Assoc. Prof.
Ivan Lambev
[Link]
ANTICANCER
DRUGS
Possible causes of cancer
Physical agents (radiation,
mobile phones(?), or injury)
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)
Uncontrolled proliferation
Can be invasive
Can metastasize
Lack of function
(lack of differentiation)
Characteristics
of cancer cells
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
sustained therapy
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 Burkitts 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
ot cell bronchogenic carcinoma
sex-related cancers of the breast,
ovary, endometrium, prostate
Solid tumors
surgery or irradiation,
plus CHEMOTHERAPY
Non-solid tumors
CHEMOTHERAPY
Metastases
CHEMOTHERAPY
Myelotoxicity (reduction of leukocytes
increases susceptibility to infections)
Hair loss
Adverse effects
Most of the anticancer agents have
a limited selectivity and damage
all dividing cells. As a result
general adverse effects are:
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
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.
Criteria for selecting combinations
ANTICANCER DRUGS
I. CYTOTOXIC AGENTS
II. IMMUNOMODULATORS
III. ENDOCRINE AGENTS
IV. RADIOPHARMACEUTICS
(
131
I,
32
P,
89
Sr strontium)
I. CYTOTOXIC AGENTS
The majority of cytotoxic
agents inhibit the process
of DNA synthesis within
the cancer cells.
Resting cells (those in the G
o
phase) are resistant to many
anticancer drugs.
Precursors
Precursors
Purine
Pyrimidine
Ribonucleotides
Deoxiribonucleotides
DNA
RNA
Proteins
Methotrexate
Mercaptopurine
Alkylators
Cis-platin
Antibiotics
Nitrosoureas
Mitotic inhibitors
Asparagine
Asparaginase
Action of cytotoxic agents
on the cell cycle
Cycle non-specific
Alkylators
Antibiotics
Phase specific
Antimetabolites
Mitotic inhibitors
Alkylating agents
These drugs were developed from the
sulfur mustard gases used in the 1
st
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 dichlor-ethyl-amine side chain:
RN
CH
2
CH
2
Cl
CH
2
CH
2
Cl
The dichlorethylamine chains are highly
reactive and produce alkylating groups
which bind covalently to sites within the
DNA such as N7 of guanine.
Chlorambucil
Cyclophosphamide
First
alky-
lators
are
Di-(2-chlor
ethyl)-
amines
Cyclophosphamide and Chlorambucil
are commonly used for Hodgkins
and non-Hodgkins lymphoma, chronic
lymphocytic leukemia.
Cyclophosphamide is also used for
immunosuppression in non-malignant
disorders (severe rheumatoid disorders,
myasthenia gravis, multiple sclerosis).
Busulfan (alkyl sulfonate agent with
cancerogenic activity!): used in
chronic myelogenous leukemia.
Cyclophosphamide is a prodrug.
One of its metabolites is acrolein.
Acrolein causes bladder toxicity
with haemorrhagic cystitis which
can be prevented by prior treatment
with Mesna.
Bladder cancer may
develop years after
cyclophosphamide chemotherapy.
Cancer
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
Hodgkins lymphoma.
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 t
1/2
(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.
A number of useful chemothera-
peutic agents have been produced by
simple modifications to the
structures of normal purine and
pyrimidine bases.
Antimetabolites
produce lethal synthesis
5-Fluorouracil (5-FU
: i.v.) used for the treatment of
carcinoma of stomach, colon, rectum, breast, and pancreas.
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)
a) Analogues of pyrimidine
5-FU
5-FU blocks thymidine synthetase
b) Analogues of purine
Mercaptopurine (6-MP) and
Thioguanine (6-TG): used in
childhood acute leukemia; Fludarabine
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.
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.
C N
O H
CH
COOH
CH
2
CH
2
COOH
N C
H
NH
2
H
2
N
N
N
N
OH
Folic acid
Methotrexate
H
2
C N
O H
CH
COOH
CH
2
CH
2
COOH
N C
CH
3
NH
2
N
N
N
N
NH
2
(It has immunosuppressive activity too.)
Methotrexate is given
for the treatment of:
acute lymphoblastic leukemia
non-Hodgkins lymphomas
chorionepithelioma
non-malignant disorders
(such as psoriasis).
Adverse effects of methotrexate
Vasculitis
Arachnoiditis
Pharyngitis, pneumonitis
Cystitis
Vomiting
Hepatotoxicity
Renal dysfunction
PRC: D
Mitotic inhibitors
Vinca alkaloids
Podophyllin derivatives
Taxans (taxoids), 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.
Podophyllin derivatives
May apple (Podophyllum
peltatum India, USA)
Epipodophyllotoxin
Etoposide
Podophyllin
Etoposide
Inhibits mitosis
Acts in late S- or early G
2
-phases
Used in treatment of lymphoma;
lung, testicular,
bladder and
prostate
cancer
Taxans (toxoids)
Docetaxel
in breast cancer
Paclitaxel
Inhibit the
depolymerization
of tubulin and
block mitosis.
