ANTICANCER DRUGS

DR. R. JAMUNA RANI MD,

PROFESSOR & HOD
DEPT. OF PHARMACOLOGY
ANTICANCER DRUGS
 GENERAL PRINCIPLES IN
CHEMOTHERAPY OF CANCER
„ Bacterial metabolism differs markedly
from that of host. While in malignant cells
in fact host cell with minor differences
therefore selectively is limited.
„ Infecting microorganisms are amenable
to immunological and other host defence
mechanisms. This is absent or minimal
with malignant cells.
„ A single colonogenic malignant cell is
capable of producing progeny that can kill
the host therefore ALL MALIGNANT CELLS
MUST BE KILLED OR REMOVED
„ Drugs kill cancer cells by first order
kinetics
 Drug regimens which can effectively
palliative large tumor burdens may be
curative when applied to minute residual
tumor cell population after
surgery/irradiation. This is the basis of the
combined modality approach.
 Complete remission should be the goal of
cancer chemotherapy:
„ Drug are used in maximum tolerated
doses. Combination of 2-6 drugs are given
in intermittent pulses to achieve total cell
kill – giving time in between for normal
cells to recover.
 GENERAL TOXICITY OF
CYTOTOXIC DRUGS
„ Nausea and vomiting
„ Alopecia
„ oligozoospermia
„ Impotence
„ Amenorrhoea
„ Abortion
„ Carcinogenicity
„ Hyperuricemia
„ Opportunistic infections.
„ Cystitis, alopecia – cyclophosphamide
„ Neuropathy - vincristine
„ Cardiac toxicity – doxorubicin
„ Pulmonary fibrosis – bleomycin and
busulfan
„ Cisplatin – Nephrotoxicity
„ Methotrexate – Megaloblastic anemia &
pancytopenia
 TOXICITY AMELIORATION
„ Folinic acid rescue for methotrexate
toxicity
„ Cystitis caused by cyclophosphamide and
ifosphamide can be blocked by mesna and
by irrigating bladder with acetylcysteine.
Both are – SH containing metabolites
compounds that combined with the toxic
metabolite and make them into water
soluble non toxic compounds in the
bladder.
„ Vomiting - ondansetran
„ Hyperuricemia - allopurinol
„ Pulse therapy – MOPP regimen for Hodgkin’s
lymphoma
„ Selective exposure of tumors
„ Bone marrow depression – G-CSF/GM-CSF –
Sargramostim, filgrastim, pegfilgrastim
„ Bleeding – platelet or granulocyte growth factors
– thrombopoietin
„ Bone marrow transplantation
„ Thalidomide – suppress TNFα & modulate IL2
Amifostine – Amifostine (Ethyol, WH-2721) is
an agent designed to produce preferential
cytoprotection of normal tissues from cytotoxic
therapies. The preferential cytoprotection is
due to the metabolism of amifostine to the free
thiol,WR-1065, the active from, by membrane-
bound alkaline phosphate at normal tissue sites
followed by rapid uptake into the normal
tissues by facilitated diffusion. Normal tissues
accumulate the free thiol, whereas uptake into
neoplastic tissue is relatively slow.
The free thiol protects by covalently binding
reactive anticancer drugs, such as
alkylating agents, anthracyclines, and
taxanes, to inactivate these agents in
normal tissues. There is also evidence that
amifostine can stimulate bone marrow
growth in patients with marrow disorders
such as the myelodysplastic syndrome and
cisplatin nephrotoxicity.
NH2-(CH2)3-NH-(CH2)2-S-PO3H2
Amifostine

Alkaline Phosphate
NH2-(CH2)3-NH-(CH2)2-SH
WR-1065
 CANCER AS A DISEASE OF CELLS
ALKYLATING AGENTS

