This document discusses the biochemical basis of cancer therapy. It defines cancer and chemotherapy and describes the cell cycle and its phases. It then summarizes the major classes of anti-cancer drugs, including cell cycle-specific agents that target specific phases of the cell cycle and cell cycle-nonspecific alkylating agents. Examples are provided for each class with details on their mechanisms of action and phase specificity. Monoclonal antibodies and targeted therapies are also summarized.

1. BIOCHEMICAL BASIS
OF
CANCER THERAPY
Dr MANJU JHA
Department of Biochemistry
RUHS College of Medical Sciences, Jaipur

2. DEFINITIONS
CANCER: A group of disease involving abnormal cell
growth with the potential to invade or spread to other
part of the body.
CHEMOTHERAPY: The use of chemicals or drugs to
treat cancer.
CYTOTOXIC DRUG: Drugs that lysis both normal and
cancer cells

3. cell cycle:
It is a series of
events that takes
place in a
proliferating cell
(normal and
malignant ) leading
to its division and
duplication

4. G0: RESTING
When the cell get a signal
to reproduce, they move
into the G₁ Phase.
Limitation to successful
eradication of many
tumours by
chemotherapy:
They re-enter the cycle
after therapy.
INTERPHASE
:
G0, G1, S,
G2

5. G₁ PHASE (Pre-synthetic
phase):
The cell starts to produce
proteins and enzymes
necessary for DNA
synthesis.
During this phase, RNA
synthesis occurs.

6. S-PHASE (synthetic phase)
DNA synthesis
Cellular DNA is duplicated
in preparation in
preparation for cellular
division.
A weak link, and large
number of anticancer agent
act.

7. G₂ Phase (pre-mitotic
phase):
The cell checks the DNA
Gets ready to start splitting
into 2 cells
Here both protein, RNA,
and the precursors to the
mitotic spindle apparatus
are produced.

8. MITOTIC PHASE:
In this phase, which last
only 30-60min, the cell
actually split into 2 new
cells.
Mitotic phase:
PROPHASE
METAPHASE
ANAPHASE
TELOPHASE

9. Summary

11. Major classes of anti-cancer drugs
Cell Cycle-Specific (CCS) Agents Cell Cycle-Nonspecific (CCNS) Agents
Antimetabolites (S phase)
Folic acid analogue
Methotrexate (MTX)
Pralatrexate
Purine analogues
6-Mercaptopurine (6-
MP)
6-Thioguanine (6-TG)
Fludarabine
Cladribine
Clofarabine
Nelarabine
Pyrimidine analogue
Cytarabine (ara-C)
5-Fluorouracil (5-FU)
Gemcitabine
Capecitabine
Vinca alkaloids (M phase)
Vinblastine
Vincristine
Vinorelbine
Alkylating agents
Altretamine
Bendamustine
Busulfan
Carmustine
Estramustine
Chlorambucil
Cyclophosphamide
Ifosphamide
Dacarbazine,
procarbazine
Lomustine
Mechlorethamine
Melphalan
Temozolomide
Thiotepa
Streptazocin
Anthracyclines
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Mitoxantrone
Taxanes (M phase)
Albumin-bound paclitaxel
Cabazitaxel Exabepilone
Docetaxel
Paclitaxel
Platinum analogs
Carboplatin,
Cisplatin,
Oxaliplatin
Topoisomerase II inhibitor
(G1–S)-Epipodophyllotoxins
Etoposide, Teniposide
Antitumor
antibiotics
Dactinomycin,
Mitomycin,
Bleomycin,
Daunorubicin,
Idarubicin,
Doxorubicin,
Epirubicin,
Mitoxantrone,
Topoisomerase I inhibitor-
(Camptothecins, G2-M)
Irinotecan,
Topotecan
Antitumor antibiotics Microtubule inhibitor (G2-M Protein tyrosine kinase Monoclonal

14. Cells in s-phase are more
sensitive to the cytotoxic
effects of Mtx.
RNA & Protein synthesis is
also inhibited.
Arrest: G1 to S phase
Leucovorin (folinic acid)
rescues normal cells from
toxicity, as normal cells are
affected by high dose of
mtx only.
Folic acid analogue

15. 6-mercaptopurine
ribosephosphate
Purine analogue
Nonfunctional RNA/DNA
Fludarabin
e
Cladribine
Clofarabine
Nelarabine
Converted intracellularly by
de-oxycitidine kinase to an
active metabolite which
exhibits its cytotoxicity by
fraudulent incorporation
into DNA

16. Pyrimidine analogue:
Cytarabine (ara-C)
5-Fluorouracil (5-FU)
Gemcitabine
Capecitabine

17. Bleomycin: Binds to DNA, generates free radicals, and induces
DNA cleavage via deoxyribose ring damage.
Bleomycin is a small peptide
It contains a DNA-binding region and an iron-binding domain at
opposite ends of the molecule.
It acts by binding to DNA, which results in single- and double-
strand breaks following free radical formation, and inhibition of
DNA biosynthesis.
The fragmentation of DNA is due to oxidation of a DNA-
bleomycin-Fe(II) complex and leads to chromosomal aberrations.
Bleomycin is a cell cycle-specific drug that causes accumulation
of cells in the G2 phase of the cell cycle.
Bleomycin binds Fe2+ and then intercalates with DNA, resulting in damage by free radicals

18. Taxanes:
Stabilization of microtubules,
Prevents microtubule polymerization &
Disrupt mitotic spindle formation
G2 & metaphase arrest.

