1. ANTICANCER AGENTS BY
DR. GHULAM ABBAS

2. General Introduction
General Introduction
Cancers account for 20-25% of deaths in clinical practices.
Attempts to cure or palliate (less severe) cancer employ 3 principal methods: operation, radiotherapy, and
chemotherapy.
Differing from the operation and radiotherapy
that emphasize on the treatment of local tissues, the chemotherapy is concerned with that of the whole body.

3. Chemotherapy is the use of drugs to inhibit or kill proliferating cancer cells, while leaving host cells unharmed, or at least recoverable.
Growth fraction
Tumor cells can be classified as proliferating cells and non-proliferating cells.
The ratio of proliferating cells in the whole tumor tissue is called growth fraction (GF).
The faster the tumor cells proliferate, the bigger the GF is and the higher the sensitivity of tumor to a drug is.
Generally, in the early stage, the GF of atumor is bigger and the effect of a drug on the tumor is better.

4. Mechanisms of Antineoplastic Drugs
Most antineoplastic drugs act on the proliferating cycle of cell
(1) Destruction of DNA or inhibition of DNA
Duplication e.g. alkylating agents, mitomycin C
(2) Inhibition of nucleic acid (DNA and RNA)
Synthesis – e.g. 5-fluorouracil, 6-mercaptopurine, methotrexate, cytarabine, etc.

5. Mechanisms of Antineoplastic Drugs
(3) Interfering with the transcription to inhibit RNA Synthesis e.g. dactinomycin, dauoruicin, and doxorubicin
(4) Inhibition of protein synthesis
– e.g. vinca alkaloids, epipodophylotoxins, and
paclitaxel
(5) Interfering with hormone balance
– e.g. adrenal corticosteroids, estrogens,
tamoxifen etc.

6. Toxicity of Antineoplastic Drugs
Short-term toxicity
Common side reactions usually appear earlier and many of them occur in rapid proliferating tissues such as marrow, gastrointestinal tract, and hair follicle.
myelosuppression
gastrointestinal tract symptom
Alopecia
Long-term toxicity
The long-term toxicity mainly occurs in
the patients who received chemotherapy many years ago.
Examples: carcinogenesis, teratogenesis and sterility.

7. Classification of Antineoplastic Drugs
On the basis of source and action mechanisms, the drugs are also classified as:
Alkylating agents
Antimetabolites
Natural products
Hormones and antagonists
Miscellaneous agents

8. Alkylating agents
Alkylating agents act via a reactive alkyl (RCH2-CH2+ -) group that reacts to form covalent bonds with nucleic acids.
There follows either cross-linking of the two
strands of DNA, preventing replication, or
DNA breakage.
All alkylating agents are phase-nonspecific.
kill rapidly proliferating cells, also kill
non-proliferating cells.

9. Alkylating agents Examples: Mechlorethamine
The first drug used in the treatment of cancer
At present, it is mainly used for Hodgkin's disease and non-Hodgkin's lymphomas.
Examples: Cyclophosphamide
Most widely used in clinical therapy for treatment of cancer at present.
It has no antineoplastic action outside the body and must be activated in the liver.

10. Antimetabolites Antimetabolites are analogues of normal
metabolites and act by competition, replacing
the natural metabolite and then subverting
cellular processes.
Examples of antimetabolites include:
Folic acid antagonists (e.g. Methotrexate ).
Antipyrimidines (e.g. 5-Fluorouracil, Cytarabine).
Antipurines ( e.g. 6-Mercaptopurine )
Methotrexate
5-Fluorouracil

11. Natural Products This group is determined by the source of the drug
The major classes of natural products include;
Antibiotics
Vinca alkaloids
Biologic response modifiers
Enzymes
Epipodophyllotoxins
Taxanes

12. Natural Products Natural Products Vinca (plant) alkaloids
Antibiotic antineoplastic agents
Damage DNA in cycling and noncycling cells
Example: Dactinomycin (actinomycin D): This drug binds non-covalently to double-stranded DNA and inhibits DNA-directed RNA syntheisis.
Natural Products
Vinca (plant) alkaloids
Vincristine and vinblastine are alkaloids derived from the periwinkle plant, binding to tubulin, interfere with the assembly of spindle proteins during mitosis.
Act to inhibit mitosis, blocking proliferating cells as they enter metaphase.
Both can cause bone marrow suppression
and neurotoxicity.

