ANTICANCER

DRUGS
 Possible causes of cancer
•Physical agents (radiation,
mobile phones ?)
•Chemicals
(carcinogens, including
smoking)
•Hereditary factors
•Effectiveness of the immune system
(virus infections: Ca collum uteri)
•Stress, > BMI (GI cancer),
•some drugs (cyclophosphamide,
estrogens, tamoxifen)
Characteristics
of cancer cells
•Uncontrolled proliferation
•Can be invasive
•Can metastasize
•Lack of function
(lack of differentiation)
Normal cells
•Growth is controlled
by growth factors
and growth
inhibitory factors
Cancer cells
•Inactivation of
tumor-suppressor genes
•Activation of proto-oncogenes
ANTICANCER
TREATMENT
 surgery
 radiotherapy
(irradiation)
 chemotherapy
 supportive therapies
NB!
The sensitivity of
a cancer to treatment
depends on the
growth fraction –
that is the fraction
of cells undergoing
mitosis at any time.
The fraction of cell division
in Burkitt’s lymphoma is 100%
and this tumor is very sensitive.
In contrast the growth fraction
represents less than 5% of cells
in a carcinoma of the colon
and this explains its
resistance to chemotherapy.
However, metastases from
colonic carcinoma, deposited in
the liver and elsewhere initially,
have a high growth fraction and
are sensitive to chemotherapy,
which is frequently given
following surgical removal
of primary tumor.
Different forms of cancer differ
in their sensitivity to chemothe-
rapy. The most responsive are
rapidly proliferating tumors:
• lymphomas
• leukemias
• choriocarcinoma
• testicular carcinoma
Solid tumors show
a poor response:
• colorectal carcinomas
• adrenocortical carcinomas
• squamous cell
bronchial
carcinomas
An intermediate response
is shown by other cancers:
• bladder
• head and neck
• oаt cell bronchogenic carcinoma
• sex-related cancers of the breast,
ovary, endometrium, prostate
 Adverse effects
Most of the anticancer agents have
a limited selectivity and damage
all dividing cells. As a result
general adverse effects are:
• Myelotoxicity (reduction of leukocytes
increases susceptibility to infections)
• Hair loss
• Damage to GI tract
• Impaired wound healing
• Depression of growth
• Nausea and vomiting
• Carcinogenicity (in rare cases)
• Reproductive toxicity (PRC: D/X)
• Kidney damage
• Hepatotoxicity
 Resistance to cytotoxic drugs
(primary or acquired) in 90% of cases
– mechanisms:
• Increased rate of synthesis of target enzyme
(dihydrofolate reductase and methotrexate)
• Increased repair of DNA (alkylating agents)
• Insufficient activation of prodrug
– cytarabine (does not undergo phosphorylation)
•Multi Drug Resistance – increasing action of
membrane efflux system (P-gp 170 and 190), etc.
Strategy to avoid resistance
Use 3 or 4 anticancer drugs
together or in sequence,
e.g. treatment of lymphomas:
•COP treatment (COP – acronym)
– Cyclophosphamide
– Oncovin (vincristine)
®

– Prednisolone
 Criteria for selecting combinations
• Each drug should be an active anticancer
drug in its own right.
• Each drug should have a different
mechanism of action and target site within
the cancer cell (this will increase efficacy
and will reduce the resistance).
• Each drug should have a different site
for any organ-specific toxicity.
The dosage of many antineoplastic drugs
is carried out according to the body surface
of the patient, calculated in square meters
(m2) by means of nomogram according
body mass in kg and height in cm.
The best treatment regimens are become
the "gold standard" for treatment of
cancer. They are develop and annually
update by world oncotherapeutic teams.
Anticancer (antineoplastic) drugs
I. Cytotoxic drugs (cytostatics)
- Alkylators
- Antimetabolites
- Plant-derived drugs and their analogs
- Cytotoxic antibiotics
- Platinum coordination complexes
II. Endocrine agents
- Glucocorticoids
- Sex hormones and antihormones
III. Target drugs
     - Monoclonal antibodies (MAB)
     - Protein (tyrosine kinase) inhibitors
     - Inhibitors of production of TNF-α
IV. Inhibitors of bone resorption and metastases
V. Immunomodulators
- Cytokines (ILs, IFNs)
- Vaccines
VI. Radiotherapy
VII. Cancer supportive therapies
I. CYTOTOXIC AGENTS
The majority of cytotoxic
agents inhibit the process
of DNA synthesis within
the cancer cells.
Resting cells (those in the Go
phase) are resistant to many
anticancer drugs.
Precursors Methotrexate Precursors

Purine Pyrimidine

Ribonucleotides
Mercaptopurine

Deoxiribonucleotides
Alkylators
Cis-platin DNA
Asparaginase
Antibiotics
RNA
Nitrosoureas Asparagine
Mitotic inhibitors Proteins
 Action of cytotoxic agents
on the cell cycle
Cycle non-specific Phase specific

