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Chapter-48 Biochemistry of Cancer

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 Chapter 48
Biochemistry of Cancer
ChapterataGlance
The learner will be able to answer questions on the following topics:
¾¾Mutagens and carcinogens
¾¾Oncogenic viruses
¾¾Oncogenes and oncosuppressor genes
¾¾Oncofetal antigens
The term “cancer” is derived from Latin word
“cancrum” or Greek “karkinoma”, that is equivalent
to Sanskrit term “karkitakam”, which means “crab”.
The disease is so called because of swollen veins
around the area, resemble a crab’s limbs. Indian
Medical Science had identified cancer, gave the
name “arbuda”, which literally means the number 108,
identifying the extreme cellularity of the cancer tissue.
The International Union Against Cancer (UICC;
Union Internationale Contre le Cancer) has defined
cancer as a disturbance of growth characterized
by excessive proliferation of cells without apparent
relation to the physiological demands of the organs
involved. Oncology deals with the etiology, diagnosis,
treatment, prevention and research aspects of cancer.
Etiology of Cancer
All cancers are multifactorial in origin. They include
genetic, hormonal, metabolic, physical, chemical
and environ­mental factors. Most human cancers are
spontaneous.
¾¾Tumor markers
¾¾Anticancer drugs
¾¾Tumor immunology
All cancers originate usually from one aberrant
cell, which goes on to multiply and produce a tumor
mass. One mutation occurs out of 106 cell divisions. By
the time a person reaches adulthood, about 1026 cell
divisions have occurred. Thanks to the surveillance by
the immune system, these aberrant cells are usually
destroyed. As age advances, the number of mutations
accumulate, hence the statistical probability of the
incidence of cancer is increased. No wonder, cancer is
a disease of old age, especially after 60 years.
Cancer is the second most common cause
for death in developed countries, second only to
cardiovascular diseases. When the average life-
expectancy is less, as in the case of India, the death
due to cancer is also low.
Mutagens
Any substance which increases the rate of mutation
can also enhance the rate of incidence of cancer.
Therefore, all carcinogens are mutagens. Examples
604 Textbook of Biochemistry
are X-rays, gamma-rays, ultraviolet rays. Some
human cancers are caused by chemicals. These
may be introduced into the body by means of (a)
occupation (aniline, asbestos), (b) diet (aflatoxins)
or (c) lifestyle (smoking). Chemical carcinogens
act cumulatively. Tobacco, food additives, coloring
agents, and aflatoxins are common carcinogens in
our environment.
Thousands of chemicals are known mutagens
and carcinogens. A selected small list of chemical
carcinogens is given in Table 48.1. Methyl
cholanthrene is a powerful carcinogen, only
nanograms are sufficient to produce a tumor in a
mouse (Fig. 48.1).
Aflatoxins
They are a group of chemically related compounds
synthesized by the fungi, Aspergillus flavus. The
mould grows on rice, wheat and groundnut, when
kept in damp conditions. The fungi may grow in cattle
fodder, which may enter into human body through
the cow’s milk. Aflatoxins are powerful carcinogens,
which produce hepatomas.
Cigarette
Lung cancer is associated with the habit of cigarette
smoking. Cigarette contains many carcinogens, the
most important group being benzo(a)pyrenes. Other
important deleterious substances in cigarette smoke
are nicotine, carbon monoxide, nitrogen dioxide and
carbon soot. Statistically, it is estimated that one
cigarette reduces 10 minutes from the lifespan of the
individual. The incidence of lung cancer is increased
to 15 times more in persons smoking 10 cigarettes per
day and 40 times more when smoking 20 cigarettes
per day. Thus, WHO suggested the slogan ‘Cigarette
smoke is injurious to health’. Moreover, non-smoking
Table 48.1: Some chemical carcinogens
Polycyclic aromatic hydrocarbons — Benzopyrenes,
Cholanthrenes, Dimethyl
benzanthracene (DMBA)
Aromatic amines — N-Methyl-4-
aminoazobenzene (MAB)
Nitroso compounds — Dimethyl nitrosamine
Natural compounds — Aflatoxins
spouse of a heavy smoker will have 5 times more
probability to get lung cancer than a non-smoker. This
effect of ‘passive smoking’ made the International
Union against Cancer (UICC) to change the slogan to
‘Your smoking is injurious to our health’.
