Medical Hypotheses (2006) 66, 883–887

http://intl.elsevierhealth.com/journals/mehy

A new classification system of anticancer drugs

– Based on cell biological mechanisms
Xiong-Zhi Wu *

Cancer Center of Integrated Traditional and Western Medicine, Cancer Hospital of Tianjin,
Tianjin Medical University, Ti-Yuan-Bei, Huan-Hu-Xi Road, He-Xi District, Tianjin 300060, China

Received 11 November 2005; accepted 14 November 2005

Summary The arrival of a great number of new anticancer agents has made it necessary to reclassify all of them. We
established a new classification system based on cell biological mechanisms. Anticancer drugs were grouped as
cytotoxic drug and modifier, which could regulate the interaction of tumor, host and drugs. The modifiers were
subdivided into three groups: cell biological modifier which reverses the abnormal biological behaviour of tumor cells,
biological response modifier which regulates the host response of tumor and biochemical modulator which affects the
host’s metabolic pathway of cytotoxic drug to enhance the chemosensitivity or reduce the adverse reaction.
Combination with cell biological modifiers and cytotoxic drugs play a double role of killer and rectifier for tumor cells,
whereas biological response modifiers and cytotoxic drugs are combined to regulate the tumor–host interaction.
Biochemical modulators and cytotoxic drugs are combined to enhance the chemosensitivity or improve the dose of
cytotoxic drugs.

c 2005 Elsevier Ltd. All rights reserved.

Introduction and immunotherapy. Chemotherapy included a

Anticancer therapy is one of the biggest challenges
in medicine. Combination therapy is a usable tool
to improve the response of therapy and outcome.
The critical function of drug classification serves
to comprehend the mechanism of action that is
important for the design of combination therapy,
since multidrug regimens usually include drugs
belonging to different groups to increase efficacy
and decrease toxicity. Classically, anticancer drugs
were grouped as chemotherapy, hormonal therapy
* Tel.: +86 22 23558095.
E-mail address: ilwxz@163.com.
number of families – alkylating agents, antibiotics,
antimetabolites, plant drugs and others. A great
number of anticancer drugs have been arrived in
recent years, many of which cannot be included
in this classification. Therefore, it is necessary to
reclassify all of anticancer drugs.
Recently, Enrique et al. [1] suggested a new
classification based on therapeutic targets. Anti-
cancer drugs were grouped as their targets – can-
cer cells, endothelium, extracellular matrix,
immune system or host cells. Drugs that targeted
at tumor cells were divided into three groups
according to their targets – DNA, RNA or protein.
Then drugs were subdivided into many crossed
groups, such as chemotherapy, hormonal therapy,

