1. Anti-cancer drugs By
Yasar Qazi

2. Cancer
Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues.
Cancer cells can spread to other parts of the body through the blood and lymph systems, this process is called metastasis. 2

3. Cancer Categorized based on the functions/locations of the cells from
which they originate:
Carcinoma - skin or in tissues that line or cover internal organs. E.g., Epithelial cells % reported cancer cases are carcinomas.
Sarcoma - bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.
Leukemia - White blood cells and their precursor cells such as the bone marrow cells.
Lymphoma - cells of the immune system that affects lymphatic system.
Myeloma - B-cells that produce antibodies, spreads through lymphatic system.
CNS cancers - cancers that begin in the tissues of brain and
spinal cord. 3

4. Cancer Therapeutic Modalities (classical)
1. Surgery
1/3 of patients without metastasis Respond to surgery and radiation.
If diagnosed at early stage, close to 50% cancer could be cured.
2. Radiation
50% patients will undergo chemotherapy, to remove micrometastasis. However, chemotherapy is able to cure only about % of all cancer patients.
3. Chemotherapy 4

5. New types of cancer treatment
Hormonal Treatments: These drugs are designed to prevent cancer cell growth by preventing the cells from receiving signals necessary for their continued growth and division. E.g., Breast cancer – tamoxifen after surgery and radiation
Specific Inhibitors: Drugs targeting specific proteins and processes that are limited primarily to cancer cells or that are much more prevalent in cancer cells.
Antibodies: The antibodies used in the treatment of cancer have
been manufactured for use as drugs. E.g., Herceptin, avastin 5

6. New types of cancer treatment
Biological Response Modifiers: The use of naturally occuring, normal proteins to stimulate the body's own defenses against cancer. E.g., Abciximab, rituxmab
Vaccines: Stimulate the body's defenses against cancer. Vaccines usually contain proteins found on or produced by cancer cells. By administering these proteins, the treatment aims to increase the response of the body against the cancer cells. 6

7. Cancer Chemotherapy (Background)
Most of the recent progress using antineoplastic therapy is based on:
Development of new combination therapy of using existing drugs.
Better understanding of the mechanisms of antitumor activity.
Development of chemotherpeutic approaches to destroying micrometastases.
Understanding the molecular mechanisms concerning the initiation of tumor growth and metastasis.
Recognition of the heterogeneity of tumors 7

8. Cancer Chemotherapy (Background)
Recently developed principles which have helped guide the treatment of neoplastic disease
A single clonogenic cell can produce enough progeny to kill the host.
Unless few malignant cells are present, host immune mechanisms do not play a significant role in therapy of neoplastic disease.
A given therapy results in destruction of a constant percentage as opposed to a constant number of cells, therefore, cell kill follows first order kinetics. 8

9. Cancer Chemotherapy
Malignancies which respond favorably to chemotherapy:
choriocarcinoma,
Acute leukemia,
Hodgkin's disease,
Burkitt's lymphoma,
Wilms' tumor,
Testicular carcinoma,
Ewing's sarcoma,
Retinoblastoma in children,
Diffuse histiocytic lymphoma and 10.Rhabdomyosarcoma.
Antineoplastic drugs are most effective against rapidly
dividing tumor cells. 9

10. Cancer Chemotherapy E. The Main Goal of Antineoplastic Agents
IS to eliminate the cancer cells without affecting normal tissues (the concept of differential sensitivity). In reality, all cytotoxic drugs affect normal tissues as well as malignancies - aim for a favorable therapeutic index (aka therapeutic ratio).
LD50
ED50
Therapeutic Index =
A therapeutic index is the lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective dose for 50% of the population (ED50). 10