Oral cancer is strongly associated with chewing
of tobacco.
Alcohol intake increases the risk of oral,
pharyngeal, esophageal and liver cancers. Diet high
in total fat and cholesterol, increases the risk of
colon, breast and prostate cancers.
An often asked question is, why only some
smokers are getting cancer and not all smokers?
Glutathione-S-transferase (GST) is involved in
the detoxifi­cation of various carcinogens, including
cigarette smoke. About 5% of population are lacking
in GST. Smokers who are devoid of GST are more
prone to develop lung cancer.
Progression
The biological history of a tumor shows progression
of malignancy. Cells with faster growth rate have
a selection advantage. Thus, cells with increased
malignant character are progressively selected.
Familial adenomatous polyposis is a typical
example for multistep progression. Mutations in
the APC gene are inherited from parents. By the
time the patient becomes adult, there will be different
dysplastic aberrant crypts in the large intestine. Some
of the cells will get somatic mutations in the K-Ras
gene; these will progress to form adenomas. Further
mutation in TGF gene or p53 gene or Bax gene will
give the push for the development of malignancy.
Action of Chemical Carcinogens
Mechanisms of action of chemical carcinogens
are: (a) Carcinogens are generally electrophiles
(molecules deficient in electrons); they readily
attack nucleophilic (electron rich) groups of DNA, (b)
Carcinogens may bind covalently to cellular DNA.
N2, N3, and N7 atoms of guanine are highly prone to
addition of carcinogen groups, (c) These changes will
lead to DNA alterations, in spite of DNA repair, with
increased probability of mutations.

Physical Carcinogens
X-ray, gamma-ray and UV-ray may cause: (a)
formation of pyrimidine dimers, (b) apurinic sites with
consequent break in DNA, and (c) formation of free
radicals and superoxides which cause DNA break,
leading to somatic mutations. Exposure of X-ray in
fetal life will increase the risk of leukemia in childhood.
In population studies, 1 rad per year will increase the
cancer incidence by 40/million people per year.
Antimutagens
i. These are substances which will interfere with
tumor promotion. Vitamin A and carotenoids are
shown to reverse precancerous conditions.
ii. Vitamin E acts as an antioxidant, preventing the
damage made by free radicals and superoxides.
iii. Vitamin C regularly given to persons working
with aniline prevented the production of new
cancer cases.
iv. Tubers, beans and leafy vegetables are shown
to interrupt tumor promotion.
v. Curcumin, the yellow substance in Turmeric is
known to prevent mutations.
vi. The beneficial effect of the fiber content of the
diet is described in Chapter 35. Low protein, low
fat, diet decreases the risk of cancer in animal
studies.
vii. Flavinoids are phytochemicals that possess
antimutagenic properties. Phenolic compounds
found in fruits like grapes, strawberries, walnuts,
Fig. 48.1: Solid tumor in a mouse induced
by injection of methyl cholanthrene
(from author’s laboratory)
Ludwik Denis Jozsef
Gross Burkitt Marek
1904–1999 1911–1993 1868–1952
1879–1970
Chapter 48:  Biochemistry of Cancer 605
etc. are found to be antimutagenic. Green tea
is shown to be effective against smoke induced
mutations.
Oncogenic Viruses
Another etiological factor of carcinogenesis is the
integration of viral genes into the host DNA. Thus,
the genes of the virus become part and parcel of the
cellular DNA. The drive for multiplication by the viral
genome overrules the regulatory checks and balances
of the cellular mechanism. So, there is uncontrolled
multi­­plication of the cells. This is called transformation
by oncogenic virus.
Rous in 1911 demonstrated that sarcoma in
avians can be transferred from one animal to another
by injecting the soluble fractions. In 1944, Gross
finally proved that viruses could be oncogenic. A
homogenate of mice tumor was prepared, passed
through bacterial filter, and the supernatant was
injected into another mouse. A new tumor developed
at the site of injection. Gross argued that the filtrate
could contain only viruses (and not bacteria or cancer
cells) which produce a tumor. After a long time, at
the ripe age of 87, Rous was awarded Nobel Prize in
1966.