0306-9877/$ - see front matter c 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2005.11.036
884
gene therapy, antisense oligonucleotides, mono-
clonal antibodies, small molecules, metallopro-
teinases inhibitors, retinoids, interferon, vaccines
and so on. In fact, four crossed criterions were
used in this complicated system – cellular targets,
molecular targets, chemical structure and mecha-
nism of action. Some important drugs, such as
apoptosis inducing agent and biochemical modifier,
were excluded from this classification system. Fur-
thermore, only bone cells were grouped in host
cells, whereas lymphocytes, macrophages and
endothelium were classified in another group.
The new classification system based on
cell biological mechanisms
The host–tumor interaction, which could be
grouped as immune host resistance and non-im-
mune host resistance, play a critical role in the
control of growth, differentiation and apoptosis
of tumor cells. Functional interactions between
host and abnormal cells could be altered by tumor
cells at different stages of carcinogenesis [2]. This
homeostasis between host and tumor cells may be
Table 1 Classification of anticancer drugs based on cell biological mechanisms
Cytotoxic drug
Non-specific cytotoxic drug
Tumor tissue specific cytotoxic drug
Molecular targeted cytotoxic drug
Cell biological modifier
Cytostatic agent
Differentiating agent
Apoptosis inducing agent
Biological response modifier
Immune modifier
Incretion modifier
Microenvironment modifier
Biochemical modulator
Chemosensitizer
Chemoprotectant
Wu
altered by anticancer drugs too. Cytotoxic drugs
not only suppress cancer tissue but also have a sup-
pressive effect on the immune system, whereas
some non-cytotoxic drugs could modulate the
interaction of tumor cells, host response and cyto-
toxic drugs.
Therefore, we classified anticancer drugs into
cytotoxic drugs and modifiers, which could regu-
late the interaction of tumor, patient and drug.
The modifiers could be subdivided into three
groups: cell biological modifier which can reverse
the abnormal biological behaviour of tumor cells,
biological response modifier which can regulate
the host response of carcinogenesis and biochemi-
cal modulator which affects the metabolic pathway
of cytotoxic drug to enhance the chemosensitivity
or reduce the adverse reaction (Table 1).
Cytotoxic drugs
Three groups of cytotoxic agents may be distin-
guished: non-specific cytotoxic drug, tumor tissue
specific cytotoxic drug and molecular targeted
cytotoxic drug. The critical problem of classical
Alkylating agents
Antibiotics
Topoisomerase inhibitors
Mitosis inhibitors
Platinum compounds
Others
Cytotoxic monoclonal antibody
Antibody guided therapy
Hormone guided chemotherapy
Antagonist of growth factor
Growth signal transduction inhibitor
Cell cycle active drugs
Cytokines
Active specific immunotherapy
Adoptive immunotherapy
Hormonal supplementary therapy
Hormonal antagonist
New classification of anticancer drugs
cytotoxic drug is the low selectivity of tumor cells.
Recently, tumor tissue specific drugs have meet
with a great success. Capecitabine, an oral fluoro-
pyrimidine carbamate, has been synthesized as an
inactive precursor that is absorbed intact through
the intestinal mucosa and is sequentially converted
to 50 -deoxy-5-fluorocytidine, to 50 -deoxy-5-fluoro-
uridine, and finally to 5-FU. Because thymidine
phosphorylase, which converts inactive 50 -deoxy-
5-fluorouridine to active 5-FU, overexpresses in
tumor tissues, the exposure of 5-FU decreases in
normal tissues compared with tumor [3].
Since most classical cytotoxic drugs are neither
specific nor targeted to the cancer cells, improved
delivery of anticancer drugs to tumor tissues ap-
pears to be a reasonable and achievable challenge.
For this purpose, various delivery systems, which
are more affinitive to the tumor tissues, such as lip-
osomes and magnetic microspheres, have been uti-
lized to improve the concentration of drugs in
tumor tissues. For example, because of the abnor-
mal penetration of tumor vessels, the concentra-
tions of liposomal adriamycin and daunomycin in
tumor tissues are higher than normal tissues [4].
Molecular targeted cytotoxic drugs that are very
specific have appeared recently. Three groups may
be distinguished: cytotoxic monoclonal antibody,
antibody guided therapy and hormone guided che-
motherapy. The first antitumor antibody is ritux-
imab, which directed against lymphoid antigens
CD20. The mechanisms of action involved anti-
body-dependent cellular cytotoxicity and comple-
ment-dependent cytotoxicity that are the main
cytotoxic effects of immune system [5].
Antibody guided cytotoxic therapy may include
antibody guided chemotherapy, radioimmunother-
apy and immunotoxin therapy. Radioimmunoconju-
gates have the ability to provide direct cytotoxicity
by radionuclide even if antibody-dependent cellu-
lar cytotoxicity is impaired [6]. Furthermore, the
crossfire effect, which delivers radiation to un-
bound neighboring cells (e.g., inaccessible to anti-
body due to poor vascularization, or with
insufficient antigen expression), results in direct
cytotoxicity. Both agents of yttrium-90 ibritumo-
mab tiuxetan and iodine I131 tositumomab have
demonstrable efficacy in patients with relapsed or
refractory indolent B-cell non-Hodgkin lymphoma,
even after the use of rieuximab [7].
There is only one drug in the group of hormone
guided chemotherapy up to now. Estramustine
phosphate, a carbamate ester combining 17 beta-
estradiol and nor-nitrogen mustard, is long misclas-
sified as an alkylating agent dramatically. Binding
of the drug to microtubule-associated proteins,
tubulin, and proteins of the nuclear matrix are
885
presently considered to be the most likely mecha-
nisms of estramustine in androgen-independent
prostatic carcinoma [8].
Cell biological modifier
Tissue homeostasis requires a balance among cell
division, differentiation and death. The cell’s deci-
sion of proliferation, differentiation and apoptosis
are linked by cell cycle regulators. Tumor is a kind