Produce highly reactive carbonium ion

molecules which transfer alkyl groups to
cellular monomolecules by forming covalent
bonds.
„ The position 7 of guanine residue is specially
susceptible.
„ Cross linking/ abnormal pairing/ scission of
DNA strands.
 (Contd…)
„ Cross linking of nucleic acids with protein
can also takes place.
„ Cytotoxic radiomimetic action. they act in
dividing as well as resting cells.
„ CNS stimulants & cholinergic properties.
Metaclopramide – local vesicant only (IV)
Extravasation cause sloughing
 CYCLOPHOSPHAMIDE
„ Most popular anticancer drug less damaging to
platelets.
„ Alopecia & cystitis (ACROLEIN – toxic metabolite) (IV
or IM)
„ Acetylcystine bladder wash (tablets)
„ Ifospamide + mesna ( SH compound that is excreted
in in urine. Binds & inactivates the toxic metabolite of
Ifospamide and Cyclophosphamide
„ Ifospamide - less alopecia & less emetogenic and
cause haemorrhagic cystitis.
Chloramphenicol retards the metabolism of
cyclophosphamide.
 USES
„ Bronchogenic CA
„ Breast CA
„ Testicular CA
„ Bladder CA
„ Head & neck CA
„ Osteogenic sarcoma
„ Lymphoma
„ Ifosfamide inj +mesna
 CHLORAMBUCIL
Action on lymphoid tissue therefore drug of choice
of long term maintenance therapy for chronic
lymphatic leukemia Hodgkin’s disease.
Immuno suppressant property (tablets)
Melphalen: (tab & inj)
Multiple myeloma advanced ovarian cancer bone
marrow depression is most important.
Toxicity
Infection
diarrhoea
pancreatitis
Thiotepa – seldom used highly toxic(bladderCA)
 BUSULFAN
„ Highly specific for granulocytes precursors
which are more sensitive.
Side effects:
Hyperuricemia
Pulmonary fibrosis
Sterility
Chronic myeloid leukemia (tablets)
 NITROSOUREAS
„ Lipid soluble alkylating agent readily crosses
BBB
„ Brain tumor & meningial leukemias renal
damage and visceral fibrosis can occur.
Dacarbazine:
It is different from other alkylating agents
primarily inhibiting action on RNA and it is
inactivated in the liver.
„ Malignant melanoma ,Hodgkin’s disease.
Side effects:
Nausea and vomiting are important side
effects.
 ANTIMETABOLITES
„ Methotrexate
„ Inhibits dihydrofolate reductase (DHFR are)
block the conversion of DHFA Æ THFA
„ DHFA are enzyme is responsible for one carbon
transfer reactions in denova purine synthesis
and amino acid inter conversions.
„ Folic acid is not converted to the active
coenzyme. Therefore folinic acid is used for
methotrexate toxicity, which rapidly reverses
the effects. Thymidine also counteracts
methotrexate toxicity.
 USES
„ Choriocarcinoma
„ To maintain remission in children with acute leukemia
„ Rheumatoid arthritis
„ Psoriasis
„ Immunosuppresive agent
D.IMethotrexate toxicity is enhanced by Salicylate,
sulfonamide and dicumorol displace it from PPB.
Aspirin & sulfonamides decrease renal tubular
secretion of methotrexate
Adverse effects:
„ Megaloblastic anaemia and pancytopenia (tab, inj)
 PURINE ANTAGONISTS
„ Mercaptopurine
„ Thioguanine
„ Azothioprine
They are converted in the body to
corresponding mononucleotides which inhibit
the conversion of inosine monophosphate to
adenine and guanine nucleotides. There is also
feed back inhibition of denova purine synthesis.
Useful in childhood leukemia, choriocarcinoma
and also to remission in lukemia and to
maintain remission 6 mercaptopurine is used.
 AZOTHIOPURINE
„ Marked effect in T lymphocytes.
Suppress CMI primarily used in
„ Organtransplantation
„ Rheumatoid arthritis.
„ Inflammatory bowel disease.
All antipurines are absorbed orally AZP and
6MP are metabolised by XO & their metabolism
inhibited by allopurinol.
Dose of AZP, 6MP is reduce to 1/3 – ¼ if
allopurinol is given together.
 THIOGUANINE