A list of important oncogenic viruses in animals
is shown in Table 48.2. The list is only representative
and is far from exhaustive. In 1930s, an aggressive
form of lymphoma (cancer arising from lymphocytes)
was seen as an epidemic in chicken in North America,
wiping out almost two-third of the total poultry
population. For the first time, a cancer was accepted to
be transmissible. Soon, the Marek virus was isolated
which was proved to be the etiologic agent. By the end
of 1940s, an effective vaccine was prepared and the
disease was controlled. A list of possible oncogenic
viruses in man is given in Table  48.3.
Peyton Renato Michael Harold E
Rous Dulbecco Bishop Varmus
NP 1966 NP 1975 NP 1989 NP 1989
1914–2012 b. 1936 b.1939
606 Textbook of Biochemistry

Burkitt in 1964 reported a type of lymphoma seen After about 10–30 years, these cells develop invasive
mainly in African children. Epidemiology suggested cancer. Vaccines against high risk HPV16 and 18
a strong possibility for a transmitting agent for the types are now developed that provide 95% protection
Burkitt’s lymphoma (BL). In 1969, Epstein reported from infection of HPV, thereby reducing the chances
that all the biopsies of BL when placed in tissue culture of developing cervical cancer (Figs 48.2 and 48.3).
for some time, generated the viral particles which
could be seen under electron microscope (Barr was Oncogenes
the technician who first perfected this technique). The
new virus was named as Epstein-Barr (EB) virus. Oncogenes are Normal Constituents
The lymphoma progression is through 3 different of Cells
events. The first step is infection with EBV which These are genes capable of causing cancer (Box 48.1).
specifically infects B lymphocytes. The B cells are now Michael Bishop and Harold Varmus, pioneers in the
immortalized, that is, they can be cultured indefinitely oncogene research were awarded Nobel Prize in 1989.
in artificial medium. A definite proof for an oncogene was first demonstrated
The second step is the chromosome in Rous sarcoma virus. The full virus produces sarcoma
translocation, usually from chromosome 8 to 14. The in avians but a strain of virus deficient in a particular
chromosome 14 contains gene for immuno­globulin gene, could not cause the disease. Hence, this gene
heavy chain. The transposing region in chromosome was named as sarcoma gene, abbreviated as Src.
8 contains the oncogene c-myc. The third step is However, the same DNA sequences are available in
the activation of c-myc oncogene, with consequent normal avian cells also. This reveals that normal cells
malignancy. do contain DNA sequences similar to viral oncogenes.
HPV (Human Papilloma Virus) is the most To distinguish these two genes, they are denoted
common sexually transmitted infection in adults. It as V-src (viral gene) and C-src (cellular gene). The
has a circular double stranded DNA. More than 100 oncogenes present in normal cells are also called
HPV types are known. HPV types 16 and 18 are as proto-oncogenes. A few important human proto-
associated with human uterine cervical cancer; they oncogenes are abl, erb, myc, sis, etc.
cause 70% of all cervical cancers. Harald zur Hauzen
(Nobel prize, 2008) showed the HPV DNA in the Proto-oncogenes are Regulatory Genes
cancer cells. HPV infects epithelial cells in the cervical Products of many oncogenes are polypeptide
mucosa; the virus multiplies and lyses the host cells, growth factors, e.g. sis gene produces platelet
causing a lesion. In 99% of such cases healing occurs derived growth factor (PDGF). This factor is required
within 6 months to 2 years. But in about 1% cases, for normal wound healing. Some of the products act
the HPV DNA is integrated into some of the host cells. as receptors for growth factor, e.g. erb-B produces
receptor for EGF (epithelial growth factor). Some
Table 48.2: Viruses producing tumors in animals other oncogene products act on key intracellular
Virus Nucleic acid of Host Type of tumor pathways involved in growth control, e.g. src product,
virus produced a membrane-bound enzyme, phosphorylates a
Papova virus group specific tyrosine residue, leading to cascade activation
SV-40 DNA Mouse Sarcoma
Table 48.3: Human oncogenic viruses
Papilloma DNA Rabbit Papilloma
Virus Abbreviation Associated human cancer
Marek DNA Chicken Lymphoma
Epstein-Barr virus EBV Burkitt’s lymphoma
Retrovirus type C (BL); Nasopharyngeal
Gross RNA Mouse Leukemia carcinoma (NPC)
Rous RNA Avian Sarcoma Human papilloma HPV Uterine cervical
virus carcinoma
Retrovirus type B
Hepatitis B virus HBV Hepatoma
Bittner RNA Mouse Mammary tumor

of cellular events. Receptors for EGF, insulin, PDGF,
etc. are also activated by src-product protein. Proto-
oncogene activation has been demonstrated in
different types of human tumors.