of cell cycle disease that has the abnormal inter-
face of division, differentiation and death. Cell
biological modifier could be divided into three
groups – cytostatic agent, differentiation inducing
agent and apoptosis inducing agent. Three groups
of cytostatic agent may be distinguished: antago-
nist of growth factor (such as Herceptin – the
monoclonal antibody for EGFR-2 and Gefitinib – a
small molecule bind to EGFR-1), tyrosine kinases
inhibitor and cell cycle active drugs. Gleevec is
the only one drug of tyrosine kinases inhibitor up
to now. Recently, cell cycle active compounds
have shown preclinical anticancer activity [9].
Remarkable advances in tumor cell biology have
spurred the discovery of cell biological modifier.
Biological response modifier
Biological response modifier could regulate the
host response of carcinogenesis. Three groups of
biological response modifier may be distinguished:
immune modifier, incretion modifier and microen-
vironment modifier. Tumor microenvironment has
two-edged effects of carcinogenesis – suppression
and promotion. On the one hand, cell’s growth and
migrant are subject to microenvironmental con-
trol. On the other hand, tumor microenvironment
contributes to tumor progression by enhancing
spontaneous mutagenesis [10–12]. Tumor cells
create a permissive soil on which oncogene activa-
tion, genetic instability and accumulation of gene
mutations favoring disease progression can occur.
In addition, such survival-promoting microenviron-
ments can rescue tumor cells from cytotoxic ther-
apy, giving way to disease relapse [13].
Angiogenesis is a lifeline for tumor growth, pro-
gression and metastasis. Tumor-related angiogene-
sis is a multi-step process initiated by the
unbalance of antiangiogenic factor and proangio-
genic factors, which are secreted by both the tumor
and host tissues. Therefore, microenvironment
modulation is a reasonable choice for antiangiogen-
esis. Some endogenous angiogenesis inhibitors have
been administered in clinical trials. At the same
886
time, Bevacizumab (Avastintrade mark, Genen-
tech), a humanized monoclonal antibody targeting
vascular endothelial growth factor, which is a criti-
cal angiogenic factor, has been used to first-line
therapy for widespread metastatic colorectal
cancer.
Some drugs are directed to organs microenviron-
ment to antimetastasis. Osteoclast, bone resorbing
cell whose increased activity is induced by meta-
static tumor, is responsible for the deterioration
of bone structure along with the release of growth
factors that feed back and support further tumor
growth. Bone antiresorptive drugs, such as bisphos-
phonates and osteoprotogerin, specifically target
osteoclasts to antimetastasis [14].
Biochemical modulator
Biochemical modulators have been under clinical
investigation for several decades. Biochemical
modulator lacks visible antitumor activity in its
own right, but it can enhance the therapeutic
activity and reduce the adverse reaction by affect-
ing the metabolic pathway of cytotoxic drug. There
are two groups of biochemical modulators –
chemosensitizer and chemoprotectant. Drug resis-
tance is a major reason for poor responses and fail-
ures in cancer chemotherapy. Anti-estrogens agent
(such as toremifene and tamoxifen) and antide-
pressant fluoxetine has a high potential to join
the arsenal of chemosensitizer [15].
Dose-limiting toxicity secondary to chemother-
apy may reduce tumor control because of its inabil-
Drug
BCM
Immunosuppression
Drug metabolism
CTD
BRM
Immune response
Patient
Immunosuppression
Figure 1 Combination therapy based on cell biological mechanism. CTD, cytotoxic drugs; CBM, cell biological
modifier; BRM, biological response modifier; BCM, biochemical modulator.
Wu
ity to deliver adequate dose-intensive therapy
against the cancer. Based on a steep dose–re-
sponse relationship for especially alkylating agents
on tumor cell survival, high-dose chemotherapy
was considered of interest for the treatment of tu-
mors. Adverse reaction is due to the inability of
cytotoxic drugs to differentiate between normal
and malignant cells. Chemoprotectants have been
developed as a means of providing protection for
normal tissues, without compromising antitumor
efficacy. They allowed the delivery of higher cumu-
lative doses of cytotoxic agents without the
expected consequence of toxicity. Several chemo-
protective compounds have now been extensively
investigated, including mesna, calcium folinate,
amifostine, daxrazoxane and uracil.
Combination therapy
The interaction among drug, tumor and host is crit-
ical for response to therapy and outcome. There-
fore, we classified anticancer drugs to cytotoxic
drugs and modifiers – cell biological modifier, bio-
logical response modifier and biochemical modula-
tor. Cytotoxic drugs and cell biological modifiers
are used as primary drugs frequently, whereas bio-
logical response modifiers and biochemical modu-
lators are usually regarded as adjuvant drugs in
combined therapy. Combination with cell biologi-
cal modifiers and cytotoxic drugs play a double role
of killer and rectifier for tumor cells, whereas bio-
logical response modifiers and cytotoxic drugs are
combined to modulate the tumor–host interaction.
chemotherapy
Rescue
Drug resistance
Anticancer
CBM
Tumor
New classification of anticancer drugs
Biochemical modulators and cytotoxic drugs are
combined to regulate the host’s metabolic pathway
of cytotoxic drugs to enhance the chemosensitivity
or improve the dose of cytotoxic drugs (Fig. 1).
Conclusion
A great number of anticancer agents are under clin-
ical investigation at this moment. Some of them
belong to classical groups of chemotherapy, but
others are the first of new families of drugs. We
propose a classification system that is based on cell
biological mechanisms of drugs. We hope that this
classification will be both available and forthcom-
ing anticancer drugs and be a useful tool to com-
prehend the mechanism of action and the
essential principle of combination therapy.
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