11. General rules of chemotherapy
Aggressive high-dose chemotherapy
Dose- limiting is toxicity towards normal cells
Cyclic regimens - repeated administrations with appropriate
intervals for regeneration of normal cells (e.g., bone marrow cells)
Supportive therapy - to reduce toxicity
hematotoxicity – bone marrow transplantation, hematopoietic growth factors
Specific antagonists: antifolate (methotrexate) – folate
(leucovorin)
MESNA - donor of –SH groups, decreased urotoxicity of cyclophosphamide. Detoxifying agent.
dexrazoxane: chelates iron, reduced anthracycline cardiotoxicity
amifostine: reduces hematotoxicity, ototoxicity and neurotoxicity of alkylating agents 11

12. Antineoplastic Agents
Alkylating agents
Topoisomerase inhibitors
Antimetabolites
Molecularly targeted
busulfan
dactinomycin
cytarabine
erlotinib
carboplatin
daunomycin
clofarabine
imatinib
carmustine
doxorubicin
fludarabine
sorafenib
cisplatin
etoposide
gemcitabine
sunitinib
cyclophosphamide
etoposide phosphate
mercaptopurine
tretinoin
dacarbazine
idarubicin
methotrexate
Herceptin
ifosfamide
irinotecan
nelarabine
Miscellaneous
lomustine
liposomal daunomycin
thioguanine
arsenic trioxide
mechlorethamine
liposomal doxorubicin
Tubulin binders
asparaginase
melphalan
mitoxantrone
docetaxel
bleomycin
oxaliplatin
teniposide
ixabepilone
dexamethasone
procarbazine
topotecan
vinblastine
hydroxyurea
temozolomide
vincristine
mitotane
thiotepa
vinorelbine
PEG-asparaginase
paclitaxel
prednisone 12

13. Cell cycle Cell cycle can be divided into:
G0: This may be a temporary resting period or more permanent. An example of the latter is a cell that has reached an end stage of development and will no longer divide (e.g. neuron).
G1: Cells increase in size in G0, produce enzymes needed for DNA synthesis
S Phase: To produce two similar
daughter cells, the complete DNA
Mitosis or M Phase: Cell growth and protein production stop at this stage in the cell cycle. All of the cell's energy is focused on the complex and orderly division into two similar daughter cells.
instructions in the cell must be duplicated. DNA replication occurs during this S (synthesis) phase.
Gap 2 (G2): It is the gap between DNA synthesis and mitosis, the cell will continue to grow and produce new proteins & RNA.

14. Cell cycle specificity of Anti-Neoplastic Agents
G0 = resting phase
G1 = pre-replicative phase G2 = post-replicative phase S = DNA synthesis
M = mitosis or cell division
Vincristine, Vinblastine
Paclitaxel, Docetaxel
Cyclophosphamide Bleomycin Actinomycin D M G0
resting G2
G 1
Hydrocortisone S
Actinomycin D 5-Fluorouracil
Cytosine arabinoside Methotrexate
6-Mercaptopurine
6-Thioguanine
Purine antagonists Methotrexate Cyclophosphamide 5-Fluorouracil
Cytosine arabinoside Daunomycin 14

15. Cancer chemotherapeutic agents
They are classified into:
Cell-cycle non specific agents(CCNS): are cytotoxic in any phase of the cycle even on G0 phase and so are more effective against large slowly growing tumors. E.g. Bleomycin.
Cell-cycle specific (CCS): are cytotoxic on all phases but not on cells out of the cycle(at G0 ) and so are more effective against rapidly growing tumors. Work better in combination than alone
E.G. Mitomycin, doxorubicin,….etc.
Phase specific: act on specific phase of the cycle
E.g. Vinca alkaloids act more in M-phase
,antimetabolites
(mainly act on S-phase.)