Many Factors Activate Oncogenes
The oncogenes also provide an explanation for the
multifactorial origin of cancer. Thus viruses, chemical
carcinogens, chromosome translocations, gamma-
rays, spontaneous mutations, and all such factors
may converge into one biochemical abnormality,
the activation of oncogenes. This would lead to
malignancy. This unified theory is depicted in Figure
48.4.
Point mutation of proto-oncogene: The ras
gene produces a protein termed P21 (Mol. wt. 21,000),
that suppresses the activity of adenyl cyclase.
Adenyl cyclase has a key role in cellular response to
hormones (see Chapter 45). C-ras oncogene product
is a mutated version of P21. So, GTPase activity is
Fig. 48.2: zur Hausen showed that HPV is integrated into the host
DNA of human cervical cancer cells. Host cell DNA is isolated,
cut with restriction endo-nucleases, electrophoresed, and
hybridized with radioactive probes of HPV DNA. The DNA from
patients are seen to hybridize with virus probes, as shown +ve
in the slide. Details of DNA hybridization are given in Chapter
44
Fig. 48.3: HPV and host interaction. Left slide, HPV infects one
cell in the basal layer in human uterine cervix. Middle slide,
within few weeks, HPV spreads to most of the cells; replicates,
and a lesion is manifested. Some host cells will escape the
infection. In 99% cases, the lesion subsides within 6 months to
2 years time. Right slide, In 1% cases, virus is integrated into
the host DNA, remains dormant. After 10–30 years, cancer is
developed. Here malignant cells are shown to break the basal
layer and invade into surrounding tissues
Chapter 48:  Biochemistry of Cancer 607
decreased leading to continuous activity of adenyl
cyclase.
Antioncogenes or Oncosuppressor
Genes
These are the genes, which normally protect the
individual from getting the cancer. When the gene is
deleted or mutated, cancer results. Some important
oncosuppressor genes are RB (retinoblastoma),
WT (Wilms tumor), FAP (familial adenomatous
polyposis), BRCA1 (familial breast cancer) and
p53. Antioncogenes are written with capital letters,
whereas oncogenes are represented by small letters.
The p53 is so named, because it is a protein with
molecular weight 53 kDa. It is a tumor suppressor
protein and prevents formation of cancer. So, p53
has been described as “the guardian angel of the
genome,” and the “master watchman,” referring to
its role in conserving stability by preventing genome
mutation. It can activate DNA repair proteins when
DNA has sustained damage. It can initiate apoptosis
(programmed cell death), if the DNA damage proves to
be irreparable. People who inherit only one functional
copy of the p53 will most likely develop tumors in
early adulthood. The gene can also be damaged in
cells by mutagens (chemicals, radiation, or viruses),
increasing the uncontrolled cell division. More than
50 percent of human tumors contain a mutation or
deletion of the p53 gene.
The retinoblastoma protein (Rb) Molecular
weight:105,000. is a tumor suppressor protein that is
dysfunctional in many types of cancer. The function
of Rb is to prevent excessive cell growth by inhibiting
the cell cycle. Only when both alleles of the RB gene
are deleted (homozygous), retinoblastoma results.
BRCA gene mutations: A blood test is done for
women who are likely to have BRCA mutations (those
with a family history of breast cancer). Mutations are
Box 48.1: Oncogens and oncogenes are different
1. Oncogen is the chemical which produces cancer.
2. Oncogens are the chemicals that produce cancer.
3. Oncogene is the gene causing cancer.
4. Oncogenes are the genes causing cancer.
5. Oncogenes are written with small letters, and antioncogenes are
written with capital letters.
6. The gene present in normal cell is named with prefix c- (to show
that it is in the cell), whereas the corresponding gene present in
the virus is denoted with prefix v- (standing for virus).
