This document provides an overview of anticancer agents, including their classification, mechanisms of action, and common side effects. It discusses how cancer develops due to changes in cell growth mechanisms and classifies anticancer drugs based on their specificity in the cell cycle and their mechanisms of action. The major classes covered are antimetabolites, alkylating agents, antitumor antibiotics, topoisomerase inhibitors, and taxanes. Common side effects of anticancer agents include bone marrow suppression, nausea, vomiting, and alopecia.

1. Anticancer agents
Dr. Sarah Nanzigu
Makerere University College of Health Sciences
All Chemical Agents that act against Neoplasia

2. Outline
• Relevant Background- Cancer development
• Classification of anticancer agents
– Classes based on mechanism of action
• Antimetabolites
• Alkylating agents
• Topoisomerase Inhibitors
• Antitumor antibiotics
• Hormone antagonists
• Mitotic inhibitors
• Plant alkaloids
• Targeted therapies
• Immunotherapies
• Other agents with anticancer activity
– General mechanisms of resistance to anticancer agents

3. BACKGROUND

4. Cancer Development
• Cancer development follows changes in the growth control
mechanisms of normal cells (often genetic/ chromosomal changes)
– These changes eventually lead to development and reproduction of
abnormal cells (cancerous cells)
– The replication is uncontrollable, and hence form a tumor
• Cancer cells may eventually metastasize to other organs via the
circulatory and lymphatic systems
• There are some recognizable agents that are pro-cancer
(Carcinogenic agents: Tobacco, Alcohol, UVL, Ionizing Radiation,
Low fiber diet, Oncogenic viruses)
80 - 90% of all cancers may be related to environmental agents
including diets, lifestyles, and viruses
Several environmental agents often act together (co-carcinogenesis)

7. CANCER CELLS NORMAL CELLS
Loss of contact inhibition
Increase in growth factor secretion
Increase in oncogene expression
Loss of tumor suppressor genes
Evidence of contact inhibition
Intermittent/ coordinated growth factor
secretion
Oncogene expression is rare
Presence of tumor suppressor genes
Frequent
mitoses
Nucleus
Blood vessel
Abnormal
heterogeneous cells
Normal
cell
Few
mitoses
Cancer Cells and Normal Cells

8. Cell Division and Cancer Developement
G0 = Resting or differentiation phase
G1 or first Gap phase = Synthesis of cellular
components for DNA synthesis.
The cell grows and prepares to replicate its DNA
S, or synthesis phase = Replication of DNA Genome
G2, or second gap phase = Synthesis of Cellular
components for mitosis
The cell prepares to divide itself
M, or mitosis phase = Entire Cell division occurs
Cell division cycle occurs in phases
 Replication of its DNA (S phase)
 Replication of other cellular
componemts (M phase)
 Rests in between (Gaps) to allow synthesis and
verifying the components ahead of replication
 Control mechanisms to limit harzard replication
and use of unfit cellular components in replication

9. Details of controlled cell division
• As a cell approaches the end of G1 phase, it is controlled at a vital checkpoint, G1/S,
where the cell determines whether to replicate its DNA or not .
– The cell is checked for DNA damage to ensure that it has all the necessary cellular machinery
needed for successful cell division. Cells with intact DNA continue to S phase; cells with
unrepairable damaged DNA are arrested and commit suicide through apoptosis.
• A second checkpoint occurs at the G2 phase between the synthesis of DNA in S
phase but before cell division in M phase.
• When functioning properly, cell cycle regulatory proteins act as the body's tumor
suppressors by controlling cell growth and inducing the death of damaged cells.
– Genetic mutations causing malfunction/ absence of one/ more regulatory proteins at
checkpoints can cause "molecular switch", permitting uncontrolled cell multiplication.

10. Tumor Suppressor Genes
× Basically: A shift in control mechanisms that govern cell proliferation and differentiation
× Excessive proliferation: Formation of local tumours (compress or invade) or cell migration
× Cells have some chromosomal abnormalities but retain ability to undergo repeated proliferation
cycles

11. Treatment of Cancer
• Surgery to remove solid tumors
• Radiation to kill cancer cells that have spread to adjacent local
or regional tissues
• Chemotherapy to kill cancer cells located throughout the body
Use of chemical agents (Antineoplastics) to destroy cancer cells
• Alas! Antineoplastic drugs cannot differentiate between
normal and cancerous cells- Hence side effects

12. CANCER CHEMOTHERAPY
General biochemical mechanisms utilized by
anticancer agents
• 1) Impact the structure and function of DNA
• 2) Interfere with nucleotide synthesis.
• 3) Interfere with transcription and block RNA synthesis.
• 4) Interfere with protein synthesis and functions.
• 5) Change hormone lever.