16. Anticancer Drugs There are three Major Groups of Anticancer Drugs:
Cytotoxic Drugs (largest group)
-Alkylating agents
-Antimetabolites
-Antitumor antibiotics
-Plant alkaloids
-Miscellaneous cytotoxic drugs
Hormones and hormone antagonists
These are among the best-tolerated chemotherapeutics because they target specific receptors, and thus only specific cell types e.g. Tamoxifen
Immunomodulators
-Immunostimulants, including interferons and interleukins
-Immunosuppressant

18. Chemotherapy
Alkylation Agents
Antimetabolites
Antibiotics
Antimitotic Agents
Micellaneous Antineoplastic Agents

19. I-Alkylating Agents (CCNS)
Mechanism of action
These drugs work by alkylation with nucleophilic substitution. They alkylate a variety of cellular constituents, such as cell membranes, proteins, and most importantly DNA. More specifically, the nitrogenous bases of DNA are alkylated.
The drugs start off as pro-drugs that become activated when a chlorine atom is extracted. A carbonium ion is thus formed. This “carbonium ion” is very electrophilic and will then attack any free pair of electrons (i.e. on the N7 of guanine). This electrophilic attack results in a bond being formed between the drug and the guanine of DNA. As a result of this “alkylation”, there are a few consequences:
Miscoding (In transcription)
Cross linking- this only occurs if the drug is bifunctional The net result is cancer cell undergo apoptosis.

20. I-Alkylating Agents (CCNS)

21. An Example of DNA CrosslinkingHN NH N N
H2N N
N NH2 HO OH O O O O P P O O
Crosslinking: Joining two or more molecules by a covalent bond. This can either occur in the same strand (intrastrand crosslink) or in the opposite strands of the DNA (interstrand crosslink). Crosslinks also occur between DNA and protein. DNA replication is blocked by crosslinks, which causes replication arrest and cell dea2th0 if the crosslink is not repaired.

22. Major Clinically Useful Alkylating Agents
Bis(mechloroethyl)amines Nitrosoureas Aziridines 21

23. I-Alkylating Agents (CCNS)
Nitrogen mustards (Mechlorethamine, Melphalan, Chlorambucil, Cyclophosphamide)
Nitrosoureas (Carmustine, Lomustine, Semustine)
Alkyl sulfonates (Busulphan)
Ethylenimines and methyl melamines (Thiotepa, Hexamethyl melamine)
Nitrogen Mustards Mechlorethamine
first alkylating agent employed clinically
bifunctional, thus can crosslink DNA
extremely unstable and is inactivated within a few minutes following administration.
Thus it is given IV.
Clinical Uses
-Hodgkin’s Disease
-Non-Hodgkin’s Lymphoma

24. I-Alkylating Agents (CCNS)
Cyclophosphamide
-It acts as cytotoxic and immunosuppressor agent.
Prodrug which must be activated by the cytochrome p450 system, which turns it into a nitrogen mustard.
bifunctional agent
-most widely used alkylating agent
Clinical Uses
Hodgkin’s Disease
Non-Hodgkin’s lymphoma
Solid tumors of head, neck, ovaries, and breast
frequently used in combination with methotrexate (anti-metabolite) or doxorubicin (anti-tumor antibiotic), or fluorouracil as adjuvant therapy post breast cancer surgery
Organ transplant recipients (due to immunosuppressive actions)

25. I-Alkylating Agents (CCNS)
Chlorambucil
Acts by interfering with DNA replication and damaging the DNA in a cell. The DNA damage induces cell cycle arrest and cellular apoptosis via the accumulation of cytosolic p53 and subsequent activation of Bax, an apoptosis promoter.
Clinical Uses
Mainly in chronic lymphocytic leukemia,
Can be used for treating some types of non-Hodgkin lymphoma, Waldenström macroglobulinemia, and ovarian carcinoma.
Also used as an immunosuppressive drug for various autoimmune and inflammatory conditions.

26. I-Alkylating Agents (CCNS)
Melphalan
Melphalan chemically alters through alkylation of the DNA nucleotide guanine, and causes linkages between strands of DNA. This chemical alteration inhibits DNA synthesis and RNA synthesis.
Clinical Uses
It is used to treat multiple myeloma
ovarian cancer
occasionally malignant melanoma.

