Download in cancer of

Medical University of Sofia, Faculty of Medicine
Department of Pharmacology and Toxicology
ANTICANCER
DRUGS
© Assoc. Prof. Ivan Lambev
E-mail: [email protected]
Possible causes of cancer
Physical agents
(radiation, GSM or injury)
Chemicals
(carcinogens,
including smoking)
Hereditary factors
Effectiveness of immune system
(virus infections: Ca collum uteri)
Stress, > BMI, some drugs
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
 modificators of biological response
 sustain
therapy
I. CLASSICAL
ANTICANCER DRUGS
 Alkylating agents (alkylators)
 Antimetabolites
 Mitotic inhibitors
 Cytotoxic antibiotics
 Hormones and hormone antagonists
 Enzymes etc.
Mechanism of action
and clinical use
The majority of antineoplastic
agents inhibit process of DNA
synthesis within the cancer cells.
Resting cells (those in the Go
phase) are resistant to many
anticancer drugs.
Action of cytotoxic agents
on the cell cycle
Cycle non-specific Phase specific
Alkylators
Antibiotics
Antimetabolites
Mitotic inhibitors
Precursors
Precursors
Methotrexate
Pyrimidine
Purine
Ribonucleotides
Mercaptopurine
Hydroxyurea
Deoxiribonucleotides
Alkylators
Cis-platin
Antibiotics
Sex sterioids
Nitrosureas
Mitotic inhibitors
DNA
Asparaginase
RNA
Asparagine
Proteins
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 chemotherapy. The most responsive are
rapidly proliferating tumors:
 lymphomas
 leukemias
 chorioncarcinoma
 testicular carcinoma
Solid tumors show
a poor response:
colorectal carcinomas
 adrenocortical carcinomas
 squamous cell
bronchial carcinomas

An intermediate response
is shown by other cancers,
for example:
bladder
 head and neck
 oаt cell bronchogenic carcinoma
 sex-related cancers of breast,
ovary, endometrium, prostate

Treatment of cancer
Solid tumors –
surgery or irradiation,
plus CHEMOTHERAPY
“Non-solid tumors” –
CHEMOTHERAPY
Metastases –
CHEMOTHERAPY
Adverse effects
of anticancer agents
Limited selectivity (selectivity resides
in damage to dividing cells). As a
result general adverse effects are:
•Myelotoxicity (decreased of leucocytes produce resistance to infection)
•Hair loss
•Damage to GI tract
(impaired wound healing)
•Depression of growth
•Nausea and vomiting
(controlled with the antiemetics)
•Carcinogenicity (in rare cases)
•Reproductive toxicity (PRC: D/X)
•Kidney damage
•Hepatotoxicity
Resistance to cytotoxic drugs
(primary or acquired)
•Increased rate of synthesis of target enzyme
(dihydrofolate reductase and methotrexate)
•Increased repair of DNA (alkyllating agents)
•Insufficient activation of prodrug
– cytarabine (does not undergo phosphorylation
•Multi Drug Resistans – increasing action of
membrane efflux system (P170, P190) etc.
Strategy to avoid resistance
Use 3 or 4 anticancer drugs
together or in sequence,
e.g. treatment of lymphomas:
•COP treatment (COP – acronym)
– Cyclosphosphamide
– Oncovin® (vincristine)
– Prednisolone
Criteria for selecting of combinations
•Each drug should be an active anticancer
drug its own right.
•Each drug should be have a different
mechanism of action and target site within
the cancer cell (this will increase efficacy
and reducing the resistance).
•Each drug should be have a different site
for any organ-specific toxicity.
 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 the
respiratory toxicity.
Replacement of the sulfur atom by
nitrogen allowed to receive the first
alkylating agents.
The important functional groups is
the dichlor-ethyl-amine side-chain:
CH2CH2Cl
R-N
CH2CH2Cl
The dichlorethylamine chains are highly
reactive and produce alkylating groups
which bind covalently to sites within
DNA such as N7 of guanine.
First
alkyllators
are:
Cyclophosphamide
Chlorambucil
Cyclophosphamide and Chlorambucil
are commonly used for Hodgkin’s
and non-Hodgkin’s lymphoma, chronic
lymphocytic leukemia.
Cyclophosphamide is also used for
immunosupression in non-malignant
disorders (severe rheumatoid disorders,
myasthenia gravis, multiple sclerosis).
Busulfan: in chronic myeloid leukemia.
Cyclophosphamide is a prodrug.
One of its metabolites is acrolein.
Acrolein causes bladder toxicity
with haemorrhagic cystitis which
can be prevent by prior treatment
with Mesna.