13. CLASSIFICATION OF ANTICANCER AGENTS
I. Classification based on their specificity in the cell division cycle
– Cell-cycle Specific (CCS) drugs-
Act at specific phase of the cell division cycle
- Cell cycle Non Specific (CCNS) drugs
Act on cells at all phases Preferably kill proliferating cells.
II. Classification basing on mechanism of action
– Alkylating agents-Alkylate the DNA and interfere with its replication
– Antimetabolites-Inhibit the synthesis of folic acid, purines, pyrimidines
– Topoisomerase Inhibitors- Intefere with DNA unwinding
– Antitumor antibiotics
– Hormone antagonists
– Mitotic inhibitors
Usually both classifications are required to understand how the
mechanism of action influences the drug target

14. Classes based on mechanism of action
• Classification basing on mechanism of
action regardless of cell-cycle specificity or
drug orign

15. 1. Alkylating agents: chlorambucil, cyclophosphamide, melphalan,
mechlorethamine
2. Antimetabolites: methotrexate, 6-mercaptopurine, 5-fluorouracil,
pemetrexed, cytosine arabinoside, ,capecitabine, gemcytabine
3. Mitotic inhibitors: vinblastine, vincristine, paclitaxel, docetaxel
4. Antibiotics: actinomycin D, doxorubicin, bleomycin, daunomycin,
5. Nitrosoureas: carmustine (BCNU), lomustine (CCNU)
6. Antibody: rituximab (Rituxan),cetuximab (Erbitux), trastazumab
(Herceptin), bevacizumab (Avastin)
7. Enzyme: asparaginase
8. Agents that inhibit DNA synthesis (hydroxyurea ) or damage DNA:
cisplatin, carboplatin, oxaliplatin
Classification of Anticancer Drugs

16. Classification of Anticancer Drugs
Targeted Chemotherapy
9. Signal transduction inhibitor: imatinib (Gleevec), dasatinib,
sorafinib (Nexavar), regorafenib (Stivarga), vismodegib (Erivedge)
10. Differentiation agent: all-trans retinoic acid, HDAC inhibitors
(Vorinostat)
11. Hormones and hormone antagonists: prednisone, tamoxifen,
aromatase inhibitors, abiraterone
12. Proteasome inhibitors: bortezomib (Velcade)
13. DNA topoisomerase I inhibitors: camptothecin, irinotecan and
topotecan
14. Agents that inhibit DNA repair: PARP inhibitors
15. Arsenic trioxide: increasing the degradation of the PML-RAR
oncoprotein.
16. Inhibitors of DNA methylation: Zebularin, azacitidine and 5-aza-
2′deoxycytidine.
17. Chimeric toxic protein: Ontak (IL2 + Diphtheria toxin)

17. Commonly used anticancer drugs
Antimetabolites- Methotrexate, 5-fluorouracil (5-FU), 6-
mercaptopurine, Hydroxyurea, Pentostatin, Capecitabine, Cladribine,
Clofarabine, Cytarabine, Floxuridine, Fludarabine, Gemcitabine,
Pemetrexed, Thioguanine
Alkylating Agents
• Nitrogen mustards: cyclophosphamide, chlorambucil, melphalan,
ifosfamide, and mechlorethamine
• Nitrosoureas: carmustine, lomustine, streptozocin,
• Alkyl sulfonates: busulfan
• Platinum Based: Cisplatin, oxaliplatin, and carboplatin
• Ethylenimines: thiotepa and altretamine
• Triazines: dacarbazine (DTIC) and temozolomide

18. Antimetabolites:
Group Characteristics
• Inhibit the synthesis of folic acid, purines, and pyrimidines
needed to synthesize DNA
• Resemble NORMAL substrates (folic acid)
• Most inhibit DNA synthesis, although some may inhibit RNA
synthesis and/or function.
• Highly cell cycle specific, ( predominantly S phase)
• Antimetabolites are particularly effective in treatment of
leukemias; Profoundly inhibit bone Marrow cell replication
• Common toxicities: Bone marrow suppression, GI ulcerations,
alopecia, and nausea and vomiting are

19. Methotrexate (MTX)
Mechanism of action
It is a Folic Acid Analogue
Binds strongly to DHFR to reduce formation of THF,
Therefore, interferes with NUCLEIC ACID synthesis.