Alkylators Antimetabolites
Antibiotics Mitotic inhibitors
 Alkylating agents
These drugs were developed from the
sulfur mustard gases used in the 1st WW
trenches and which caused bone
marrow suppression in addition to
respiratory toxicity.
Replacement of the sulfur atom by
nitrogen allowed the first alkylating
agents to be obtained.
The important functional group is
the di-(2-chlor-ethyl)-amine side chain:
CH2CH2Cl
R— N
CH2CH2Cl

The dichlorethylamine chains are highly

reactive and produce alkylating groups
which bind covalently to sites within the
DNA such as N7 of guanine.
guanine
 a) First
alky-
lators
are
di-(2-chlor Cyclophosphamide
ethyl)-
amines:
Nitrogen
mustards Chlorambucil
•Cyclophosphamide and Chlorambucil
are commonly used for Hodgkin’s
and non-Hodgkin’s lymphoma, chronic
lymphocytic leukemia.
Cyclophosphamide is also used for
immunosuppression in non-malignant
disorders (severe rheumatoid disorders,
myasthenia gravis, multiple sclerosis).
Cyclophosphamide is a prodrug.
One of its metabolites is acrolein.
acrolein
Acrolein causes bladder toxicity
with haemorrhagic cystitis which
can be prevented by prior treatment
with Mesna.
Bladder cancer may
develop years after
Cancer
cyclophosphamide chemotherapy.
b) Nitrosoureas (the other alky-
lators) inhibit the synthesis of
DNA, RNA, and proteins.
Carmustine crosses BBB.
It is used for brain tumors.
Carmustine and
Lomustine are
used for the treatment of
Hodgkin’s lymphoma.
  Antimetabolites –
produce lethal synthesis
A number of useful chemothera-
peutic agents have been produced by
simple modifications to the
structures of normal purine and
pyrimidine bases.
 a) Analogues of pyrimidine
• 5-Fluorouracil (5-FU®: i.v.) – used for the treatment of
carcinoma of stomach, colon, rectum, breast, and pancreas.

5-FU

• Xeloda® (p.o.) – used in colorectal carcinoma.

It is a prodrug of 5-FU with very high selectivity.
• Cytarabine: used in acute myeloid leukemias
(It acts after phosphorylation)
5-FU blocks thymidilate synthase
•Gemcitabine
is an analogue of pyrimidine too.
It inhibits DNA polymerase and impairs
DNA synthesis. It is used in various carcinomas:
non-small cell lung cancer, pancreatic cancer,
bladder cancers, breast cancer.

b) Analogues of purine
•Mercaptopurine (6-MP) and
Thioguanine (6-TG): used in
childhood acute leukemia;
leukemia Fludarabine
 c) Folic acid antagonists
•Methotrexate, Pemetrexed, Ralitrexed
Folic acid in its reduced form (THF –
tetrahydrofolic acid) is essential for syn-
thesis of the purine ring system. During
these reactions THF is oxidized to dihydro-
folic acid which has to be reduced by
dihydrofolate reductase. Methotrexate
inhibits dihydrofolate reductase and
blocks purine and thymidine synthesis.
COOH N N NH2
H
CH N C N C N
H2 N
CH2 H O OH
CH2
Folic acid
COOH

COOH N N NH2
CH3

CH N C N C N
H2 N
CH2 H O NH2
CH2
Methotrexate
COOH
(It has immunosuppressive activity too.)
Methotrexate is given
for the treatment of:
•acute lymphoblastic leukemia
•non-Hodgkin’s lymphomas
•chorionepithelioma
•non-malignant disorders
(such as psoriasis).
psoriasis
Adverse effects of methotrexate
•Vasculitis
•Arachnoiditis
•Pharyngitis, pneumonitis
•Cystitis
PRC: D
•Vomiting
•Hepatotoxicity
•Renal dysfunction
 Plant-derived drugs and their analogs

•Vinca alkaloids
•Derivatives of Podophyllotoxin
•Taxans etc.
They have cycle and phase
specific action on
the cell division.
Vinca alkaloids are complex
natural chemicals isolated from
the periwinkle plant (Vinca rosea).
•Vinblastine
•Vincristine
•Vinorelbine (Navelbine®)

 They bind to tubulin and produce

metaphase arrest.
 They are used in acute leukemia.
(mitotic inhibitors)
Derivatives of Podophyllotoxin
(epipodophyllotoxins)
Podophyllum peltatum
(May apple)

