Topic

08.09.11 Luisa Robbez-Masson

Cancer Chemotherapies

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.

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

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

Selective toxicities

drugs toxicity

anthracyclines cardiomyopathy

asparaginases anaphylaxis, pancreatitis

cisplatin renal toxicity and neurotoxicity

cyclophosphamide hemorrhagic cystitis

mitomycin endothelial cell injuries

monoclonal Antibodies hypersensitivity reactions

paclitaxel neurotoxicity, acute hypersensitive reactions

VEGF inhibitorsgastrointestinal perforation, impaired wound healing

vinca alkaloids neurotoxicity

CLASSICAL ANTICANCER AGENTS

Presented according to the point in the cell cycle at which they are most active.

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.

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.

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

Deoxyuridine monophosphate

Deoxythymidine monophosphate

5-FU

X

MethotrexateX

Thymidine Synthesis

Purine precursor

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

anthracyclines

• Topo uncoils the DNA: prevent tangleling of daughter DNA strand and maintain DNA topology.

• In the presence of Anthracyclines, topo II remain bound to the 5’ end of the DNA, preventing rejoining of the DNA breaks

Cardiotoxicity !Creation of free radicals

Topoisomerase inhibitors

• 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).

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)

EnzymesAsparaginase

• 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.

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.

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

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

• 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.

G1

M

S

G2 G0

Mitotic poison/tubulin inhibitorsPrevent formation of the mitotic spindle by binding to tubulin subunits. e.g. Vincristine, paclitaxel

G0 phaseCell in the resting phase are frequently refractory to treatment because most anticancer drugs target cells with high rate of proliferation

AntimetabolitesAnalogue of nucleic acid bases which are converted into nucleotides and incorporated into DNA. e.g. Methotrexate, 6-mercaptopurine and cytarabine

Topoisomerase inhibitorsInhibit TOPO I, e.g. CamptothecinsInhibit TOPO II, e.g. Epipodophyllotoxins. Interfering with enzyme active during DNA replication.

Cell cycle phase-independent agents

Alkylating agentsCreation of cross-links in ds DNA. Act at any point other than S-phase. E.g. Carmustine, cisplatin and cyclophosphamide.

Intercalating agents Planar conpounds intercalating between adjacent bases or external groove of DNA double helix. E.g. Doxorubicin, bleomycin and mitomycin C.

Summary

NOVEL ANTICANCER AGENTS

Tyrosine kinase inhibitors• ATP-binding cleft is the target for rationally

designed small molecules TK inhibitors• Structural analogue of ATP • e.g. Imatinib (Glivec, bcr-abl inhibitor)• Flavonoids are naturally occurring ATP

analogues• Targeting angiogenesis (gefitinib, EGFR

inhibitor)• Non-specific interactions are possible• Multi-kinase inhibitor: sunitinib

– VEGFR, Flt-3, PDGFR, c-kit, stem-cell factor receptor, Fms-like RTK3.

• Monoclonal Ab target the extracellular ligand binding domain– Herceptin (trastuzumab)– Cetuximab (EGFR)

2004

• Targeting HER2/EGFR– Herceptin (trastuzumab) FAO approval 1998

– Iressa (gefitinib, EGFR inhibitor, treatment NSCLC)– Lapatinib (dual inhibitor HER2/EGFR)

Treatment of Her2 positive breast cancer

• 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

Ras inhibitors

PROMISING TARGETS

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:

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

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

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.

Nanoparticles: the “magic bullet”

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?