20. Methotrixate:
Clinical Uses:
Broad range
Well established use in
(1) Acute childhood Lymphoblastic Leukemia
(2) Choriocarcinoma.
(3) Cancers of breast, bladder, and head & neck.
(4) Useful in non-Hodgkin's lymphomas

21. Methotrixate:
Adverse effects
Dose limiting side effects
a) Myelosuppression (Thrombocytopenia and Leukopenia,
7-10 days after Rx, Recovery 14-21 days).
b) GI toxicity (Oral mucositis is early sign of GI toxicity,
Severe mucositis, Small bowel ulceration & bleeding,
Diarrhea). Requires cessation to prevent perforation of gut
Other side effects
• Nephrotoxicity: Infrequent with conventional doses; but
toxicity can be severe at high doses
• Immunosuppression.
• Hepatotoxicity.

22. Flurouracil (5-FU)
Structure:

23. Flurouracil (5-FU):
Mechanism of action:
• Inhibits DNA synthesis:
Inhibition of Thymidylate synthase—the most important
mechanism of action (MOA) in rapidly growing tumors
• Activated by conversion to nucleotide
• 5-FU Incorporated into RNA: Interfere with RNA
processing - All types, May be most important MOA in
slowly growing tumors.

24. (1) Single agent: Palliative in advanced colorectal
carcinoma
(2) Combination: Breast cancer; Carcinomas of ovary,
stomach, pancreas
(3) Sequential MTX + 5-FU: Head and neck cancer
Flurouracil (5-FU):
Clinical Uses

25. Dose limiting:
• Bone marrow -- esp. with bolus administration. Leukopenia &
Thrombocytopenia (9-14 days after Rx; Recovery in 5- 21).
• GI Toxicity -- esp. with infusion administration. usually
Stomatitis & Diarrhea 4-7 days after Rx.
Effect of route and schedule on adverse effects:
• Myelosuppression is dominant after IV bolus; Prolonged Rx,
may cause megaloblastic anemia
• Continuous IV Infusion: Frequently produce, stomatitis, nausea,
vomiting, and diarrhea; Hepatotoxicity (elevated transaminases);
myelosuppression less common
Effect of peak 5-FU concentration:
• Acute, reversible cerebellar syndrome: somnolence, ataxia ,
unsteady gait, slurred speech, nystagmus
Flurouracil (5-FU):
Adverse Drug reactions

26. • Hyperpigmentation of skin is frequent and may be
accompanied by photosensitivity
• Toxic effect of radiation to skin may be enhanced;
Alopecia, acute and chronic conjunctivitis, and nail
changes may be observed.
Flurouracil (5-FU):
Additional Adverse Drug reactions

27. Disrupt microtubule function
• (1) Uptake by energy dependent carrier
• (2) Bind to tubulin in microtubules to cause their
dissolution.
• CSS-Act at G2/M phase
Natural Products: Derived from Plants
Vinca Alkaloids

28. Vinca Alkaloids
Vincristine sulfate and Vinblastine sulfate
• Vinca alkaloids inhibit mitosis
• Neurotoxicity and leukopenia are the primary toxicities
Taxanes: Paclitaxel and Docetaxel
Paclitaxel inhibits mitosis;
Toxicities: Peripheral neuropathy and bone marrow
suppression are the most serious toxicities
Epothilones: ixabepilone
Estramustine
Natural Products

29. Vinca Alkaloids:
Uses
(1) Drug of choice for childhood leukemias in
combination with prednisone
(2) Used for lymphoreticular neoplasms, carcinomas,
and sarcomas

31. Topoisomerase Inhibitors
Interfere with enzymes (topoisomerases)
which help separate the strands of DNA so
they can be copied
• Topoisomerase I inhibitors: Topotecan
and irinotecan
• Topoisomerase II inhibitors: Etoposide
and teniposide.
• CCS- S/?G1

32. Antitumor Antibiotics
• Anthracycline antibiotics
Daunorubicin, Doxorubicin, Epirubicin, Idarubicin
• Other Antitumor Antibiotics: Actinomycin-D,
Mitomycin-C, and bleomycin

33. Antitumor Antibiotics
General characteristics

34. Generally; these drugs have duo mechanisms of action
• (1) DNA topoisomerase II inhibitor: Crucial to DNA
replication and transcription.
• (2) Traditional explanations of MOA: a) intercalates
between base pairs of DNA and inhibits DNA-dependent
RNA synthesis. b) Generates free radicals that cause
membrane damage and DNA strand breaks.
• May also interact with other cellular substituents
LESS "phase-specific" than antimetabolites
Often classified as CCNS