608 Textbook of Biochemistry
seen in 5% of breast cancers and 10–15 % of ovarian
cancers and more than 50% of patients with positive
family history of breast or ovarian cancer.
Growth Factors
Many of the oncogenes act through the production
of growth factors. The growth factors generally cause
mitosis or differentiation of target cells. These may be
considered as local hormones. There are more than
100 growth factors; a few important ones are shown
in Table 48.4. Interleukins and interferons are growth
factors released by lymphocytes/macrophages (see
Chapter 46).
Malignant Transformation b. To facilitate detection of cancer. The presence
When a normal cell has acquired malignant character,
it is said to be transformed. For his pioneering work
in transformation studies in tissue culture, Renato
Dulbecco was awarded Nobel prize in 1975. In the
cell culture, this is seen as alterations in morphology
as well as changes in the alignment among the cells.
Normal cells form a monolayer, while cancer cells show
multilayered appearance.
Tumor Immunology
All forms of treatment of cancer (surgery, radiotherapy
and chemotherapy) leave some residual cancer cells
in the body. These are annihilated by the body’s
immune mechanism. Burnet (Nobel prize, 1960) had
postulated that the major purpose of immunological
system is the surveillance against spontaneously
occurring cancer cells. In the tumor bearing host,
appreciable level of immunological reaction against
the cancer is detected. This is because of the
presence of tumor associated antigens (TAA) on
the surface of cancer cells.
Oncofetal Antigens
During the fetal life, a particular gene is active, and the
product, a protein is therefore produced in the cell (Fig.
48.5). During the differentiation process, this gene is
suppressed and therefore the protein is not present
in adult cells. However, along with the malignant
transformation, de-differentiation occurs, the gene
is derepressed and the protein is again available in
the cell. Such products are classified as oncofetal
proteins. The best examples are the appearance of
alpha-feto protein (AFP) in hepatomas and carcino-
embryonic antigen (CEA) in colon cancers. They
generally serve as tumor markers.
Tumor Markers
They are also called as tumor index substances.
They are factors released from the tumor cells, which
could be detected in blood and therefore indicate the
presence of the tumor in the body. They are useful for
the following purposes.
a. For follow-up of cancer and to monitor the
effectiveness of the therapy and also to detect
the recurrence of the tumor (Fig. 48.6).
of tumor marker suggests the diagnosis, but
caution is to be taken to rule out other non-
malignant conditions.
c. For prognosis. Serum level of the marker may
indicate roughly the tumor load, which in turn
indicates whether the disease is curable or not.
d. Tumor markers are sometimes elevated in
nonmalignant conditions. Not every tumor will
cause a rise in the level of its associated marker,
especially in the early stages of some cancers.
Clinically Important Tumor Markers
Alpha Fetoprotein (AFP)
In 1963, Abelev demonstrated AFP. It is fetal albumin
and has similarities with adult albumin. It is increased
in the circulation of patients with hepatocellular
carcinoma, germ cell tumors, teratocarcinoma of
ovary and in pregnancy with fetal malformations
of neural tube (Table 48.5). In adult males and
nonpregnant females, the values are less than
15 ng/L. A value of AFP above 300 ng/L is often
associated with cancer, although levels in this range
may be seen in nonmalignant liver diseases. Levels
above 1000 ng/L are almost always associated with
cancer (except in pregnancy).
Carcinoembryonic Antigen (CEA)
The CEA level is markedly increased in colorectal
cancers. Its molecular weight is 180 kD (Table 48.5).
 Chapter 48:  Biochemistry of Cancer 609

In 1965, Gold and Freedman identified the CEA. liquefaction of seminal coagulum. PSA has been
Over 50% of persons with breast, colon, lung, gastric, found to be elevated in 60–70% patients with cancer
ovarian, pancreatic, and uterine cancer have elevated of the prostate. Most PSA is bound to antitrypsins in
levels of CEA. plasma but some PSA circulates unbound to protein
(free PSA). Normal blood level of total PSA is less
Beta Chain of Chorionic Gonadotropin than 4 ng/L. Persons with a borderline total PSA
(between 4–10 ng/L), but who have a low free PSA
Beta-hCG is synthesized by normal
are more likely to have malignant prostate disease.
