Mokhov AV: Mineral.Zhurnal,(1986) 8, n6, 80-84 Russia - Khabarovsk - Komsomol'sk region - Pridorochnoye deposit Supergene Yanomamite Botelho NF, R
HUMAN PERFORMANCE, 18 (4), 331–341Copyright © 2005, Lawrence Erlbaum Associates, Inc. The key to success in business is money and people. Personality psychology isabout people—it’s about the nature of human nature. Some understanding of hu-man nature—and the ability to measure its key components—would seem to offera huge advantage to applied psychologists. Despite its practical signif