Bladder cancer may
develop years after
cyclophosphamide chemotherapy.
Nitrosureas (the other alkyllators) inhibit the synthesis of
DNA, RNA and proteins.
Carmustine crosses BBB.
It is used for brain tumors.
Carmustine and
Lomustine are
used for treatment of
Hodgkin’s lymphoma.
Cis-platin binds to DNA and proteins.
It has made a significant impact on
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.
 Antimetabolites –
produce lethal synthesis
A number of useful chemotherapeutic agents have produced by
simple modifications to the
structures of normal purine and
pyrimidine bases.
a) Analogue of pyrimidine
• 5-Fluorouracil (5-FU®: i.v.) – used for 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
• Gemcitabine inhibits
DNA polymerase and impairs DNA
synthesis. Its is suitable for
treatment of chronic lymphocytic
leukemia in patients who have not
responded to alkylating agent regimen.
b) Analogues of purine
• Mercaptopurine (6-MP): in childhood acute leukemia.
• Thioguanine (6-TG): in childhood acute leukemia.
• Azathioprine suppresses T-lymphocytes:
used in organ transplantation and rheumatoid arthritis
c) Folic acid antagonists
Folic acid in its reduced form (THF tetrahydrofolic acid) is essential for synthesis of the purine ring system. During
these reactions THF is oxidized to dihydrofolic acid which has to be reduced by
dihydrifolate reductase back. Methotrexate
inhibits dihydrofolate reductase and
blocks purine and thymidylate synthesis.
COOH
CH
N
H
N
C
CH2 H
O
CH2
N
C
H2
NH2
N
N
N
OH
Folic acid
COOH
COOH
CH
N
C
CH2 H
O
CH2
COOH
N
CH3
N
C
H2
N
NH2
N
N
NH2
Methotrexate
Methotrexate is given
for treatment of:
•acute lymphoblastic leukemia
•non-Hodgkin’s lymphomas
•chorionepithelioma
•non-malignant disorders (such
as psoriasis).
Adverse effects of methotrexate
•Vasculitis
•Arachnoiditis
•Pharyngitis, pneumonitis
•Cystitis
PRC:
D
•Vomiting
•Hepatotoxicity
•Renal dysfunction
 Mitotic inhibitors
 Vinca alkaloids
 Podophyllin derivatives
 Taxans (taxoids)
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
They bind to tubulin and produce
metaphase arrest.
They use for acute leukemia.
Vinblastine
Vincristine
Podophyllin derivatives
May apple (Podophyllum
peltatum - India, USA)
Podophyllin
Epipodophyllotoxin
Etoposide
Etoposide
•Inhibits mitosis
•Acts in late S- or early G2-phases
•Treatment of lymphoma;
lung, testicular,
bladder and
prostate
carcinoma
Taxans (toxoids)
Inhibit the
depolymerization
of tubulin and
block mitosis.
•Docetaxel
in breast cancer
•Paclitaxel
 Cytotoxic antibiotics
•Inhibit DNA replication.
a) Anthracyclines
•Daunorubicin
– in advanced HIV-associated
Kaposi’s sarcoma
•Doxorubicin (Adriamycin®)
– possesses myelosupression and
dose-related irreversible myocardial
damage due to free radical attack
•Epirubicin, Idarubicin
Daunorubicin
Epirubicin
Doxorubicin
Idarubicin
•Other antibiotics
Mitomycin
– in cancer of
bladder (locally)
Bleomycin in:
– tetsicular carcinoma
– melanomas, sarcomas
– squamous cell carcinomas
 Hormones and
hormone antagonists
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.
Glucocorticoids
are also helpful in reducing
oedema around a tumor.
They have antiemetic activity too.
•Hydrocortisone, Prednisone
•Dexamethasone, Prednisolone
Estrogens suppress prostate cancer
cells both locally and metastases,
and provide symptomatic improvment. Gynecomastia is a common
side-effect.
• Fosfestrol
• Polyestradiol phosphate
®
(Honvan )
Progestins suppress
endometrial cancer
cells and lung secondaris:
•Gestonorone
•Medroxyprogesterone
Androgens are used
in treating of carcinoma
ovarii and uteri
• Drostanolon
• Testosterone
Androgen antagonists
suppress prostate cancer cells.
Unwanted effects include:
gynecomastia,
decreased spermatogenesis,
decreased libido.
• Cyproterone
• Flutamide
p.o.
i.m.
Cyproterone (Androcur®)
- antiaphrodisiacum too -
Inhibitors of alpha-reductase
(e.g. Finasteride)
• Alfa-reductase converts testosterone in
more active dihydrotestosterone.