(Taxus brevifolia)
a) Anthracyclines
Daunorubicin
in advanced HIV-associated
Kaposis sarcoma
Doxorubicin (Adriamycin
)
possesses myelosuppression and
dose-related irreversible myocardial
damage due to free radical attack
Epirubicin, Idarubicin
Cytotoxic antibiotics
(inhibit DNA replication)
Daunorubicin
Idarubicin
Doxorubicin
Epirubicin
Mitomycin C
in cancer of the
bladder (locally after TUR)
Other antibiotics
Bleomycin in:
testicular cancer
melanomas, sarcomas
squamous cell carcinomas
Enzymes
(Asparaginase and other
inhibitors of protein synthesis)
Asparaginase removes circulating
asparagine which is essential for cancer
cells. It has been given by i.v. infusion
in acute lymphoblastic leukemia.
It causes severe toxicity to the liver and
pancreas as well as anaphylactic reactions.
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.
O 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.
Hydrocortisone, Prednisone
Dexamethasone, Prednisolone
Glucocorticoids
are also helpful in
reducing oedema around a tumor.
They have antiemetic activity too.
O 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
O Androgens
are used rarely
in the treatment
of carcinoma
ovarii and uteri
Testosterone
Side anabolic
effect:
Androgen antagonists
suppress prostate cancer cells.
Unwanted effects include:
gynecomastia, decreased
spermatogenesis, decreased libido.
Bicalutamide, Cyproterone, Flutamide
1 2 3
PSA >> 5
Cyproterone (Androcur
)
p.o.
i.m.
anti-aphrodisiac too.
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
Treatment with the aromatase inhibitor letrozole
reduces the occurrence of distant metastases in Ca mammae
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
The immune system probably
contributes to the final removal
of residual malignant cells, and
most cytotoxic anticancer agents
compromise immune responsiveness.
III. MODIFICATORS
OF BIOLOGICAL RESPONSE
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.
Interferon alfa-2b (Intron
A) in:
chronic hepatitis, hairy cell leukemia
AIDS-related Kaposis sarcoma
renal carcinoma
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.
Papular cutaneous Kaposis sarcoma
Kaposi's sarcoma (KS) is a tumor caused by Human herpesvirus 8.
O Blockers of the
cell transduction signalling
(anti-angiogenic agents)
They block receptors of the growth
and other angiogenic factors:
VEGF vascular endothelial growth factor
EGF epidermal growth factor
PDGF platelet-derived growth factor
TNF tumor-necrosis factor alpha, etc.
PDGF EGFR
TNF-beta
(+) (+)
()
VEGF
TNF-alfa
(+) (+)
T
h
a
l
i
d
o
m
i
d
e
A
c
t
i
m
i
d
e
R
e
v
e
m
i
d
e
()
Bevacizumab
()
Cetuximab
()
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
Colorectal cancer
Prof. Dr. Yaman Tokat
specialist in general surgery
and liver transplantation in Istanbul
Avastin
(Macula)
Macular Degeneration
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.
[Link]/symptoms
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, 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: Thalidomide and analogues
Vaccines
BCG Immunotherapeuticum
locally in bladder cancer
after TUR
Silgard
and Cervarix
are vaccines against
certain types of cancer-
causing human papillomavirus
(HPV type 6, 11, 16, and 18)
Cancer
Cancer of the cervix uteri
H
P
V
Normal Early Stage
IB
Late Stage
IB
Stage
IB
HPV vaccines:
SILGARD
:
0, 2, and 6 month i.m.
(from 9 to 26 years old)
CERVARIX
Cervarix
HPV
Prof. G. Gorchev, MD, DSc
Oncogynecologist, Medical University Pleven
Medical University Pleven
IV. SUSTAINED THERAPY
IN ONCOLOGY
Analgesics
Antiemetics
Bisphosphonates
derivatives
Radioprotectors
Wobe-Mugos E
, etc.
Analgesics in
Analgesics in
chronic
chronic
tumour
tumour
pain
pain
according to WHO
according to WHO
1
1
st st
step (weak pain):
step (weak pain): Paracetamol (Acetaminophen)
or NSAIDs
2
2
nd nd
step (moderate pain):
step (moderate pain): weak opioids (e.g.
Codeine, Dihydrocodeine, Oxycodone,
Propoxiphen, Tramadol) Paracetamol or NSAIDs
3
3
th th
step (
step (
sivere
sivere
pain):
pain): strong opioids (e.g. Fentanyl
Durogesic
TTS, Morphine or Pethidine)
Paracetamol or NSAIDs
Cisplatin
Carmustine
Cyclophosphamide
Mitomycin C
L-Asparginase
Fluorouracil
Methotrexate
Etoposide
Vincristine
Emetogenic activity
5-HT
3
-blockers
D
2
-blockers
Glucocorticoids
H
1
-blockers
Antiemetic activity
Bisphosphonate derivatives
inhibit bone resorption
via action on osteoclasts
Alendronate
Clodronate
Ibandronate
Pamidronate
Hypercalcemia, associated with malignancy
Osteolytic bone lesions in multiple
myeloma or metastatic breast cancer
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.
Molgramostim
(Recombinant Human
Granulocyte-Macrophage
Colony-Stimulating Factor rHuGM-CSF)
Filgrastim
(Recombinant Human
Granulocyte Colony-
Stimulating Factor
rHuG-CSF)
BURNOUT syndrome