„ Thioguanine is not the substrate for XO

and the dose of TG should not be reduced
if allopurinol is given.
 PYRIMIDINE ANTAGONISTS
Fluorouracil (5 – FU)
It is converted in the body to the
corresponding nucleotide 5 – fluoro – 2 –
deoxyuridine MP which inhibits the
conversion of DEOXYURIDILIC ACID to
DEOXYTHYMIDYLIC ACID
Selective failure of DNA synthesis occur.
Thymidine partially reverse the toxicity.
Resting cells are affected rapidly,
multiplying cells are more susceptible
Solid tumors:
„ Breast
„ Colon
„ Urinary bladder
„ Liver
„ Topical application for cutaneous basal cell CA
„ Cytarabine: It is phosphorylated in the body to
corresponding nucleotide which inhibits the DNA
synthesis.
The triphosphate of cytarabine inhibits DNA
polymerase and blocks the generation of cytidilic acid.
USES: Remission in acute leukemia in children
Hodgkin’s disease and Non Hodgkin lymphoma
 USES
Metastatic:
„ ovarian & breast CA.
„ Advanced head & neck CA
„ Small cell lung CA
„ Oseophageal adeno CA
„ Hormone refractory prostate CA
„ ‘stocking & glove neuropathy’ arthralgia,
myalgia, mucositis and oedema.
TAXANES: Paclitaxel-It is obtained from bark
of western yew tree.It enhances
polymerization of tubulin. The microtubules
are stabilized and depolymerization is
prevented –which affect normal dyanamic
reorganization of microtuble network that is
essential for vital interphase and mitotic
functions.
Uses: Metastatic breast and ovarian
carcinoma,head and neck cancer,small cell
lung cancer,oesophageal adenocarcinoma
and hormone refractory prostate cancer.
Docetaxel: Congener of paclitaxel
Breast & ovarian CA
S.E: Neutropenia, arrhythmias, fall in BP,
heart failure are reported.
EPIPODOPHYLLOTOXINS:
Etoposide: Semisynthetic
Podophyllotoxin
Plant glycoside
MOA: arrest cells in G2 phase and causes
DNA breaks by affecting DNA
topoisomerase II
USE:
„ Testicular tumors
„ Lung CA
„ Hodgkin’s lymphoma
„ CA bladder
ADR:
„ Alopecia, leucopenia and GIT
disturbances.
 VINCA ALKALOIDS
„ These are mitotic inhibitors, bind to
microtubular protein – ‘tubulin’, prevent its
polymerization and assembly of
microtubules, cause disruption of mitotic
spindle ad interfere with cytoskeletal
function. The chromosomes fail to move
apart during mitosis: metaphase arrest
occurs. They are cell cycle specific and act in
the mitotic phase. Vincristine and vinblastine,
though closely related chemically, have
somewhat different spectrum of antitumour
activity and toxicity.
 VINCRISTINE (ONCOVIN)
„ It is a rapidly acting drug, very useful for
inducing remission in childhood acute
leukemia, but is not good for maintenance
therapy. Other indications are
lymphosarcoma, Hodgkin’s disease, Wilm’s
tumour, Ewing’s sarcoma and carcinoma
lung. Prominent adverse effects are
peripheral neuropathy and alopecia. Bone
marrow depression is minimal.
 VINBLASTINE
„ It is primarily employed with other drugs
in Hodgkin’s disease and testicular
carcinoma. Bone marrow depression is
more prominent while neurotoxicity and
alopecia are less marked than with
vincristine
 CAMPTOTHECIN ANALOGUES
Topotecan, Irinotecan is obtained from a Chinese
tree.
MOA:
Interact with DNA topoisomerase I