27. I-Alkylating Agents (CCNS)
2) Nitrosoureas (Carmustine and Lomustine)
bifunctional
active against broad spectrum of neoplastic disease
inhibits synthesis of both DNA and RNA, as well as proteins
highly lipophilic, so they can easily cross BBB, and are great for CNS
tumors.
Major toxicity is DELAYED bone marrow depression & Pulmonary fibrosis.
Clinical uses
Carmustine
Lomustine
primary and metastasis tumors of the brain
Hodgkin’s Disease
Non-Hodgkin’s lymphoma
Adenocarcinoma of stomach, colon, and rectal cancer
Hepatocarcinoma

28. Synthesis of Carmustine

29. I-Alkylating Agents 3) Alkyl Sulfonates (Busulfan) Clinical uses
Great effect on for Chronic granulocytic Leukemia
Toxicity/ Side Effects
Dose limiting toxicity is bone marrow depression.
Pulmonary infiltrates and pulmonary fibrosis
-- Nausea and vomiting
Alopecia
Sterility
Skin hyper pigmentation
Cataracts
Hepatitis

30. I-Alkylating Agents
4) Ethylenimines and methyl melamines (Thiotepa, Hexamethyl melamine)
Thiotepa (N, N', N''-triethylenethiophosphoramide) is an organophosphorus compound with the formula SP(NC2H4)3. This molecule features tetrahedral phosphorus and is structurally akin to phosphate. It is derived from aziridine and thiophosphoryl chloride.
Use:
Adenocarcinoma of the breast, adenocarcinoma of the ovary, superficial papillary carcinoma of the urinary bladder

31. Synthesis of Thiotepa
Aziridine
Thiophosphoryl chloride.
Thiotepa

32. Synthesis of Mechlorethamine

33. Synthesis of Melphalan

34. Synthesis of Cyclophosphamide

35. Synthesis of Chlorambucil

36. Synthesis of Busulfan

37. I. Alkylating Agents 5) Platinum Coordination Compounds Cisplatin
Forms crosslinks within DNA strands.
Cis-platin is not really an “alkylating” agent, but since it operates
via the same mechanism as the alkylating agents, it is placed within that group.
Carboplatin
A derivative of cisplatin with less nephero- ,neuro- & ototoxicity.
Clinical Uses
Very powerful against TESTICULAR CANCER
Also good for carcinomas of ovary, bladder, head, and neck

38. Chemotherapy
Alkylation Agents √
Antimetabolites
Antibiotics
Antimitotic Agents
Micellaneous Antineoplastic Agents

39. II. Antimetabolites (CCS)
An antimetabolite is a chemical with a similar structure to a metabolite required for normal biochemical reactions, interfere with the normal functions of cells, including cell division.
All antimetabolites are used in cancer treatment, as they interfere with DNA production and therefore cell division and the growth of tumors (mainly in S-phase specific).
They are classified into:
Folic acid analogues (Methotrexate)
Purine analogues (6-Mercaptopurine, thiogunine)
Pyrimidine analogues (5-fluorouracil, Cytarabine)
Purine and pyrimidine antagonists are phosphorelated inside the body into nucleotide form in order to be cytotoxic
Uses
leukemia.
non-Hodgkin's lymphoma
inflammatory bowel disease such as Crohn's Disease and ulcerative colitis
widely used as immunosuppressant in transplantations to control rejection reactions.

42. II. Antimetabolites (CCS)
O P O
Base O
R=H in DNA R=OH in RNA O R O
NH2
NH2 O
DNA HN N N N N HN
O N
O N N N
H2N N N
Guanine
Thymin
Cytosin
Adenine O
RNA HN
Cytosin
Adenine
Guanine
O N
Uracil

43. Cytarabine (ARA-C) D-ribose D-arabinose Inhib. DNA polymerase
O N
O N
O N
metabolic activation
O N
P P P O
P O
P O HO O O O O OH OH HO
HO OH HO HO
ARA-C
ARA-C
Metabolic inactivation (fast)
Inhib. DNA polymerase
Incorporation DNA/RNA; misreading O HN
O N HO O OH HO
D-ribose
D-arabinose