35. Antitumor Antibiotics:
Development of Resistance
• (1) Alterations in Topoisomerase II activity.
• (2) Increased inactivation of radicals: a) Increase in
glutathione-dependent enzymes, e.g., glutathione-
peroxidase. b) Altered NADPH contents.
• (3) Increase drug efflux:

36. Antitumor Antibiotics:
Clinical Indications:
They have broad spectrum anti-cancer activity.
• Hodgkin's disease, non-Hodgkin's lymphomas,
sarcomas, acute leukemia, and breast, lung, and
ovarian carcinomas all responsive
• Activity observed in bladder tumors, and
carcinomas of prostate, thyroid, endometrium,
head and neck, and other solid tumors

37. Antitumor Antibiotics:Adverse effects:
• Three categories of toxicity:
• 1) Local toxicities 2) Acute toxicities 3) Chronic toxicities
Local toxicities- Following Extravasation
Severe local tissue necrosis to point of damaging underlying
structures; If occurs, remove IV line immdeiately; Apply ice, and
steroid cream
Local Toxicity may also result as interaction of Doxirubicin with
radiation in some tissues.
• Reactions include: a) Skin: ulceration and necrosis.
b) Pulmonary: fibrosis and sloughing of esophageal mucosa.
c) Heart, and intestinal mucosa may also be affected

38. • (2) Acute Toxicities
• a) Hematologic: Leukopenia with nadir 7-10 days;
recovery typically by 21 days; Thrombocytopenia and
anemia may occur but are less common
• b) If given too fast: "Histamine-release" syndrome;
Cardiac arrest preceded by ECG changes
• (3) Chronic Toxicities
• a) Cardiomyopathy and congestive heart failure:
require cessation of Rx after cumulative dose of 550 to
600 mg/m2; must maintain record of total dose.

39. Nitrogen mustards: chlorambucil, cyclophosphamide,
ifosfamide, melphalan and mechlorethamine
Nitrosoureas: streptozocin, carmustine, lomustine
Alkyl sulfonates: busulfan
Triazines: dacarbazine (DTIC) and temozolomide
Ethylenimines: thiotepa and altretamine
Platinum Based: Cisplatin, oxaliplatin, and carboplatin

40. Alkylator Drugs
General Characteristics
• Irreversibly bind to DNA and interfere with cell
replication and synthesis of essential cell proteins and
metabolites
• Some alkylators are vesicants and will cause blistering
if spilled on the skin
• Dose-limiting toxicity is bone marrow suppression
and resulting susceptibility to infection
• Adverse effects also include nausea, vomiting,
alopecia, and ulcerations of the GI tract and mucous
membranes

41. Nitrogen mustard
• General view:
• (1) Developed from mustard war gases of Word War I
which were highly reactive vesicants.
• (2) First chemicals used for cancer Rx.
• (3) Not cell cycle specific, but still more active in
dividing tissues.
• (4)"Radiomimetic" -- action on DNA resembles
radiation.

43. • (1) Highly reactive: Form covalent bonds with
DNA, RNA and protein
• (2) Consequences: a) DNA-DNA strand and DNA-
Protein cross-links. b) Misreading of genetic code. c)
DNA Chain breaks
Alkylating Agents/ Nitrogen mustard:
Mechanism of Action

44. • (1) More toxic to bone marrow and gut than to
liver and kidney, etc.
• (2) Infertility to both males and females.
• (3) Mutagenic.
• (4) Carcinogenic.
• Tumor resistance:
• Develops slowly & may require several genetic /
biochemical changes
Alkylating agents
Adverse Drug Reaction

45. Alkylating Agents:
Clinical Uses
• Wide spectrum; Lymphoreticular tissue
tumors; Limited activity against
sarcomas.

47. Cyclosphosphamide
Mechanism of action
• Hepatic cytochrome P-450 system, enzymes
phosphatase and phosphamidase are primary
activators (hydrolyze P-N bond) to
intermediate, aldophosphamide, which
nonenzymatically breaks down to --
Phosphoramide mustard (bifunctional) &
Acrolein

