Anti-Cancer Drugs

Dr. Muhammad Sarfraz

College of Pharmacy Al-Ain University
Al Ain, UAE.
 The Biology of Cancer

Special characteristics of cancer cells.

1. Uncontrolled proliferation
2. Dedifferentiation and loss of function.
3. Invasiveness
4. Metastasis
The cell cycle  2 key events :
I. S phase : Synthesis of DNA
II. M phase : Division of parent cell into two
daughter cells during mitosis.
G1 (gap) : Synthesis of cellular
components needed for DNA
synthesis.
G2 : Synthesis of cellular components
for mitosis
 CLASSIFICATION OF ANTICANCER DRUGS
1. CYTOTOXIC DRUGS : acts directly on neoplastic / cancer cells.
1 . 1 A L K Y L AT I N G A G E N T S
1.1.1 NITROGEN MUSTARDS : Mechlorethamine / Mustine
Hydrochloride, Cyclophosphamide, Chlorambucil and
Melphalan
1.1.2 ALKYL SULPHONATE : Busulphan
1.1.3 NITROSUREAS : Carmustine , Lomustine
2. ANTIMETABOLITES : affects normal metabolism of neoplastic cells –
structurally similar to important intermediates/ enzymes .
2.1 Folate antagonists : Methotrexate
2.2 Purine antagonists : 6- Mercaptopurine, 6- Thioguanine,
Azathioprine , Fludarabine, Cladirabine
2.3 Pyrimidine antagonists : 5- Flurouracil, Cytarabine
CLASSIFICATION OF ANTICANCER DRUGS
3 . A N T I B I O T I C S : p r o d u c e a n t i b i o s i s : E x a m p l e Bleomycin,
Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idrabucin
4. MICROTUBULE INHIBITORS : A f f e c t c e l l d i v i s i o n o f
neoplastic cells – separation into daughter cells
4.1 Vinca alkaloids : Vincristin, Vinblastine ,Vinrelabine
4.2 Taxol derived : Docetaxol , Pacitaxel
5. STEROIDAL HORMONES & IT’S ANTAGONISTS: Since some tumours
are dependent on availability of hormones for it’s sustenance and
excess / antagonists disrupt the growth and development.
5.1 Synthetic Estrogens : Fosfestrol and Anti estrogens : Tamoxifen,
5.2 Antiandrogens : Flutamide
5.3 Glucocorticoids : Prednisolone
5.4 Gn RH – Naferelin , Gosrelin
5.5 Progestin : Hydroxy progesterone.
CLASSIFICATION OF ANTICANCER DRUGS
6 . MONOCLONAL ANTIBODIES : Cell cancer exterior – unique
antigenic feature >>> antibodies combine and neutralizes and in the
process neoplastic cells destroyed in the process.
Bevacizumab , Cetuxizumab, Rituximab , Trastuzumab.
7. Others
Asparginase ( Enzymatic ),
Cisplatin , Carboplatin, (Platinum compound )
Etoposide ( Resin from Podophyllum)
Interferons.
MECHANISM OF ACTION
1-Alkylating agents
Formation of Carbonium ion is main step.
↓
Attacks lone pair of electron in DNA.
↓
Cross linked with DNA.
Most of cytotoxic anticancer alkylating agents are
bifunctional i.e., they have two alkylating groups.
Alkylating agents
Nitrogen mustards :
Cyclophosphamide is most commonly used alkylating agent.
Its is given orally or I.V. and also given through I.M.
Toxic effects: Nausea.
Vomiting.
Bone marrow depression and
Haemorrhagic cystitis.
Estramustine is a combination of mustine with an estrogen.
It has both cytotoxic and hormonal action .
Alkylating agents
Nitrosoureas:
They are lipid soluble and cross BBB.
Most of nitrosoureas have a severe cummulative depressive effect on
bone marrow that starts 3-6 weeks after initiation of treatment.
Alkyl sulfonates :
Busulphan has a selective effect on bone marrow depressing the
formation of granulocytes and platelets in lower dose and RBC in
higher dose.
It is used in chronic granulocytic leukaemia.
2-Antimetabolite
 Are structural analogues to natural chemicals within the cell… Utilized for normal
metabolism.
 Generally interferes with the availability of normal purine / pyrimidine nucleotide
precursors.
 Inhibiting their synthesis and or competing with them in DNA/ RNA synthesis.
 M o s t e f f e c t i ve a t S - P h a s e o f t u m o r c e l l c y c l e
 Commonly refereed to as cell- cycle specific
 Methotrexate – a folate antagonist… related to Folic acid – important for DNA
synthesis ( in tumor and normal cell)
 Purine and pyrimidine antagonists – purine and pyrimidine >… DNA ….
Methotrexate
 METHOTREXATE … earliest and still useful folate antagonists.
 Folic acid >>> central role in variety of metabolic reactions + essential for cell
replication.
 Enters the target cell by active transport / diffuses at higher concentration of drug>>>
following the same pathway that tetrahydrofolate enters.
 Inhibits DHFR ase >>> thus blocking the conversion of DHFA-----THFA.
 THFA >>> an essential co-enzyme required for one- carbon transfer reactions in the
de novo synthesis of purine
 Almost irreversible – as the drug has greater affinity for the than the natural enzyme
 Cell cycle specific >>> kill cells in S-phase and kills only rapidly proliferating cells.
 Results primarily in inhibition of DNA synthesis >> But also RNA and protein ( synthesis
depressed) >>> cell death.
 Non-proliferating cells are resistant to the effect
 Resistance ? – Disadvantage.
 METHOTREXATE
DHFR ase Enters tumor cell by
Active transport /
Diffusion