syncytiotrophoblasts (cells of placental villi). hCG is a
glycoprotein; it has alpha and beta subunits. The alpha
subunit is identical with those of FSH, TSH and LH. Estrogen Receptor (ER)
The beta subunit is specific for hCG. It is increased It is a protein found in the nucleus of breast and
in hydatidiform mole, choriocarcinoma and germ cell uterine tissues. The level of ER in the tissue is used
tumors (Fig. 48.6). to determine whether a person with breast cancer
is likely to respond to therapy with tamoxifen, which
binds to the receptors blocking the action of estrogen.
Cancer Antigen 125 (CA-125)
Women who are ER-negative have a greater risk of
CA-125 is a tumor maker for ovarian cancers. It is recurrence than women who are ER-positive.
a glycoprotein with a molecular weight of 10 million;
one of the biggest molecules identified. Approximately Progesterone Receptor (PR)
75% of persons with ovarian cancer will have elevated Tissue that does not express the PR receptors is less
serum levels. (50% of persons with stage I disease likely to bind estrogen analogs used to treat the tumor.
and 90% with stage II). Elevated levels of CA-125 Persons who test negative for both ER and PR have
are also found in approximately 20% of persons with less than a 5% chance of responding to endocrine
pancreatic and digestive tract cancers. therapy. Those who test positive for both markers
have greater than a 60% chance of tumor shrinkage
Prostate Specific Antigen (PSA) when treated with hormone therapy.
Chu isolated it in 1980. It is produced by secretory
epithelium of prostate gland. It is normally secreted
into seminal fluid, where it is necessary for the
Table 48.4: Some important growth factors
Growth factor Abbreviation Function
Epidermal growth factor EGF Stimulates epidermal and
epithelial cells
Transforming growth factor-α TGF-α Similar to EGF
Transforming growth factor-β TGF-β Inhibition of fibroblasts
Platelet derived growth factor PDGF Accelerates wound healing
Nerve growth factor NGF Growth of sensory neurons
Insulin-like growth factor IGF-1 Sulfation into cartilage
Erythropoietin EP Stimulates erythropoiesis
Granulocyte macrophage colony GMCSF Stimulates granulocytes,
stimulating factor monocytes, magakaryocytes
Granulocyte colony stimulating GCSF Stimulates granulocytes
factor
Monocyte colony stimulating factor MCSF Stimulates monocytes
Tumor necrosis factor- alpha TNF-α Necrosis of tumor cells,
proliferation of leukocytes
610 Textbook of Biochemistry
HER2/neu (or erbB-2, or EGFR2)
It is a protein that stimulates breast cancer cells to
grow. Higher than normal levels can be found in
some other cancers, too. The HER2 level is usually
found by testing a sample of the cancer tissue itself,
not in blood. HER2 is positive in about 1 in 5 breast
cancers. These cancers tend to grow and spread more
aggressively than other breast cancers. All newly
diagnosed breast cancers should be tested for HER2.
HER2-positive cancers are more likely to respond to
certain treatments such as trastuzumab (Herceptin)
and lapatinib (Tykerb), which work against the HER2
receptor on breast cancer cells.
Paraproteinemias and multiple myeloma are
described in Chapter 46. Oncofetal proteins and tumor
markers are listed in Table 48.5.
ANTICANCER DRUGS
Surgery and radiotherapy are most effective to reduce
the initial tumor load. These are the prime modalities of
treatment in solid tumors. Chemotherapy is the sheet
anchor of therapy in leukemias, advanced lymphomas,
choriocarcinoma and other widely disseminated malig­
nancies. The effectiveness of cytotoxic drugs is directly
proportional to the doubling time of the tumors, and is
inversely proportional to the number of cancer cells.
Cytotoxic drugs affect all the cells which are in the dividing
phase. Rapidly dividing normal cells (gastrointestinal
tract, hematopoietic system, hair follicles, gonads) are
also affected by chemotherapeutic drugs, leading to
toxicity. In fact, pharmacological dose and toxic dose
usually overlap in the case of these drugs.
Some important anticancer drugs are listed in
Tables 48.6 and 48.7.
