1. Antineoplastic agents

2. Cancer
Cancer is a group of neoplastic diseases that occur in humans in all ages and in all races as well as in animals
It is basically a disease of cells characterized by uncontrolled cell division.
Factors inducing cancer (carcinogenic factors):
Physical factors : e.g. exposure to radiation (X-Ray, UV)
Viruses have been implicated in human cancer (e.g.HCV)
Chemical substances; ( e.g. cigarette smoke, Aflatoxin B1)
Metabolic and hormonal factors
Genetic factors
Food and environment

3. According to the type of tissue from which they arise
Classification of types of cancer
According to the type of tissue from which they arise
Sarcoma
Carcinoma
Mesodermal tissue
Epithelial tissue
Liver
Kidney
Brain
Lung
Connective tissue
Muscle
bone
Leukemia
Lymphoma
Blood
Lymphoid
The cells divide excessively forming local tumor that invades adjacent organs.
They also can migrate through blood or lymph to other organs causing metastasis

4. Chemotherapeutic agents
Treatment of cancer
In order to obtain good result in cancer treatment, the concept of total cell eradication must be applied.
Three main lines are adopted either individually or in combination
Surgical line : Total excision of the tumor if localized
Radiation therapy: Using different types of ionizing radiations.
Chemotherapy: Used alone or along with surgery or radiation
Chemotherapeutic agents
They are also called antineoplastic, cytotoxic, cytostatic, antitumor or anticancer.
They act in different way on cell division.
They show activity only on cells in the process of division (high growth rate).
Accordingly malignancies showing high percentage of cells in the process of division are more susceptible to chemotherapeutic agent.
Normal cells that divide rapidly are affected e.g. Hair follicle, mucous membrane of the stomach.

5. Classification of chemotherapeutics
Alkylating agents
Nitrogen mustards
Alkyl sulfonates
Nitrosoureas
Aziridines
Triazines
Antimetabolites
Folic acid antagonist
Purine antagonist
Pyrimidine antagonist
III. Natural products
Vinca Alkaloids
Antibiotics
IV. Hormones
V. Miscellaneous

6. Mechanism of action of alkylating agents (nitrogen mustard)
They are highly electrophilic agents that react by alkylation
of important nucleophilic groups including:
Proteins ( NH2, SH, COOH)
N7 in guanine base of DNA causing cell death
Alkylation of DNA leads to cell death because they cause:
Miscoding and formation of abnormal base pair of guanine with thymine instead of cytosine
Interstrand cross-linking : the 2 chloroethyl chain with 2 guanidine bases
Depurination by excision of purine moiety from the strand residue
Cleavage of imidazole ring.

7. Cross linking

8. nucleotide A T C G T A G C

9. Alkylating agents (1) Nitrogen mustards SAR
ethylene moiety between N and Cl is essential for activity to form
the aziridinium ion
CH2 or CH2CH2CH2 abolish activity
Halogen other than Cl ↓ activity

10. A) Nitrogen mustard Mechlorethamine HCL Mustine HCL Synthesis
In 1st world war sulphur mustard gas was used as a war gas however, it was found that it cause atrophy of the lymphoid tissue.
Mechlorethamine HCL
Mustine HCL
Synthesis

11. Mechanism of action Formation of reactive aziridinium cation which can alkylate DNA (SN2)
Assay
Hydrolysis with KOH yields KCl which can be determined using Volhard’s method

12. Chlorambucil
COOH gp improve water solubility (water soluble Na form absorbed orally)
Aromatic ring electron density of N therefore no formation of aziridinium
cation
The reaction goes through ( SN1 ) reaction

13. Cyclophosphamide Oxazaphosphorines The most commonly used
It has a broad application
It is a prodrug and is not toxic itself
Activation takes place by cytochrome P 450 monooxygenase in the liver

14. Activation of cyclophosphamide in the liver by cytochromeP450
The active phosphoramide mustard reacts with nucleophile

15. Unfortunately How to overcome this toxicity
The acrolein released cause kidney toxicity?
Because it reacts with cysteine residues in cell protein
How to overcome this toxicity
Toxicity can be reduced by co-administration of 2-mercaptoethane sufonate sodium (Mesna) that interacts with acrolein and convert it to water soluble product eliminated in urine
acrolein
Mesna
Safe addition product

16. Synthesis SAR Bis(2-chlorothyl) is essential for activity
Replacement of Cl with F, Br or I →↓ activity

17. Melphalan Has COOH group, so has good water solubility
It mimic amino acids , as a result the drug can be recognized as amino acid and taken into cells by carrier protein
It has also good stability (can be take orally)