44. 6-Mercaptopurine (6-MP)
S-Analog hypoxanthine
S Me N SH
S S
Metabolic activation N N N N HN HN N N
N H N
N H N N N N
P O
P O O O
6-MPMP
Inhib. several steps
OH in purine biosynth
HO OH
also antimetabolite HO S N HN N N
P P P O O
HO OH
Incorp . DNA / RNA instead og guanine

45. 1. Purine analogues
Purines are integral components of RNA, DNA and coenzyme that are synthesized in proliferaton of cancer cells. Therefore, an agent that antagonizes the purine will certainly lead to formation of false DNA and these include analogues of natural purine bases, nucleosides and nucleotides.
A few drugs belonging to this classification are, namely : Mercaptopurine and Azathiopurine
o-Mercapto-6-purine ; 6 MP

46. Mercaptopurine Mercaptopurine is found to inhibit
experimental orthoimmune encephalomyletis and thyroiditis and hence used in combination with vincristine, methortrexate and prednisone in the treatment of childhood leukemia.
As such 6-MP may cause hyperuricamia but it is usually administered with allopurinol—an analogue of hypoxanthine which blocks the conversion of 6-MP to uric acid and hence the dose of 6-MP is reduced and still the desired response is obtained.

47. Synthesis of Mercaptopurine
It may be prepared by the interaction of hypoxanthine with phosphorus pentasulphide.

48. Azathiopurine
The main use of azathiopurine is as an adjunct for the management and prevention towards the rejection of renal homotransplants.

49. Synthesis of Azathiopurine
It is prepared by treating 6-mercaptopurine with 5-chloro-1- methyl-4-nitroimidazole

50. 2. Pyrimidine analogues
Pyrimidine analogues have the capacity to interfere with the synthesis of pyrimidine nucleoside and hence the DNA synthesis. Aside from their antineoplastic effects they are also found to be equally effective in psoriasis and fungal infections.
A few characteristic compounds of this category are, namely
: Fluorouracil and Cytarabine.

51. 5-FU
It is used in the palliative treatment of carcinoma of the breast, pancreas, prostrate, colon and hepatoma for which surgery or irradiation is not possible.
It is also found to be beneficial in tropical treatment of premalignant solar keratosis.

52. Synthesis of 5-FU
This official compound is prepared by the direct fluorination of uracil with fluoroxytrifluoromethane.

53. Cytarabine
It is indicated in both adult and childhood leukemia. It is specifically useful in acute granulocytic leukemia and found to be more effective when combined with thioguanine and daunorubacine.

54. Synthesis of Cytarabine
Cytarabine may be synthesized by the acetylation of uracil arabinoside followed by treatment with phosphorus pentasulphide and subsequent heating with ammonia.

55. 3-Folic acid analogues Methotrexate:
A folic acid analogue, prevents the formation of THF, essential for purine and pyrimidine synthesis,
Inhibits DHF reductase, leads to inhibition of production of DNA, RNA and proteins (as tetrahydrofolate is also involved in the synthesis of amino acids as serine and methionine).
It is actively taken up into the cells by the same transport system for folate.
folic acid
Methotrxate

56. Cont: Folic acid analogues
Methotrexate folic acid inhibits it.
compete with for DHFR and Therefore, it
inhibits the synthesis of DNA, RNA and proteins.
Also, DHFR catalyses the conversion of DHF to the active THF which is needed
for the synthesis deoxynucleoside phosphate DTMP for DNA synthesis)
of the thymidine (required

58. Folic Acid analogs as antimetabolites
O CO2H
NH2
N H
CO2H
Metotreksat N N N
H2N N N
O CO2H O S
N H
CO2H N
Raltitrexed HN N
N N

59. Chemotherapy
Alkylation Agents √
Antimetabolites / Nucleoside Analogs √
Antibiotics
Antimitotic Agents
Micellaneous Antineoplastic Agents