Methotrexate
It inhibits dihydrofolate reductase. Methotrexate
has structural similarity to folic acid, and hence will
competitively inhibit folate reductase. So in presence
of methotrexate, tetrahydrofolic acid is not produced,
which is necessary for incorporation of C2 and C8
of purines and C5 methyl group in thymidine. Thus,
there is inhibition of DNA synthesis and consequently
of cell division. Methotrexate is commonly employed
in the treatment of choriocarcinoma, which is a
curable cancer. It is also useful in acute leukemia.
6-Mercaptopurine
It is a purine analogue which prevents amination of
IMP to AMP, so that the availability of AMP is reduced
(see Fig. 38.11). This leads to inhibition of synthesis
of DNA, and in turn cell division. It is commonly
employed in treating acute lymphoblastic leukemia.
Monoclonal Antibody
These drugs are a relatively new innovation in
cancer treatment. Technique for monoclonal antibody
production is described in Chapter 44. The mechanism
of action of monoclonals against cancer may be:
a. The antibody marks the cancer cell and makes it
easier for the immune system to attack. The drug
rituximab attaches to CD20 found only on B
cells; makes the cells more visible to the immune
system, which can then attack.
b. Block growth factors. Certain cancer cells make
extra copies of the growth factor receptor. This
makes them grow faster than the normal cells.
Monoclonal antibodies can block these receptors
and prevent the growth signal. For example,
Cetuximab attaches to epidermal growth factor
receptors (EGFR) on cancer cells. Blocking this
signal from reaching its target on the cancer cells
may slow or stop the cancer from growing.
c. Stop new blood vessels from forming. To
attract blood vessels, cancer cells send out
growth signals. Monoclonal antibodies that block
these growth signals may help prevent a tumor
from developing a blood supply, so that it remains
small. The monoclonal antibody bevacizumab
intercepts vascular endothelial growth factor
(VEGF) and stops them from connecting with
their targets (Table 48.7).
Related Topics
Anti-oxidants (see Chapter 30), telomerase (see
Chapter 39), cell cycle (see Chapter 42), and
apoptosis (see Chapter 42).
Clinical Case Study 48.1
A 40-year-old female presented to the clinic with lump
in right breast. A mammogram performed revealed
a breast mass measuring 3 cm with numerous

microcalcifications suggestive of breast cancer. The
family history revealed that she had a sister who was
diagnosed with breast cancer at the age of 35. She
also recalls that one of her aunts had died long ago
with great abdominal distension (probably ovarian
carcinoma). On physical examination, there was a
fixed and nontender mass on right breast, measuring
3 cm. Axillary lymph nodes were palpable on the
right side. Skin was not involved. The biopsy report
was intraductal carcinoma. What cancer gene might
be associated with cancer breast? What is the likely
mechanism of activation of oncogene in this case?
Clinical Case Study 48.1 Answer
Most likely cancer gene: Breast cancer (BRCA) gene
Likely mechanism: Inhibition of tumor-suppressor
gene Discussion: This patient has developed breast
cancer. Her two relatives had breast or ovarian cancer
prior to menopause. This makes BRCA gene mutation
likely. Proto-oncogenes are normal genes that are
present in normal cells and involved in normal growth;,
but if mutated, they become oncogenes, leading to
Fig. 48.4: Unified concept of carcinogenesis. 1= ionising radiation;
2= chromosome translocation; 3= chemical carcinogens;
4= oncogenic viruses; 5= spontaneous mutations
Chapter 48:  Biochemistry of Cancer 611
cancer. The BRCA1 gene encodes a protein which
is necessary for DNA repair. A woman with a BRCA1
mutation has 70% risk of developing breast cancer,
and 30% risk of ovarian cancer. However, it should be
emphasized that the vast majority of breast cancers
are not genetically based, but occurs sporadically.
BRCA2 mutations are also associated with ovarian
cancers and male breast cancers.
LEARNING POINTS CHAPTER 48
1. All cancers are multifactorial in origin. They
include genetic, hormonal, metabolic, physical,
chemical and environ­mental factors. Examples
of physical carcinogens are X-ray, gamma-ray,
ultraviolet ray. Examples of chemical mutagens
are Aflatoxins, Methylcholanthrene, Nicotine.