Damage DNA
Act in S phase and arrest cell cycle at G2 phase.
Topotecan & Irinotecan – injection.
USES: Advanced colorectal carcinoma
Carcinoma of lung, cervix and ovary
ADR:Haemorrhage, thrombocytopenia
 ANTIBIOTICS
MOA:
All antitumor antibiotics have antitumor
activity. They intercalate between DNA
strands and interfere with DNA template
function.
Actinomycin D (Dactinomycin):
Potent antineoplastic drug
Efficacious in Wilm’s tumor,
Rhabdomyosarcoma, Mtx resistant
choriocarcinoma
Daunorubicin (Rubidomycin),Doxorubicin
USE: Solid tumors
MAO: Activate DNA topioisomerase II and
generate quinone type free radical.
They have mutagenic and carcinogenic
potential
ECG changes arrhythmias, hypotension,
CHF, cardiomyopathy.
Mitoxantrone:
Lower cardiac toxicity
Use: In acute nonhaemolytic leukemia
Chronic myelogenous leukemia
Non Hodgkin lymphoma
CA breast
Bleomycin:
„ Glycopeptide antibiotic, chelates copper
and iron.
„ Produce superoxide and intercalate DNA
strands
USES:
testicular tumor, squamous cell carcinoma
of skin, head & neck cancer, CA
oesophagous, CA genito urinary tract
S/E: pulmonary fibrosis
Mitomycin – toxic compound reserved for resistant
cases of stomach, cervix, rectum bladder CA
Mithramycin: (Plicamycin)
Uses:
Embryonal testicular tumor, disseminated cancer,
bonymetastasis & hypercalcemia
Miscellaneous drugs:
Hydroxyurea:
Ribonucleotide
Ribonucleoside
diphosphate
reductase
Deoxyribonucleotide
Interfere with DNA synthesis.
 PROCARBAZINE
It depolymerizes the DNA and cause
chromosomal damage
Inhibit nucleic acid synthesis
Component of mopp regimen
Used in oat cell carcinoma of lung
Weak MAO inhibitor
Alcohol cause disulfuram like reaction
L - asparginase:
Leukemic cells are deficient in L - aspartate
synthetase and depends on L - aspargin.
L - asparginase derived from E.Coli degrades
L - aspargine to L-aspartic acid and cause cancer
cell death. Though remission occurs in acute
leukemia in short lasting. It is used with other
drugs in leukemia.
Typical anticancer symptoms are not seen
S/E: liver damage, pancreatitis, allergy and
anaphylaxis
 CISPLATIN
Platinum co-ordinated complex produce highly
reactive compound cause cross linking of DNA
(N7 guanine residue)
Also react with SH group proteins
Radiomimetic property effective in metastatic
testicular and ovarian carcinoma
S/E: Highly Emetogenic, nephrotoxicity
(to reduce nephrotoxicity amifostine is used)
ototoxicity, pheripheral neuritis and shock like
state on IV infusion.
Good hydration should be maintained.
Carboplatin & oxaliplatin-less toxic.
Glucocorticoids: Reduce the symptoms of
Hyperurecemia, haemolysis, bleeding,
intracranial tension and mediastinal edema.
Has antipyretic and mood elevating action
Potentiate the antiemetic action of ondansetron
and metaclopramide
Prednisolone and dexamethaxone are used.
Hypercorticism is a side Effect
Mitotane-used in adrenal cortex CA
 Estrogens:
„ Carcinoma prostate
„ Androgen dependent tumour
„ Male breast carcinoma
Fosfestrol - Carcinoma of prostate
„ Carcinoma breast more than 5yrs
postmenopausal women who have been
non responsive to tamoxifen, estrogens
are used.

TUMOURS THAT LACK ESTROGEN

RECEPTORS DO NOT RESPOND.
 TAMOXIFEN:
„ Pre and postmenopausal women
„ Estrogen receptor positive and estrogen
receptor negative tumours
„ Carcinoma breast after mastectomy
Antiandrogen:
„ Flutamide + GnRH analogs – used in prostate
carcinoma
Finasteride – 5-Alpha reductase inhibitor
Testosterone is converted to
dihydrotestosterone by 5-Alpha reductase
enzyme. Used in advanced carcinoma
prostate and benign enlargement of prostate.
 GnRH analogs –Leuprolide, Buserelin,
nafarelin used in prostate carcinoma
Progestins:
„ Advanced recurrent and metastatic
endometrial carcinoma and metastatic
carcinoma breast
 DRUG RESISTANCE
„ Increase production of glutathione which
inactivates the alkylating agents
„ P-glycoprotein expel the drug molecule
from the site of action.
 NEW DRUGS
„ Pemetrexed – Antifolate used in
mesothelioma
„ Arsenic trioxide – chronic myeloid leukemia
„ Retinoids –Tretinoin is used in prevention
and treatment of cutaneous malignancy
„ Imatinib – CML
„ Gefitinib – epidermal growth factor inhibitor
used in non small cell lung cancer
„ Estramustine – estradiol + semustine – used
in prostate carcinoma
 (Contd…)
„ Drugs used in breast carcinoma:
„ Selective estrogen receptor modulator –
tamoxifen & toremifene
„ Selective estrogen receptor down
regulator – Fulvestrant used in metastatic
breast carcinoma
„ Aromatase inhibitors – Androstendione is
converted to testosterone by aromatase
enzyme. It is inhibited by
Aminoglutethimide, anastrazole, letrazole,
formestane, exemestane
„ Monoclonal antibodies:
Trastuzumab: Recombinant DNA derived
humanized monoclonal antibodies binds to
HEGF receptor blocks and down regulates
the receptors, antibody dependent
cytotoxicity and apoptosis in malignant
cells. Used in metastatic breast carcinoma.
Rituximab – used in indolent lymphoma
Alemtuzumab – used in T-cell lymphoma
Cituximab – Used in metastatic colorectal
cancer
Bevacizumab – used in metastatic
colorectal cancer
interferons – alpha, inhibit cell proliferation
used in hairy cell leukemia and kaposi’s
sarcoma