2. Principles of cancer chemotherapy
• The aim of cancer chemotherapy is to induce
remission (complete eradication of the disease
for at least 1 month)
• The challenge is to prevent recurrence (may
occur locally or at a distance-metastasis)
• Short and long-term toxicity remain a
problem.
• Follow guidelines set by the European Society
for Medical Oncology (ESMO) for instance.
3. Classification of chemotherapy (timing)
• Induction
– Initial therapy, aim of achieving significant cytoreduction
• Consolidation/intensification
– Consolidation uses the same drug as induction
– Intensification uses drugs that are non-cross resistant
• Adjuvant
– Following surgery of radiotherapy
• Neoadjuvant
– Given prior surgery to maximise efficacy
• Maintenance
– Prolonged, low dose
• Salvage
– Given after failure of other treatment
• Combination
– Maximise tumour cell kill using drugs with different mode of actions
– Decrease toxic effect
Clinical biomarkers are used to select and monitor cancer treatment
4. Common acute toxicity
• Myelosuppression
• Nausea, vomiting and other gastrointertinal effects
• Mucous membrane ulceration
• Alopecia
Late organ toxicities
• Cardiac
• Pulmonary
• Nephrotoxicity
• Neurotoxicity
• Hematologic and immunologic impairement
• Second malignancies
• Premature menopause, endocrine problems (thyroid)
• infertility
6. Presented according to the point in the cell cycle at which they are most
active.
CLASSICAL ANTICANCER AGENTS
7. 1. Alkylating agents (historical agents)
• Includes nitrogens mustards and platinum
based alkylating agents among others.
• They impair cell function by forming covalent
bonds with the
amino, carboxyl, sulfhydryl, and phosphate
groups in biologically important molecules.
• e.g. Cisplatin
• prolonged use of alkylating agents can lead to
secondary cancers, particularly leukemias.
8. Alkylating agents (historical agents)
Loss of chlorine radical
They act by transferring an alkyl group to the N7
guanine residues in DNA. Cross links result in
fragmentation of the DNA as a consequence of
the action of DNA repair enzymes.
9. 2. Anti-metabolites
• Have a similar structure to substrate involve of enzymes
involve in DNA synthesis. They disrupt DNA structure
and functionality, leading to cell death.
– Structural analogues of precursor and intermediates
• dihydrofolate reductase (DHFR) inhibitors (Folic acid analogue:
methotrexane and trimethoprim)
– ‘false’ bases
• Purine analogue: 6-mercaptopurine
• thymidylate synthase inhibitors (pyrimidine analogue: 5-fluorouracil)
• Nucleoside analogue : gemcitabine
10. Thymidine Synthesis
5-FU
X
Methotrexate
X
Deoxyuridine Deoxythymidine
monophosphate monophosphate
Purine precursor
11. 3. Natural products:
Cytotoxic antibiotics
• Early example were produced by microorganisms
• Main group is Anthracyclines
• Cell cycle non-specific: use in the treatment of slow
growing tumours
• Diverse mode of action:
– Intercalation between DNA bases
– Production of free radicals
– Inhibition of topoisomerase II
– etc...
• Example: Mitomycin C (used against bladder tumours)
– Activated by tumour-specific enzymes
– Induce DNA cross-linking
12. Topoisomerase inhibitors
anthracyclines
• Topo uncoils the DNA: prevent • In the presence of
tangleling of daughter DNA Anthracyclines, topo II remain
strand and maintain DNA bound to the 5’ end of the
topology. DNA, preventing rejoining of the
DNA breaks
Cardiotoxicity !
Creation of free radicals
13. • Inhibition of type I or type II topoisomerases interferes
with both transcription and replication of DNA by
upsetting proper DNA supercoiling.
– type I topoisomerase inhibitors (cut 1 strand)
• include camptothecins.
– type II topoisomerase inhibitors (cut both strands)
• include amsacrine, etoposide, etoposide
phosphate, and teniposide.
• These are semisynthetic derivatives
of epipodophyllotoxins, alkaloids naturally occurring in
the root of American Mayapple (Podophyllum
peltatum).
14. Tubulin inhibitors
• Suppress microtubule dynamics and therefore
the function of the mitotic spindle.
• Vinca alkaloids (bind to the + end)
• Colchicine
• Taxanes (bind the interior surface of the
cylinder)
15. Enzymes
Asparaginase
• Convert L-asparagine to aspartate
• Leukaemic lymphoblast, lack L-asparagine
synthetase so L-asparagine becomes an
essential aa.
• They become sensitive to depletion of L-
asparagine by asparaginase.
• Induce death by inhibiting tumour protein
synthesis, leaving normal cells unaffected.
16. 4.Hormone therapy
• Many hormone dependent cancer, including breast, prostate,
ovary, uterus and testicules.
• Selective oestrogen receptor modulator (SERMs)
– Oestrogen and androgens are derived from cholesterol
– Tamoxifen: first oestrogen antagonist (non-steroid)
• Partial agonist effect in endometrium and bone
Tamoxifen is a prodrug, having relatively little affinity for its target protein, the
estrogen receptor. It is metabolised in the liver by the cytochrome P450 into
active metabolites such as 4-hydroxytamoxifen (see Afimoxifene) and N-
desmethyl-4-hydroxytamoxifen (endoxifen).
These active metabolites compete with estrogen in the body for binding to
the estrogen receptor. In breast tissue, 4-hydroxytamoxifen acts as an estrogen
receptor antagonist so that transcription of estrogen-responsive genes is
inhibited.
17. 4.Hormone therapy
• Many hormone dependent cancer, including
breast, prostate, ovary, uterus and testicules.