2. Examples of antimutagens include Vitamin A,
Vitamin E, Vitamin C and Curcumin.
3. Example of viruses producing tumors in animals
are Polyoma, SV 40, Gross, Rous, etc.
4. Viruses possibly oncogenic in man are EBV, HPV
and Hepatitis B.
5. Genes capable of causing cancer are termed
oncogenes, e.g. myc, src, ras, abl, erb-B etc.
6. Genes which normally protect the individual from
getting a cancer are called Anti-oncogenes or
Oncosuppressors, e.g. p53, pRB.
7. Examples of oncofetal antigens are alpha-
fetoprotein (AFP) in hepatomas and carcino-
embryonic antigen (CEA) in colon cancers.
8. Tumor markers are useful for diagnosis and
follow-up of cancer chemotherapy, e.g. CA-125,
VMA, Placental ALP, Prostate specific antigen.
612 Textbook of Biochemistry
Fig. 48.5: Oncofetal antigen
Group
Oncofetal Products
Tissue Antigens
Enzymes
Hormones and their Metabolites
Serum Proteins
Table 48.5: Common tumor markers
Name
Alpha fetoprotein (AFP)
Carcinoembryonic antigen (CEA)
Carbohydrate Antigens
CA-125
Tissue polypeptide antigen
Alkaline phosphatase (ALP)
Placental type ALP (Regan)
Prostatic acid phosphatase (PAP)
Prostate specific
Neuron Specific Enolase
Beta-hCG
Calcitonin
Vasoactive intestinal polypeptide (VIP)
Vanillyl mandelic acid (VMA)
Hydroxy indole acetic acid
Immunoglobulins (Ig)
Bence-Jones proteins (in urine)
Serum level increased in
Hepatoma, germ cell cancers
Colorectal, gastrointestinal, and lung cancer
Ovarian cancer of epithelial origin
General cancer load
Bone secondaries
Lung, seminoma
Prostate cancer
Prostate cancer Antigen (PSA)
Neuro-endocrine tumors
Choriocarcinoma
Medullary thyroid carcinoma
Apudomas (Amine precursor uptake decarboxylation-
omas)
Pheochromocytoma and neuroblastoma
Carcinoid syndrome
Multiple myeloma, macroglobulinemia
Multiple myeloma
 Chapter 48:  Biochemistry of Cancer 613

Fig. 48.6: Monitoring of serum level of beta-HCG in chorionic

carcinoma (The level is decreased after treatment and goes up
when the disease recurs)

Table 48.7: Some monoclonal antibodies used as

anticancer agents
Name Target Used against the cancer
Rituximab CD20 on B cells NHL, CLL, B cell leukemia
Trastuzumab HER-2/neu Breast cancer
(Herceptin) (EGFR2, Erb-B2)
Bevacizumab VEGF Colorectal, solid tumors of
kidney, breast
Alemtuzumab CD52 on B cells CLL
Cetuximab KRas Colorectal, head and neck
Panitumumab EGFR Colorectal
Imatinib Tyrosine kinase CML

Table 48.6: Common anticancer drugs

Name Type Mode of action
Methotrexate Folic acid analogue Competitive inhibitor of dihydrofolate reductase. THFA is
required for nucleotide synthesis
6-Mercapto purine Purine analogue Inhibits the conversion of IMP to AMP
6-thio guanine Purine analogue Inhibits the conversion of IMP to AMP
Cyclophosphamide Alkylating agent Cross linking of bases of DNA; inhibition of strand separation
MitomycinC Antibiotic Cross bridges are formed between DNA base pairs
Actinomycin D Antibiotic Intercalates with guanine bases of DNA; prevents transcription
Vincristine and Vinblastine Alkaloids from Vinca rosea Interferes with assembly of cytoskeleton and inhibits
Stathmokinesis (spindle movement)
Adriamycin Anthracyclins Topo-isomerase mediated breaks in DNA
Etoposide Podophyllotoxin Stabilises topo-isomerase-II-DNA cleavage complexes
Cisplatin Platinum compound Forms intrastrand DNA adducts
Imatinib Monoclonal antibody Tyrosine kinase inhibitor
Fluorouracil (FU) Pyrimidine analog Inhibits thymidylate synthase

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