48. Cyclosphosphamide:
Pharmacokinetics

50. Cyclosphosphamide:
Adverse Drug reactions

51. Hormone Antagonists

53. Chemotherapy against cancer cells
CELL CYCLE SPECIFIC DRUGS (CCS)
Primary action during specific phases of cycle
CELL CYCLE NON-SPECIFIC DRUGS
(CCNS)
Acts during any phase, including G0
Plant alkaloids ( G2-M Phases)
Disrupt microtubule function
Vinca alkaloids: vinblastine, vincristine,
vinorelbine
Taxanes: paclitaxel and docetaxel
Epothilones: ixabepilone
Estramustine
Mitotic Inhibitors (often plant alkaloids)
Act in M phase but can damage cells in all phases
For cancers of breast, lung, myelomas, lymphomas,
leukemias
Alkylating Agents crosslinking agents
Alkylates and Damage the DNA
Nitrogen mustards: chlorambucil, cyclophosphamide,
ifosfamide, melphalan and mechlorethamine
Nitrosoureas: streptozocin, carmustine, lomustine
Alkyl sulfonates: busulfan
Triazines: dacarbazine (DTIC) and temozolomide
Ethylenimines: thiotepa and altretamine
Platinum Based: Cisplatin, oxaliplatin, and carboplatin
Treat leukemia, lymphoma, Hodgkin disease, multiple
myeloma, sarcoma, cancers of lung, breast, ovary
The ability to kill cancer cells depends on its ability to halt cell division

54. Chemotherapy against cancer cells
CELL CYCLE SPECIFIC DRUGS (CCS)
Primary action during specific phases of cycle
CELL CYCLE NON-SPECIFIC DRUGS
(CCNS)
Acts during any phase, including G0
DNA synthesis inhibitors ( S Phase)
Antimetabolites: 5-fluorouracil (5-FU), Methotrexate, 6-
mercaptopurine, Capecitabine, Cladribine, Clofarabine,
Cytarabine, Floxuridine, Fludarabine, Gemcitabine,
Hydroxyurea, Pemetrexed, Pentostatin, Thioguanine
Antitumor antibiotics
Anthracycline antibiotics
Interfere with enzymes involved in DNA replication
Daunorubicin, Doxorubicin, Epirubicin, Idarubicin
Other Antitumor Antibiotics: Actinomycin-D,
Mitomycin-C, and bleomycin
Topoisomerase Inhibitors
Interfere with enzymes (topoisomerases) which help
separate the strands of DNA so they can be copied
Topoisomerase I inhibitors: Topotecan and irinotecan
Topoisomerase II inhibitors: Etoposide and teniposide.
Mitoxantrone is similar to Doxorubicin but also
inhibits topoisomerase II
The ability to kill cancer cells depends on its ability to halt cell division

55. Other anticancer agents
• Targeted Therapies (attack cancer cells more specifically). Most attack cells with certain mutant genes, or cells
that express too many copies of a particular gene.
imatinib, gefitinib, sunitinib and bortezomib
• Differentiating Agents: Make cancer cells to mature into normal cells; Ex retinoids, tretinoin, bexarotene,
arsenic trioxide
• Hormone therapy: Change the action or production of hormones needed for growth of certain cancer cells
The anti-estrogens: fulvestrant, tamoxifen, and toremifene
Aromatase inhibitors: anastrozole, exemestane, and letrozole
Progestins:megestrol acetate
Anti-androgens: bicalutamide, flutamide, and nilutamide
Agonist and Analogs of GnRH, or LHRH: leuprolide and goserelin
They are used to slow the growth of breast, prostate, and endometrial cancers

56. Other Anticancer Approaches
Immunotherapy
Stimulate the immune systems to recognize and attack cancer cells
Active immunotherapies: stimulate the body’s own immune system to fight the cancer
Passive immunotherapies: do not rely on the body; instead, they use immune components (e.g.
antibodies) created outside the body.
• Monoclonal antibody therapy (passive): rituximab, alemtuzumab (Campath)
• Non-specific immunotherapies and adjuvants (boost the immune response): BCG,
interleukin-2 (IL-2), and interferon-alfa
• Immunomodulating drugs: thalidomide and lenalidomide (Revlimid®)
• Cancer vaccines (active specific immunotherapies).
Provenge vaccine for advanced prostate cancer); other are being studied

57. Other agents with Anticancer Activity
• Corticosteroids: Prednisone, Methylprednisolone and dexamethasone
Considered as chemotherapy if used to kill or slow the growth cancer cells
Treat: lymphoma, leukemias, and multiple myeloma
As anti-emetics to prevent nausea and vomiting caused by chemotherapy
Used before chemotherapy to help prevent severe hypersensitivity reactions
• Miscelenious: L-asparaginase (enzyme), bortezomib (proteosome inhibitor)

58. General Resistance Mechanisms
for Anticancer agents

59. General Resistance Mechanisms
for Anticancer agents

60. Common Drug Toxicities for
Anticancer agents

61. Cell Cycle Specific (CCS) & Cell Cycle Non-Specific
Agents (CCNS)