• Selective oestrogen modulator (SERMs)
– Oestrogen and androgens are derived from cholesterol
– Tamoxifen: first oestrogen antagonist
• Partial agonist effect in endometrium and bone
– Fulvestral (Faslodex, second generation) induce ER deregulation and dimerisation
18. 4.Hormone therapy
• Many hormone dependent cancer, including
breast, prostate, ovary, uterus and testicules.
• Selective oestrogen modulator (SERMs)
– Oestrogen and androgens are derived from cholesterol
– Tamoxifen: first oestrogen antagonist
• Partial agonist effect in endometrium and bone
– Fulvestral (Faslodex, second generation) induce ER deregulation and dimerisation
– Aromatase inhibitors
• Block the aromatisation of androgens
• Exemestane is used in adjuvant hormonal therapy of postmenopausal
ER positive early BC after Tamoxifen 2-3 year course
• Contraindicated in premenopausal women
19. • Anti-androgens
– Cyproterone (treatment of locally advanced prostate
cancer)
• Loss of sexual function
• Non-steroidal anti-androgens are more specific and display
less side-effects
• Endocrine therapy
– Manipulate the hypothalamus-pituitary axis
• Oestrogen agonist, GnRH agonist/antagonist
• Oestrogen agonists are used rarely, but reduced
cardiovascular toxicity
• Initially, increase production of testosterone, which is then
downregulated (tumour flare effect)
• Long term treatment with high concentration leads to
downregulation of GnRH receptors and inhibition of LH
release.
20. Summary Mitotic poison/tubulin inhibitors
Prevent formation of the mitotic spindle by binding to tubulin
subunits. e.g. Vincristine, paclitaxel
Cell cycle phase-independent
agents
Alkylating agents
Creation of cross-links in ds DNA.
Act at any point other than S-
M
phase. E.g. Carmustine, cisplatin
and cyclophosphamide.
Intercalating agents
Planar conpounds intercalating G2 G1 G0
between adjacent bases or
external groove of DNA double
helix. E.g. Doxorubicin, bleomycin
and mitomycin C.
S
Antimetabolites
Analogue of nucleic acid bases which are converted into G0 phase
nucleotides and incorporated into DNA. e.g. Cell in the resting phase are frequently
Methotrexate, 6-mercaptopurine and cytarabine refractory to treatment because most
anticancer drugs target cells with high rate of
Topoisomerase inhibitors proliferation
Inhibit TOPO I, e.g. Camptothecins
Inhibit TOPO II, e.g. Epipodophyllotoxins.
Interfering with enzyme active during DNA replication.
24. Treatment of Her2
positive breast cancer
• Targeting HER2/EGFR
– Herceptin (trastuzumab) FAO approval 1998
– Iressa (gefitinib, EGFR inhibitor, treatment NSCLC)
– Lapatinib (dual inhibitor HER2/EGFR)
25. Ras inhibitors
• Proto-oncogene occurring
in different forms:
– H-Ras, N-Ras and K-Ras
– coding for a GTPase
localise at the plasma
membrane and activates
growth factor mediated
signals
– Sunitinib (B-Raf inhibitor)
• Targeting multiple
oncogenic pathways via
inhibition of a single
critical oncogene
27. Synthetic lethality strategy
• PARP (poly ADP-ribose polymerase) inhibitors
• Alan Ashworth’s group
• Critical for Base excision repair (BER)
• BRCA1 mutations and inhibition of PARP:
28. Targeting the Akt/PKB pathway
• Pro-apoptotic activity in vitro via induction of caspases
• Perifosine (phase II clinical trial)
– Poor clinical response
– Now tested in combination therapy (with anti-angiogenic
agents)
Survival signal
29. c-Myc inhibitors
• Work pioneered by Gerard
Evan
• Transcription factor necessary
for growth and proliferation
• Mouse model of Ras-induced
lung carcinoma
• Concerns over side effect on
proliferative tissues
– Effect were reversible and well
tolerated
• Practical difficulties to design
anti c-Myc drugs
30. Omomyc: reshaping the Myc transcriptome
• In the presence of Omomyc, the Myc interactome is channeled to
repression and its activity appears to switch from a pro-oncogenic to a
tumour suppressive one.
33. Other targets
• Tumour hypoxia
• Antiangiogenic and antivascular agents
• Stress proteins HSP90
• The proteasome (ubiquitylation)
• Checkpoint protein kinase (rapamycin and mTOR)
• Telomerase
• Histone deacetylase (epigenetic targets)
• FGFR inhibitors?
Editor's Notes
Tamoxifen compete with estrogen for binding sites. Tamoxifen itself is a prodrug, having relatively little affinity for its target protein, the estrogen receptor. It is metabolized in the liver by the cytochrome P450 isoformCYP2D6 and CYP3A4 into active metabolites such as 4-hydroxytamoxifen (see Afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen)[23] which have 30-100 times more affinity with the estrogen receptor than tamoxifen itself. These active metabolites compete with estrogen in the body for binding to the estrogen receptor. In breast tissue, 4-hydroxytamoxifen acts as an estrogen receptor antagonist so that transcription of estrogen-responsive genes is inhibited.
Tamoxifen compete with estrogen for binding sites. Tamoxifen itself is a prodrug, having relatively little affinity for its target protein, the estrogen receptor. It is metabolized in the liver by the cytochrome P450 isoformCYP2D6 and CYP3A4 into active metabolites such as 4-hydroxytamoxifen (see Afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen)[23] which have 30-100 times more affinity with the estrogen receptor than tamoxifen itself. These active metabolites compete with estrogen in the body for binding to the estrogen receptor. In breast tissue, 4-hydroxytamoxifen acts as an estrogen receptor antagonist so that transcription of estrogen-responsive genes is inhibited.