13. Hormones and antagonists
The growth of some cancers is hormone dependent. Growth of such cancers can be inhibited by surgical removal of hormone glands, increasingly, however, administration of hormones or antihormones is preferred.
Examples:
Adrenocortical steroids to inhibit the growth of cancers of lymphoid tissue and blood.
Oestrogen antagonists ( tamoxifen ) is indicated for breast cancer.
Oestrogen is used for prostatic cancers.

14. Miscellaneous agents Examples: Hydroxyurea
Hydroxyurea inhibits ribonucleotide
reductase. inhibition of DNA synthesis.
It is specific for the cells of S phase
The major adverse effect of this drug is
bone marrow depression.

15. Antioxidants – an overview
Antioxidants are molecules capable of reducing the causes or effects of oxidative stress
Oxidative stress can be caused by environmental factors, disease, infection, inflammation, aging (ROS production)
ROS or “reactive oxygen species” include free radicals and other oxygenated molecules resulting from these factors
The body produces some endogenous antioxidants, but dietary antioxidants may provide additional line of defense
Flavonoids & other polyphenolics, Vitamins C & E, and
carotenoids are the most common dietary antioxidants
Many herbs and botanicals also contain antioxidants.

16. Sources of antioxidants in the diet

17. Radicals and ROS
The enemy: “Reactive Oxygen Species” (ROS) are highly reactive free radicals
Superoxide (O2-.) – protonation forms .OOH
Hydroxyl radical (.OH) most reactive
Peroxyl radicals (.OOH,.OOR) more selective
Alkoxy radicals (.OR)
Peroxynitrite (ONOO-)
They form as the result of stress, inflammation, and the human body’s natural defenses
in vivo, many are formed in the mitochondria, by various activities.
They target tissue, proteins, lipids and DNA
Aging = cumulative damage over the years
Hydroxyl radical is the most reactive and may act as initiator for lipid peroxidation. Peroxyl radicals act more slower, more selectively over a longer distance. Superoxide is less likely to target lipids, but if protonated it forms OOH, which does target lipids. Alkoxy and peroxy radicals can form from iron-catalyzed decomposition of hydroperoxides (ROOH) 17

18. Reactive Oxygen Species (ROS) Reactive Nitrogen Species (RNS)
Radicals:
O2.- Superoxide
OH. Hydroxyl
RO2. Peroxyl
RO. Alkoxyl
HO2. Hydroperoxyl
Non-Radicals:
H2O2 Hydrogen peroxide
HOCl- Hypochlorous acid
O3 Ozone
1O2 Singlet oxygen
ONOO- Peroxynitrite
Reactive Nitrogen Species (RNS)
Non-Radicals:
ONOO- Peroxynitrite
ROONO Alkyl peroxynitrites
N2O3 Dinitrogen trioxide
N2O4 Dinitrogen tetroxide
HNO2 Nitrous acid
NO2+ Nitronium anion
NO- Nitroxyl anion
NO+ Nitrosyl cation
NO2Cl Nitryl chloride
Radicals:
NO. Nitric Oxide
NO2. Nitrogen dioxide

19. Defining “antioxidant”
The term “antioxidant” has many definitions
Chemical definition: “a substance that opposes oxidation or inhibits reactions promoted by oxygen or peroxides”
Biological definition: “synthetic or natural substances that prevent or delay deterioration of a product, or are capable of counteracting the damaging effects of oxidation in animal tissues”
Institute of Medicine definition: “a substance that significantly decreases the adverse effects of reactive species such as ROS or RNS on normal physiological function in humans

20. Introduction
An imbalance between formation of reactive oxygen species and antioxidants in vivo plays a major role in multiple diseases.
The excessive production of free radicals in the biological system leads to multiple diseases including atherosclerosis, renal failure, diabetes mellitus and diabetic complications.