FH2/ DHFA / Di hydrofolic acid

TUMOUR CELL
FH4 / THFA / Tetrahydrofolic acid

N 5-N10 –Methylene FH4

DENOVO SYNTHESIS OF ADENOSINE ,

GUANINE, THYMIDINE .
METHIONINE AND SERINE
 Methotrexate
 ADME >>> Variable oral absorption >>> parenteral better>> little metabolism
>>. Largely excreted unchanged in urine.
 Adverse effects : Renal damage- in higher doses – due to renal accumulation -
long term use >>> Hepatotoxicity >>> rarely pulmonary toxicity >>
neurological toxicity due to intrathecal inj. >>> TERATOGENICITY.
THERAPEUTIC USES
 Effective against A c u t e l y m p h o c y t i c l e u k e m i a ( Highly effective in
maintaining remission in children ),Choriocarcinoma ( curative) , Burkitt’s lymphoma
in children , Neck and head cancer, Breast cancer etc.
 PHARMACOLOGY OF PURINE ANTAGONIST 17

[Mercaptopurine , Thioguanine]
 a r e P R O D R U G S > > > P h o s p h a t e g r o u p s a r e r e m o ve d i n t h e
plasma >>>> whic h is taken up the tumor cells >>>
a g a i n p h o s p h o r y l a t e d ( Triphosphates) > > > i n c o r p o r a t e s i n t o
b o t h R N A a n d D N A – Specifically at synthetic phase and affects it’s
function.
THERAPEUTIC USES OF MERCAPTOPURINE
1. Useful in Childhood leukemia.
2. Choriocarcinoma and several solid tumours.
3. Likely to produce remission, when used along with other drugs.
THERAPEUTIC USES OF THIOGUANINE
1. Primarily used in the treatment of acute non- lymphocytic leukemia
along with Cytarabine and an antibiotic.
THERAPEUTIC USES OF FLUDARABINE
1. In Chronic lymphocytic Leukemia
2. as an alternative to Chlorambucil
3. Effective in hairy cell leukemia and Non- Hodgkin’s Lymphoma
PHARMACOLOGY OF PYRIMIDINE 18

A N T A G O N I S T 5 - F L U RO U R AC I L
 Prodrug … enters into the tumor cell via Carrier mediated transport system >>>
converted into Deoxynucleotide.
 Fluorine part interferes with conversion of deoxyuridilic acid into Thymidylic acid – an
essential precursor for DNA synthesis.
 i.e., When 5-flurouracil is administered – it deprives the tumor cells of an
important precursor for DNA synthesis. >>> as a result reduction in number of
cancer cells.
 Employed for cancers of slowly growing solid tumours - like Colorectal, ovarian, breast,
pancreatic and gastric carcinoma.
 Possible development of resistance
 Faster metabolism and elimination.
 GIT toxicity on oral administration >>> IV route >>> skin cancer >>> locally applied.
3-Antibiotics
1- Bleomycin is a glycopeptide mixture (CCS) that alters nucleic acid
functions via free radical formation.
a. It is used in regimens for Hodgkin’s and other lymphomas and
squamous cell and testicular cancers.
b. Pulmonary toxicity, skin thickening, and by hypersensitivity reactions
are distinctive.
c. It is used in regimens for Hodgkin’s and other lymphomas and squamous cell alar
2- cancers.
Doxorubicin and daunorubicin are anthracyclines (CCNS) that
intercalate
d. Pulmonarywith DNA,
toxicity, skininhibit topisomerases,
thickening, and form
and by hypersensitivity free radicals
reactions are
a. distinctive.
Doxorubicin is widely used in breast, endometrial, lung, and ovarian
cancers and in Hodgkin’s lymphoma.
b. Daunorubicin is used in leukemias.
c. Myelosuppression is marked, but cardiotoxicity is dose limiting.
3-Antibiotics
3- Other antibiotics include dactinomycin and mitomycin.
a. Dactinomycin (CCNS) inhibits DNA-dependent RNA
synthesis and is used in melanoma and Wilms’tumors.
b. Mitomycin (CCNS) is biotransformed to an alkylating agent
and is used for hypoxic tumors.
c. Both of these agents cause bone marrow suppression.`
4. MICROTUBULE INHIBITORS