Podophyllotoxin

Epipodophyllotoxin

Etoposide
Teniposide
Etoposide
•Inhibits mitosis
•Acts in late S- or early G2-phases
•Used in treatment of lymphoma;
lung, testicular,
bladder and
prostate
cancer
Taxans
Inhibit the
depolymerization
of tubulin and
block mitosis.
•Docetaxel –
in breast cancer
•Paclitaxel (Taxus brevifolia)
  Cytotoxic antibiotics
(inhibit DNA replication)
a) Anthracyclines
•Dau no ru bi cin
– i n advan ced HIV-associ ated
Kap o si ’s sarcoma
•Do xo rubi ci n (Adriamycin ®)
– p ossesses myel o su pp ressi on and
d ose-related irreversi bl e myocardi al
d amag e d ue to free rad ical attack
•Epi ru bi cin , Id arubi ci n
Daunorubicin Doxorubicin

Epirubicin Idarubicin
•Other antibiotics
Mitomycin C
– in cancer of the
bladder (locally)
Bleomycin in:
– testicular cancer
– melanomas, sarcomas
– squamous cell carcinomas
 Platinum coordination complexes
Cis-platin binds to DNA and proteins.
It has made a significant impact on the
treatment of testicular teratoma and
ovarian tumors. It has a long t1/2 (72 h)
due to extensive protein binding and
slow renal elimination.
•Renal toxicity is a major
problem. Severe nausea
and vomiting are often
troublesome too. PRC: D.
 II. Endocrine agents
Some cancer arise from cell lines with
steroid receptors. Steroid hormones
cause remissions in certain types of
cancer. They usually do not eradicate
the disease, but can alleviate
symptoms for a long period and
do not depress the bone marrow.
 Glucocorticoids
suppress lymphocyte mitosis
and are used in combination with
cytotoxic agents in treating of
lymphomas, myeloma
and to induce
a remission in
acute lymphoblastic
leukemia.
leukemia
Glucocorticoids
are also helpful in
reducing oedema around a tumor.
They have antiemetic activity too.
•Hydrocortisone, Prednisone
•Dexamethasone, Prednisolone
 Estrogens
suppress prostate cancer
both locally and metastases, and
provide symptomatic improvement.
Gynecomastia is a common
side effect.
• Ethinylestradiol
• Polyestradiol
phosphate
 Progestagens
suppress
endometrial cancer cells
and lung secondaries:
• Gestonorone
• Medroxyprogesterone
 Androgens
are used rarely Side anabolic
in the treatment effect

of carcinoma
ovarii and uteri
•Testosterone
 Androgen antagonists
suppress prostate cancer cells.
Unwanted effects include:
gynecomastia, decreased
spermatogenesis, decreased libido.
• Bicalutamide, Cyproterone, Flutamide

PSA >> 5
1 2 3
 Inhibitors of alpha-reductase
• Alpha-reductase converts
testosterone in more active
dihydrotestosterone.
• Finasteride is useful orally in the
treatment of benign prostatatic
hyperplasia.
 Estrogen antagonists
•Fluvestrant, Toremifen
•Tamoxifen (p.o.) suppresses breast
cancer cells. The trans isomer of Tamoxifen
blocks competitively estrogen receptors.
Adverse effects include
hot flushes and amenorrhoea
in premenopausal women
and vaginal bleeding in
postmenopausal women.
 Aromatase inhibitors
• Aminoglutethimide
• Exemestane (Aromasin®)
• Formestane, Letrozole
- They inhibit aromatase and block conversion
of androgens to estrogens.
- Inhibition of aromatase reduces estrogen
production in adipose tissue, skin, muscle,
and liver of postmenopausal women
(because ovarian aromatase is resistant
to such inhibition!).
Aromatase is also presented in the cells of
two-thirds of breast carcinomas and about
80% of these tumors are estrogen-
dependent. Aromatase inhibitors are used
in postmenopausal women with
advanced breast carcinoma.
Side effects include symptoms of estrogen
withdrawal, e.g. headache, hot flushes,
and lethargy; dyspepsia, nausea, alopecia,
skin rash, hypotension, tachycardia.
Breast cancer
 Gonadotrophin releasing
hormone agonists (GnRHAs)
Continuous daily administration
of GnRHAs results in suppression
of testicular and ovarian steroido-
genesis due to decreased levels of
LH and FSH with subsequent
decrease in testosterone (in man)
or estrogens (in women).
 Gonadotrophin releasing
hormone agonists:
•Leuprolide (Leuproreline)
•Goserelin (Zoladex®) –
3.6 mg/30 days s.c. in:
– palliative treatment of advanced
prostatic carcinoma
– endometriosis
III. Target drugs
They block receptors of the growth
and other angiogenic factors:
VEGF – vascular endothelial growth factor
EGF – epidermal growth factor
PDGF – platelet-derived growth factor
PlGF – placental transfer growth factor
TNF-α – tumor-necrosis factor alfa, etc.
 a) Monoclonal AntiBody (MAB)
•BEVACIZUMAB (Avastin®) – anti-VEGF agent
blocks angiogenesis and the growth of new blood
vessels. It is used to treat various cancers,
including colorectal, lung, and kidney cancer, etc.