21. Antioxidants
Antioxidants prevent free radical induced damage by several ways such as by scavenging, preventing radicals formation, or by promoting their decomposition process 21

22. Are you ready to fight the attack of prooxidants?
Antioxidant
O-2, 1O2, .OH, H2O2,
Cu, Fe. R•, RO•, ROO •
Prooxidant Jail
R•, RO•, ROO•,
1O2, O-2,
-OH, H2O2,
Cu, Fe 22

23. Prooxidant Activities of Transition Metals
Formations of alkyl free radical by direct reaction with fats and oils. Fe 3+ + RH Fe 2+ + R
+ H +
Hydroperoxide decomposition to form peroxy or alkoxy radical. Fe 3+ +
ROOH Fe 2+
+ ROO
+ H + Fe 2+ +
ROOH Fe 3+
+ RO -
+ OH
Activation of molecular oxygen for singlet oxygen formation. Fe 2+ + O Fe 3+
+ O - 1 O 2 2 2 23

24. Preventive Antioxidants
Superoxide dismutase
Catalase
Glutathione peroxidase
Preventive antioxidants minimize the formation of initiating radicals. 24

25. Superoxide dismutase Catalase Superoxide dismutase 2O2·- H2O2 O2 + H2O
Glutathione Oxidase
GSSG + 2H2O
2GSH
Glutathione Reductase
NADP+
NADPH + H+
NADP+ Reductase 25

26. General free radical-scavenging ability: the DPPH Assay
Antioxidant activity of extracts and compounds can be
evaluated by a general radical-scavenging assay that
predicts ability to quench OH., ROO. and other ROS.
antioxidant
Violet > Yellow
Radical-scavenging activity is determined by measuring degree
of absorbance quenching for varying sample concentrations
Activity expressed as EC50 = concentration required to quench % of DPPH radical
DPPH: 2,2-diphenyl-1-picrylhydrazyl radical
lmax = 517nm . H 26

27. Radical Scavenging Antioxidant
Vitamin C
Tocopherol
Quercetin
Anthocyanin
Radical scavenging antioxidants break free radical chain reaction by donating hydrogen to free radicals. 27

28. Standard One-Electron Reduction Potential
Compounds E (mV)
HO· H+ / H2O
RO· H+ / ROH
HOO. H+ / ROOH
ROO· H+ / ROOH
R· H+ / RH 600
Catechol· H+ / Catechol 530
- Tocopheroxyl· H+ / - Tocopherol 500
Ascorbate· H+ / Ascorbate 282 28

29. Characteristics of Antioxidants
The major antioxidants currently used in foods are monohydroxy or polyhydroxy phenol compounds with various ring substitutions.
These compounds have low activation energy to donate hydrogen. The resulting antioxidant free radical does not initiate another free radical due to the stabilization of delocalization of radical electron.
The resulting antioxidant free radical is not subject to rapid oxidation due to its stability.
The antioxidant free radicals can also react with lipid free radicals to form stable complex compounds. 29

30. Antioxidants Butylated Hydroxy Toluene Butylated Hydroxy Anisole O H C( 3 ) C ( H 3 ) O
Butylated Hydroxy Toluene
Butylated Hydroxy Anisole 30

31. Antioxidants TBHQ Propyl Gallate Gossypol O H C O H C ( ) C H O 3 7 331

32. Mechanism of Antioxidants
Hydrogen donation to free radicals by antioxidants.
Formation of a complex between the lipid radical and the antioxidant radical (free radical acceptor). 32

33. Reaction of antioxidants with radicals+ AH RH + A RO + AH
ROH + A
ROO + AH
ROOH + A R + A RA RO + A
ROA
ROO + A
ROOA
Oxidized Antioxidant
Antioxidant + O 2 33

34. Stable Resonance Formation of BHA( 3 ) R
, RO
, or ROO . C ( H 3 ) O O C H 3 ( ) .
RH, ROH +
or ROOH C ( H 3 ) O O . C ( C H 3 ) 3 . O C H 3 34

35. Ideal Antioxidants No harmful physiological effects
Not contribute an objectionable flavor, odor, or color to the fat.
Effective in low concentration
Fat-soluble
Carry-through effect  No destruction during processing
Readily-available
Economical 35

36. Sources of antioxidants in the diet
Antioxidants come in all colors and flavors.

37. THE END
Thank you!!