Cancer Chemotherapies Final

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Mini lecture on the topic of Cancer drugs

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  • 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.
  • Cancer Chemotherapies Final

    1. 1. Cancer Chemotherapies Topic08.09.11 Luisa Robbez-Masson
    2. 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. 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. 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
    5. 5. Selective toxicitiesdrugs toxicityanthracyclines cardiomyopathyasparaginases anaphylaxis, pancreatitiscisplatin renal toxicity and neurotoxicitycyclophosphamide hemorrhagic cystitismitomycin endothelial cell injuriesmonoclonal Antibodies hypersensitivity reactionspaclitaxel neurotoxicity, acute hypersensitive reactions gastrointestinal perforation, impaired woundVEGF inhibitors healingvinca alkaloids neurotoxicity
    6. 6. Presented according to the point in the cell cycle at which they are mostactive.CLASSICAL ANTICANCER AGENTS
    7. 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. 8. Alkylating agents (historical agents) Loss of chlorine radicalThey act by transferring an alkyl group to the N7guanine residues in DNA. Cross links result infragmentation of the DNA as a consequence ofthe action of DNA repair enzymes.
    9. 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. 10. Thymidine Synthesis 5-FU X Methotrexate X Deoxyuridine Deoxythymidine monophosphate monophosphate Purine precursor
    11. 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. 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. 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. 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. 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. 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 boneTamoxifen is a prodrug, having relatively little affinity for its target protein, theestrogen receptor. It is metabolised in the liver by the cytochrome P450 intoactive metabolites such as 4-hydroxytamoxifen (see Afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen).These active metabolites compete with estrogen in the body for binding tothe estrogen receptor. In breast tissue, 4-hydroxytamoxifen acts as an estrogenreceptor antagonist so that transcription of estrogen-responsive genes isinhibited.
    17. 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. 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. 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. 20. Summary Mitotic poison/tubulin inhibitors Prevent formation of the mitotic spindle by binding to tubulin subunits. e.g. Vincristine, paclitaxelCell cycle phase-independentagentsAlkylating agentsCreation of cross-links in ds DNA.Act at any point other than S- Mphase. E.g. Carmustine, cisplatinand cyclophosphamide.Intercalating agentsPlanar conpounds intercalating G2 G1 G0between adjacent bases orexternal groove of DNA doublehelix. E.g. Doxorubicin, bleomycinand mitomycin C. SAntimetabolitesAnalogue of nucleic acid bases which are converted into G0 phasenucleotides and incorporated into DNA. e.g. Cell in the resting phase are frequentlyMethotrexate, 6-mercaptopurine and cytarabine refractory to treatment because most anticancer drugs target cells with high rate ofTopoisomerase inhibitors proliferationInhibit TOPO I, e.g. CamptothecinsInhibit TOPO II, e.g. Epipodophyllotoxins.Interfering with enzyme active during DNA replication.
    21. 21. NOVEL ANTICANCER AGENTS
    22. 22. 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)
    23. 23. 2004
    24. 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. 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
    26. 26. PROMISING TARGETS
    27. 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. 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. 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. 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.
    31. 31. Nanoparticles: the “magic bullet”
    32. 32. 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?

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