Avastin®
Thalidomide

Revemide
TNF-alfa VEGF Bevacizumab
Actimide (–) (–)
(+) (+)

(+) (+)
PDGF EGFR

(– )

(–) Cetuximab

TNF-beta
Colorectal cancer
•TRASTUZUMAB (Herceptin®) is part of a treatment
plan for the adjuvant treatment of patients with HER2
overexpressing, node-positive HER2+ breast cancer.
•CETUXIMAB (an inhibitor of EGF receptor):
used in metastatic colorectal cancer.
b) Protein kinase inhibitors
•Imatinib (Glivec®):
used for the oral treatment of chronic myelogenous leukemia
•Everolimus (Afinitor®) – mTOR inhibitor:
mammalian Target Of Rapamycin) is used: in renal cancer, pancreatic
neuroendocrine tumors,
tumors as an immunosuppressant to prevent
rejection of organ transpalntants (including in drug-eluting coronary
stents to prevent restenosis).
•Lapatinib, Pasopanib
•Sorefenib (used in renal and liver cancer)
c) Inhibitors of the production
of TNF-α:
Thalidomide and analogs
- in with Kaposi's sarcoma, glioblastoma,
multiple myeloma, erythema nodosum
leprosum
IV. Inhibitors of bone resorption and metastases
V. IMMUNOMODIFICATORS
The immune system probably
contributes to the final removal
of residual malignant cells, and
most cytotoxic anticancer agents
compromise immune responsiveness.
responsiveness
 Cytokines –
peptide regulators of inflam-
matory and immune reactions.
•Interleukins, interferons,
colony-stimulating factors,
tumour necrosis factors.
IL-2 produced
by T-lymphocytes
which activate
cytotoxic killer
cells. It is received
by recombinant
DNA technology. IL-2 has been
given by i.v. infusion in patients with
metastatic renal carcinoma. IL-2 causes
many ADRs.
 Interferons (alpha, beta, gamma)
are glycoproteins produced as part
of the natural host defenses to virus
infections. They have antiviral
activity, immunoregulatory function,
reduce multiplication of cancer cells.
Interferon alfa-2b (Intron® A) – in:
•chronic hepatitis, hairy cell leukemia
• AIDS-related Kaposi’s sarcoma
•renal carcinoma
 Papular cutaneous Kaposi’s sarcoma
Kaposi's sarcoma (KS) is a tumor caused by Human herpesvirus 8.
 Vaccines
•BCG Immunotherapeuticum –
locally in bladder cancer
Cancer

•Silgard® and Cervarix®

are vaccines against
certain types of cancer-
causing human papillomavirus
(HPV – type 6, 11, 16, and 18)
H
P
V

Normal Early Stage Late Stage Stage

IB IB IB

Cancer of the cervix uteri

HPV vaccines:
SILGARD®:
0, 2, and 6 month i.m.
(from 9 to 26 years old)
CERVARIX®
HPV

Cervarix®
VI. Radiotherapy
 Radio-pharmaceuticals (radionuclides)
- Irradiated with beta-rays):
I, P (Sodium phosphate),
131 32

183
Pal - palladium, 145Sm - samarium
89
Sr (strontium)
 Brahiterpiya
(locally in prostate or vaginal cancer)
 Photodynamic cancer therapy
(irradiation with laser light, with consequent
formation of free radicals):
- Porfimer, Temoporfin
VII. CANCER SUPPORTIVE
THERAPIES
 Analgesics in
chronic tumour pain
according to WHO
1st step (weak pain): Paracetamol (Acetaminophen)
or NSAIDs
2nd step (moderate pain): weak opioids (e.g.
Codeine, Dihydrocodeine, Oxycodone,
Propoxiphen, Tramadol) ± Paracetamol or NSAIDs
3th step (sivere pain): strong opioids (e.g. Fentanyl,
Morphine or Pethidine) ± Paracetamol or
NSAIDs
 Emetogenic activity
Cisplatin
Carmustine
Cyclophosphamide
Mitomycin C
L-Asparginase
Fluorouracil Antiemetic activity
Methotrexate
5-HT3-blockers
Etoposide D2-blockers
Vincristine
Glucocorticoids
H1-blockers
 Colony-stimulating
factors (CSFs)
•are used in special cancer
therapy centers to reduce the
severity and duration of
neutropenia induced by cytotoxic
anticancer chemotherapy;
•used in aplastic anaemia;
•used in anaemia in AIDS too.
Filgrastim
(Recombinant Human
Granulocyte Colony-
Stimulating Factor –
rHuG-CSF)
Molgramostim
(Recombinant Human
Granulocyte-Macrophage
Colony-Stimulating Factor – rHuGM-CSF)