19. Camptothecans (topoisomerase I
inhibitors)(G2-M):
Topotecans:
Irinotecans
Epipodophyllotoxins (topoisomerase II inhibitors)(G1-S):
Etoposide,
Teniposide
Inhibit topoisomerase action and NA synthesis.

20. ENZYME
L-
asparaginase:
Cell death in
G1-phase
Required for protein
synthesis

22. Ixabepilone (semisynthetic analogue) binds to
tubulin and promotes tubulin polymerization and
microtubule stabilization, thereby arresting cells
in the G2-M phase of the cell cycle and inducing
tumor cell apoptosis.
Eribulin inhibits the formation of mitotic spindles and
blocks cell cycle progression at the G 2 /M phase,
resulting in apoptotic cell death .
MICROTUBULE INHIBITOR (NON-TAXANE)(G2-M Inhibitor):

23. Binds to microtubular proteins and inhibit the
polymerization of tubulin….
Disruption of microtubule assembly leading to
metaphase arrest.
Vinca alkaloids:
Vincristine
Vinblastine
Vinorelbine

24. Alkylating agents act by cross-linking strands of DNA, particularly at the N-7 position of guanine.
They are nonspecific for cell cycle phase
CARMUSTIN
E
ALKYLATING AGENTS

25. Cisplatin, carboplatin, oxiplatin
Platin analogues:
They form platinum coordination complex or platin-adducts
Additionally oxiplatin also blocks DNA-replication and
transcription

26. Miscellaneous:
Hydroxy-urea:
Inhibit ribonucleotide reductase enzyme and prevents
conversion of ribonucleotides to deoxynucleotides & impair
DNA synthesis.
S-phase/G1-S phase inhibitor

27. Miscellaneous:
Procarbazine:
Alkylating metabolite, methylates RNA, DNA & Protein
synthesis.
CELL CYCLE NON-SPECIFIC

28. Miscellaneous:
Hexamethyl melamine (HMM) or Altretamine:
Inhibit incorporation of thymidine & uridine into DNA &
RNA, inhibiting their synthesis.
CELL CYCLE NON-SPECIFIC

29. Miscellaneous:
ARSENIC TRIOXIDE:
Promote apoptosis by upregulating the genes involved in
apoptosis.
CELL CYCLE NON-SPECIFIC

30. Miscellaneous:
Thalidomide:
Inhibit angiogenesis, prevent tumor growth and metastasis.

31. Imatinib (+ c-kit)
Dasatinib
Nilotinib (c-kit)
Lepatinib (HER2/neu)
Causes apoptosis or growth arrest in cells
expressing Bcr-Abl oncoprotein.
Tyrosine kinase inhibitor:

33. Gftinib (Iressa)(EGFR-TK)
Sorafenib (VEGF-inhibitor)
Sunitinib (VEGF-inhibitor)
Eriotinib (VEGF-inhibitor)
Erlotinib (VEGF-inhibitor)
Causes apoptosis or growth arrest in cells
expressing Bcr-Abl oncoprotein.
EGFR/factor inhibitor:

34. Bortezomib:
PROTEOSOME inhibitor:
Gn RH agonists
Goserelin
Buserelin
Leuprolide
Hormones and antagonists:
Gn RH antagonists
Cetrorelix
Ganorelix
Abarelix

35. Adrenocortical suppressants
Aminoglutethimide
Trilostane
Corticosteroids
Dexamethasone
Prednisolone

36. Estrogen receptor antagonists:
Tamoxifen
Toremifen
Fulvestrant
Aromatase inhibitor: (for ER-Positive)
Anastrozole
Letrozole
Exomestene
Androgen receptor antagonists:
Flutamide
Bicalutamide
Nilutamide
Progestins
Estrogens
Androgens
Protectants (GM-CSF)

37. Malignant cells express tumor associated antigens on their
surface.
Monoclonal antibody recognizes specifically that antigen.
Chimerised or humanized antibody used for treatment.
Rituximab Trastuzumab
Cetuximab Alemtuzumab
These target and block selected growth factor receptors to
prevent growth rate.
MONOCLONAL ANTIBODIES:

38. Trastuzumab: Epidermal GFR protein-2
Cetuximab: Inhibit binding of Epidermal GF to EGF-receptor
Bevacizumab: Inhibit binding of VEGF to VEGF-receptor
Biological ‘smart bomb’ carrying ……..:
Radio-immuno conjugates-
Ibritumomab
Tostitumomab
Cytotoxic conjugates of MAb-
Gemtuzumab-ozogamicin
Denileukin-diftitox
MONOCLONAL ANTIBODIES:

39. 39
Herceptin (Trastuzumab)–
targets HER2/neu, a growth factor receptor
Gleevec (Imatinib) – targets tyrosine kinase enzymes
Iressa (Gefitinib) –
targets the epidermal growth factor (EGFR)
Tarceva (Erlotinib)-
targets epidermal growth factor receptor (EGFR)
Lapatinib –
HER2/neu and epidermal growth factor receptor (EGFR)
Avastin (Bevacizumab) - targets circulating VEGF ligand