• Finasteride is useful orally in the treatment
of benign prostatatic hyperplasia.
Unlabeled use: Adjuvant monotherapy
after radical prostatectomy in the
treatment of prostatic cancer.
Estrogen antagonists
(e.g. Tamoxifen - p.o.) suppress breast
cancer cells. Transisomer of Tamoxifen
binds competitively to estrogen receptors.
Adverse effects include
hot flushes and amenorrhoea
in premenopausal women
and vaginal bleeding in
postmenopausal women.
Aromatase inhibitors
• Aminoglutethimide (p.o.)
• Formestane (i.m.)
- 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 present in the cells of
two-thirds of breast carcinomas and about
80% of these tumors are estrogendependent. 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.
Gonadotropin releasing
hormone agonists (GnRHAs)
Continuous daily administration
of GnRHAs results in suppression
of testicular and ovarian steroidogenesis due to decreased levels of
LH and FSH with subsequent decrease in testosterone (in man) or
estrogens (in women).
Gonadotropin releasing
hormone agonists:
• Goserelin - 3.6 mg/30 days s.c.
• Leuprolide
Indications:
- palliative treatment of advanced
prostatic carcinoma
- endometriosis
 Enzymes
(Asparaginase and other
inhibitors of protein synthesis)
Asparaginase removes circulating
asparagine which essential for cancer
cells. It has been given by i.v. infusion
in acute lymphoblastic leukemia.
It causes sever toxicity to liver and
pancreas, anaphylactic reactions too.
II. MODIFICATORS
OF BIOLOGICAL RESPONSE
The immune system probably
contributes to the final removal
of residual malignant cells, and
most cytotoxic anticancer agents
compromise immunoresponsiveness.
Many modificators of biological
response act really as
immunostimulants.
 Cytokines –
peptide regulators of inflammatory and immune reactions.
•Interleukins, interferons,
colony-stimulating factors,
tumour necrosis factors ...
Aldesleukin (IL-2)
Produced by T-lymphocytes
which activate cytotoxic killer
cells. Received by recombinant
DNA technology. IL-2 has been
given by i.v. infusion in patients with
metastatic renal carcinoma. It can
produce hypotension, edema, fluelike symptoms, vomiting, anaemia.
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
Colony-stimulating
factors (CSFs)
•are used in special cancer
therapy centers to reduce the
severity and duration of the
neutropenia induced by cytotoxic
anticancer chemotherapy;
•used in aplastic anaemia;
•used in anaemia in AIDS.
Filgrastim
(Recombinant Human Granulocyte
Colony-Stimulating Factor rHuG-CSF)
Molgramostim
(Recombinant Human GranulocyteMacrophage Colony-Stimulating
Factor - rHuGM-CSF)
 Blockers of cell transduction signalling
Thalidomide
Actimide
Revemide
a) Antiangiogenic drugs (used in colorectal cancer)
PDGF
(–)
VEGF
TNF-alfa
(+)
(–)
Bevacizumab
(+)
(+)
(+)
EGFR
(–)
(–)
TNF-beta
Cetuximab
b) Monoclonal antibodies –
blockers of receptors for growth factors
TRASTUZUMAB
(Herceptin®): i.v. inf.
RITUXIMAB
(MabThera®) – NHL
c) Inhibitors of tyrosinekinase
Imatinib
®
(Glivec )
–
– for oral treatment
of chronic myeloid leukemias
 Vaccines
®
Immunotherapeuticum
•BCG
– locally in bladder cancer
®
•Silgard : Ca colli utrei (HPV – type 16 и 18)
 Immune stimulation
•Levamisole (out of date)
®
•Polyerga (improves quality of life)
III. SUSTAIN THERAPY
IN ONCOLOGY
•Analgesics
•Antiemetics
•Bisphosphonate
derivatives
•Etc.
Analgesics in chronic
tumour pain
according to WHO
1st step: weak pain – Paracetamol
2nd step: mild pain – Paracetamol + NSAIDs
3rd step: moderate pain – Paracetamol or NSAIDs
+ weak opioid (e.g. Codeine or Dihydrocodeine)
4th step: strong pain – Paracetamol or NSAIDs
+ strong opioid (e.g. Fentanyl – Durogesic TTS,
Morphine or Pethidine)
Emetogenic activity
Cisplatin
Carmustine
Cyclophosphamide
Mitomycin C
L-Asparginase
Fluorouracil
Methotrexate
Etoposide
Vincristine
Ondansetron (Zofran®)
Antiemetic activity
5-HT3-blockers
D2-blockers
Glucocorticoids
H1-blockers
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