18. B) Nitrosourea CARMUSTINE 1,3-Bis-(2-chloroethyl)-1-nitrosourea
It is a chloroethylnitrosourea derivative
It is lipid soluble (can cross BBB)
Used for treatment of brain tumor

19. Mechanism of activation
Decompose spontaneously in the body to release
Alkylating agent (alkylation of DNA
Carbamoylating agent that reacts with proteins

20. Busulfan C) 3-Methane sulfonate
Sulfonate gp is a good leaving gp act as chlorine in nitrogen mustard
Mechanism: SN1 and does not involve intermediate like aziridinium ion
It alkylate the N7 position in guanidine

21. Synthesis
Assay
Busulfan is hydrolyzed in water and liberate methane sulfonic acid that can be titrated with NaOH using phenolphthalein as indicator

22. D) Aziridines
They are strained ring system (aziridine ring). The reactivity of the aziridine group is increased by protonation.

23. Thiotepa N,N`,N``Triethylenethiophosphoramide,
tris(1-aziridinyl) phosphine sulfide.

25. Uses of Thiotepa Thiotepa is most active at low pH.
It has been used in carcinomas of the breast and ovary and malignant lymphomas.

26. E) Triazenes
Dacarbazine: Deticene, DTIC, 5-(3,3-dimethyl-1-triazenyl)-1H-imidazol-4-carboxamide.

27. Uses of Dacarbazine
It is taken parenterally for the treatment of metastatic malignant melanoma and in combination therapy for Hodgkin`s disease.

28. Mechanism of action of Dacarbazine
Activation of DTIC by a microsomal enzyme in the liver can produce a methyldiazonium ion, a precursor to methyl carbonium ion.

30. II. Antimetabolites Folic acid Purines Pyrimidines Nucleoside
Nucleotide
DNA
PROTEINS
RNA
ENZYMES

31. A) Folic acid antagonist
Methotrexate
DHFR
Folic acid Dihydrofolic acid FH tetrahydrofolic acid (FH4)
FH4 transfer 1 carbon (CHO formyl group)
Methotrexate binds to DHF reductase stronger than DHF and therefore inhibits1 carbon transfer essential for purine de novo synthesis FR
DHFR

32. 6-Mercaptopurine B) Purine antagonist:
It is prodrug that is converted in the body to thio-dGTP which
Inhibits the synthesis of guanine nucleotides
6-MP is incorporated into DNA instead of guanine base leading to cell death
Metabolism

33. Fluorouracil C) Pyrimidine antagonist:
Inhibits thymidylate synthase (suicidal inhibition)
Thymidylate synthase convert dUMP → dTMP
This reaction require loss of proton as H+
in case of 5-fluorouracil , fluorine atom can not leave as positive ion
So the enzyme is irreversibly inhibited → no dTMP → no DNA synthesis

34. D) DNA polymerases inhibitor
They are enzymes that catalyse the synthesis of DNA using the nucleotide bases dATP, dGTP, dCTP & dTTP
Cytarabine
It is prodrug
It is an analogue of deoxycytidine
It is competitive inhibitor of DNA polymerase
S.E.: metabolized by hepatic deamination to give inactive uracil derivatives

35. e.g.1,2. Doxarubicin and Daunorubicin
III. NATURAL PRODUCTS
A) Antibiotics
Anthracyclines
e.g.1,2. Doxarubicin and Daunorubicin

36. They are coloured crystalline compounds and are administered intravenously as hydrochloride.
Daunorubicin is used in the treatment of acute lymphocytic and granulocytic leukemias.
Doxorubicin, on other hand, has a significant role in the treatment of solid tumors, such as, carcinoma of breast, lung, thyroid, and ovary, as well as, soft tissue sarcoma
Mechanism of action: They act by different postulated mechanisms:
1) Intercalation. Initially they were found to bind DNA by intercalation between base pairs perpendicular to the long axis of the double helix. This intercalation causes partial unwinding of the helix and thus disrupts DNA polymerases and transcription.
2) Free-radical generation. Free-radical formation (highly reactive compounds with an unpaired electron) occurs during the metabolism of anthracyclines.
3) Membrane interaction. When anthracyclines bind to cell membrane, changes in membrane glycoproteins, transmembrane flux of ions, and membrane morphology have been demonstrated in a variety of cells.
4) Metal ion chelation. The anthracyclines are capable to chelate divalent cations such as calcium and ferrous ions by virtue of the quinone and phenolic functions.