M.O.A – Vinblastine and Vincristine

Bind to β-tubulin (drug tubulin complex)

inhibits its polymerization into microtubules

No intact mitotic spindle

cell division arrested in metaphase

• PK- given parenterally, penetrate most tissues except CSF
cleared mainly via biliary secretions
• Clinical use –
Vincristine - Acute leukemias, lymphomas, Wilm’s Tumor and
Neuroblastoma
Vinblastine – Lymphomas,Neuroblastomas,Testicular ca.and
Kaposi’s sarcoma
Vinorelbine – non-small cell lung carcinoma and breast Ca
.
• Toxicity – Vinblastine and Vinorelbine cause GI distress,
Alopecia and bone marrow suppression
Vincristine is ‘marrow sparing’ but neurotoxic
4- Microtubule inhibitors
• TAXANES – Paclitaxel , docetaxel
Derived from the bark of the western yew tree
Paclitaxel binds to β-tubulin stabilizes
microtubules formation of abnormal microtubules
inhibits mitosis
Prevent microtubule disassembly into tubulin monomers
- Given I.V
- Advanced breast, ovarian, lung, oesophageal and bladder
ca.
- Paclitaxel-neutropenia,thrombocytopenia,high incidence of
peripheral neuropathy and possible hypersensitvity
reaction
- Docetaxel cause neurotoxicity
5-Steoridal hormone and its antagonist
• GLUCORTICOIDS –
Prednisolone - most commonly used glucorticoid in
Ca.chemo. Used for combination chemotherapy in
leukemia and lymphomas
• ESTROGEN –
Physiological antagonists of androgens
Antagonizes the effects of androgens in androgen
dependent prostatic tumors- fosfestrol ( prodrug) –
stilboestrol (prostatic tissue)
• TAMOXIFEN-
Anti-oestrogen mainly used in the palliative treatment in
hormone dependent breast ca
• PROGESTINS –
2nd line hormonal therapy for metastatic hormone dependent
breast ca and endometrial ca
• ANTI-ANDROGENS –
Flutamide and bicalutamide – bind to androgen receptor – inhibit
androgen actions
Prostatic ca, used along with GNRH agonist – strategy known as
‘complete androgen blockade’
Flutamide can cause – hot flushes, hepatic dysfunction and gynaecomastia
• GnRH agonists -
Goserelin, Nafarelin and leuprolide act as agonist of GnRH
used in advanced prostatic ca
• GnRH antagonist –
Cetrorelix, ganirelix and abarelix are antagonist of GnRH
Decrease the release of gonadotropins without causing initial stimulation
Can be used in prostatic ca without the risk of flare up reaction
6- Monoclonal antibodies

These are immunoglobulins produced by cell culture to react

with antigen expressed on cancer cells.
Rituximab is a monoclonal antibody that attaches to CD20
protein on B cells and kills complement mediated lysis.
Unwanted effects hypertension, chills, and fever during initial
infusion.
Trantuzumab is a humanised monoclonal antibody.
Unwanted effects similar to Rituximab.
7-Others
• ETOPOSIDE and TENIPOSIDE –
Etoposide , a semisynthetic derivative of
podophyllotoxin,induces DNA breakage through its inhibiton
of topoisomerase ІІ
Most active in late S and early G2 phase of the cell cycle
Teniposide is an analogue with similar properties
PK- orally well absorbed and distributes to most body tissues
Elimination is mainly via kidneys
Clinical use – Testicular and lung ca. in combination with
cytotoxic agents. Non-hodgkin’s lymphoma and AIDS
related Kaposi’s Sarcoma
Others
Etoposide and Teniposide

forms complex with DNA and topoisomerase ІІ

prevent resealing of broken DNA strand

Cell death
Toxicity – Etoposide and Teniposide are GI irritants and cause
alopecia and bone marrow suppression
AntiCancer drugs