60. III. Antibiotics
The recognition of antibiotics as an important class of antineoplastic agents is quite recent. Consequently, the production of antineoplastic agents through proper strain selection and controlled microbial fermentation conditions may ultimately optimize the formation of a particular component in an antibiotic mixture.
A few important members of this category are described below, namely ; Dactinomycine; Daunorubicin ;
Metabolites from microorg., too toxic as antibiotics - anticancer comp.
Bleomycins
Actinomycins
Mitomycins
Antracyclins
Coformycins

61. Dactinomycine
The first antibiotic to be isolated from a species of Streptomyces was Actinomycin A and many related antibiotics including Actinomycin D were latter obtained. Actinomycin D is commercially available as Dactinomycine.
It is found to the acitve against L-1210, P-1534, P-388 and adenocarcinoma strains. It binds to DNA thereby preventing DNA transcription
It is used in the treatment or rhabdomyosarcoma in children and methotrexate-resistant choricarcinoma in women. It has also been used to inhibit immunoligical response particularly the rejection
of renal transplants.

62. Anthracyclines Daunorubicin R1 = OMe, R2 = H, R3 = H; R4 = OH
Anthracyclines constitute another complex and bigger family of antibiotics. They mostly occur as glycosides of the anthracyclinones (aglycone residue). They act by intercalation with the DNA in both normal and neoplastic cells. O
O OH R2 OH
Daunorubicin
R1 O OH
R1 = OMe, R2 = H, R3 = H; R4 = OH O R3 R4
CH3
Doxorubicine
R1 = OMe, R2 = OH, R3 = H; R4 = OH
NH2

63. Daunorubicin
Daunorubicin is useful in the treatment of acute lymphoblastic leukemia in children.
It is normally employed in combination therapy, for instance
: with cytosine arabinoside in the treatment of myclogenous leukemia ;
With cytarabine in the treatment of non-lymphoblastic leukemia in adult.

64. Chemotherapy
Alkylation Agents √
Antimetabolites / Nucleoside Analogs √
Antibiotics √
Antimitotic Agents
Micellaneous Antineoplastic Agents √

65. Vinca alkaloids Discovered in the 1950’s byHO N
N H
H OCOMe
CO2Me
Vinca alkaloids (Indols) from Vinca rosea (Catharantus roseus)
MeO2C
N R
MeO OH
Discovered in the 1950’s by
R=-Me: Vinblastin, Velbe®
R=-CHO: Vinkristin, Vincristine®
Canadian scientists, Robert Noble and Charles Beer.
Binds to microtubuli- Supression of microtubuli dynamics- Metaphase arrest
Depolymerization of microtubuli high conc.

66. Taxanes O R1 R2 NH O O O OH HO O HO H
O O O O
First isolated from bark of Western / Pacific yew (Taxus brevifolia) O
R1 = -Ph, R2 = -COMe: Palitaxel,
R1 = -OBut, R2 = -H: Dodetaxel, T
Mecanism ≈ Vinca alkaloids, different binding sites

67. Colchicine From Colchicum autumnale seeds
H3CO NH
H3CO
CH3O
O OCH3
Binds to microtubuli - metaphase arrest, too toxic too be used in cancer treatment
Used to treat gout (podagra)

68. Podophyllotoxines From Podophyllum peltarum May appleOH O
From Podophyllum peltarum
May apple O O O
MeO OMe OMe
Podophyllotoxin
Antiviral, veneric warts
Toxic - lead for anticancer drugs
Affects DNA topoisomerase II (not intercalating)
DNA strand breakage

69. Camptothecins Irinotecan First isolated Camptotheca acuminata
NIH screening
Later found in several plants O N N O
OH O
Camptothecin,
toxic, Lead comp.
Topotecan
Irinotecan N N HO O
N O N O N O N O N O
OH O
OH O
Semisynth. inhib. DNA topoisomerase II, DNA strand breakage

70. Other agents Imatinib Leukemia types Gefitinib Lung cancer H3CO N N N
H N N O N
Imatinib
Leukemia types
H3CO N N N O O HN F Cl
Gefitinib
Lung cancer