37. e.g.3. Mitomycin C Mechanism
Alkylating agent (Interstrand cross linking)
In the body it is activated by reduction and loss of methoxy group
Work better in anaerobic condition (as in solid tumor)
Has several side effects (one of the most toxic)

38. b) Natural alkaloids
Vinca alkaloids: (vincrestine & vinblastine ) & its semisynthetic derivative vindesine, They appear to exert their major anti-tumor effect by binding to critical microtubular proteins within cells Which are essential contractile proteins for the mitotic spindle of dividing cells, this binding leads to mitotic arrest.
Acridone alkaloids e.g. acronycine

39. IV- Hormone-based therapies
A) Therapy for treatment prostate cancer
1)Estrogens & 2)Antiandrogens
B) Therapy for treatment breast cancer and or endometrial carcinoma
1)Antiestrogens & 2) Aromatase inhibitors & 3)Progestins

40. A) Therapy for treatment prostate cancer 1) Estrogens
Diethylstilbestrol is used in treatment of prostatic cancer, but a feminizing effect is observed, this has been overcome by its phosphate derivative fosfesterol, which is more specific due to the presence of phosphatase enzyme in cancer cells, and it is used also in the treatment of prostatic cancer.

43. Estramustine sodium phosphate
It was designed to carry the nitrogen mustard selectively into cells with estrogen receptors. It is used also in the treatment of prostatic cancer.
Has 2 mechanisms of action :alkylating agent and estrogenic activity

44. 2) Antiandrogens Flutamide
It is used to treat the prostate cancer by blocking the action of androgens on their receptors

45. B) Therapy for treatment breast cancer and or endometrial carcinoma 1) Antiestrogens
Tamoxifen has been used successfully in the treatment of advanced breast cancer in postmenopausal women.

47. 2) Aromatase inhibitors
Anastrazole
They tend to be used as second line drugs for the treatment of oestrogen-dependent breast cancers that prove resistant to tamoxifen.

48. 3) Progestins
They are active against certain neoplasms that are stimulated by estrogens.
They appear to exert anti-estrogenic effects of uncertain mechanism.
Megestrol acetate is used against endometrial carcinoma.

50. IV. Miscellaneous 1- Cisplatin
In the body the 2Cl groups are replaced by nucleophiles in DNA especially N7 guanine
It is bifunctional alkylates 2 guanine base causing cross linking

51. 2- Hydroxyurea, hydrea. It can be given orally.
It is active against melanoma, chronic myelocytic leukemia, and metastatic ovarian carcinoma.

52. Mechanism of action
It interferes with DNA synthesis by inhibiting ribonucleotide reductase, and this action results in decreased levels of deoxyribonucleotides. Hydroxyurea may interfere with the function of the enzyme by chelating with its ferrous iron cofactor.

53. 3- Protein kinase inhibitors
They are enzymes which phosphorylate specific amino acids in protein substrate.
Tyrosine kinases
Serine kinases
Histidine kinases

54. A) non-receptor enzyme inhibitors Imatinib mesylate (Gleevec)
Tyrosine kinase inhibitors: A) non-receptor enzyme inhibitors B) receptor enzyme inhibitors
A) non-receptor enzyme inhibitors Imatinib mesylate (Gleevec)
Gleevec is It is administered orally and indicated for the treatment of patients with chronic myeloid leukemia (CML).

55. 4-[(4-methyl-1-piprazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]-benzamide methanesulfonate.

56. Mechanism of action
Protein tyrosine kinases are important in the transduction of signals initiating cellular replication and transformation. Gleevec is a protein tyrosine kinase inhibitor that inhibits the constitutive active abnormal tyrosine kinase (protein termed bcr-abl) created by the philadelphia chromosome abnormality in CML. It inhibits proliferation and induces apoptosis in leukemia cells.

58. B) receptor enzyme inhibitors
Gefitinib (Iressa®)
Gefitinib is designated chemically as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-quinazolin-4-amine.

59. Gefitinib is currently only indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received chemotherapy.
It is used in the treatment of other cancers where EGFR overexpression is involved.
Gefitinib is the first selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase.

61. 4- Intercalating agents
Amsacrine
It contain a planar heteroaromatic ring system which can slip into the double helix of the DNA and distort its structure.
As a result it can inhibit replication and transcription