MD204_23-24_Cancer+chemotherapy+Lecture+1.pdf

Cancer Chemotherapy I Dr Oliver Treacy Lecturer Discipline of Pharmacology & Therapeutics [email protected] Lecture 1 Cancer Chemotherapy (4 lectures) The disease and important concepts Targeting cell proliferation with cytotoxic drugs How cytotoxic drugs kill cells Targeting nucle...

Cancer Chemotherapy I Dr Oliver Treacy Lecturer Discipline of Pharmacology & Therapeutics [email protected] Lecture 1 Cancer Chemotherapy (4 lectures) The disease and important concepts Targeting cell proliferation with cytotoxic drugs How cytotoxic drugs kill cells Targeting nuclear receptors Targeting enzymes Immunotherapies Cancer statistics (Europe) Cancer statistics (US) CA A Cancer J Clinicians. DOI: (10.3322/caac.21763) Tumour development Cancers arise by the stepwise accumulation of mutations and epigenetic factors that alter gene expression to confer the so-called ‘hallmarks of cancer’ Hallmarks of cancer The six hallmarks of cancer—distinctive and complementary capabilities that enable tumor growth and metastatic dissemination—continue to provide a solid foundation for understanding the biology of cancer Adapted from Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000. Emerging hallmarks of cancer Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011. The pathogenesis of cancer Cancer cells manifest, to varying degrees, four characteristics that distinguish them for normal cells. These are: – – – – Uncontrolled proliferation De-differentiation and loss of function Invasiveness Metastasis Uncontrolled proliferation Cancer cells don’t necessarily proliferate faster than normal cells The issue is that cancer cells have escaped from the mechanisms that normally regulate cell division and tissue growth; the normal brakes on cell division, present in a healthy cell, have been cut Inactivation of tumour suppressor genes or transformation of proto-oncogenes into oncogenes can confer autonomy of growth on a cell and thus result in uncontrolled proliferation by producing changes in cellular systems Uncontrolled proliferation These include: – growth factors, their receptors and signalling pathways – the cell cycle transducers, for example, cyclins, cyclin-dependent kinases (cdks) or the cdk inhibitors – the apoptotic machinery that normally disposes of abnormal cells – telomerase expression – local blood supply, resulting from tumour-directed angiogenesis Uncontrolled proliferation Uncontrolled proliferation The genesis of cancer is usually multifactorial, involving more than one genetic change. ‘Other factors’, as mentioned in the diagram, may involve the actions of promoters, cocarcinogens, hormones, etc., which, while not themselves carcinogenic, increase the likelihood that genetic mutation(s) will result in cancer Uncontrolled proliferation Colon Carcinogens Tobacco Mutations Radiation Viruses X-rays (inherited) Asbestos Hep B/C HPV Epstein Barr virus The pathogenesis of cancer Cancer cells manifest, to varying degrees, four characteristics that distinguish them for normal cells. These are: – – – – Uncontrolled proliferation De-differentiation and loss of function Invasiveness Metastasis De-differentiation and loss of function Multiplication of normal cells in a tissue begins with the division of undifferentiated stem cells, giving rise to two daughter cells, one of which differentiates to become a mature non-dividing cell, ready to perform functions appropriate to that differentiated tissue One of the main characteristics of cancer cells is that they de-differentiate to varying degrees In general, poorly differentiated cancers carry a worse prognosis than well-differentiated cancers The pathogenesis of cancer Cancer cells manifest, to varying degrees, four characteristics that distinguish them for normal cells. These are: – – – – Uncontrolled proliferation De-differentiation and loss of function Invasiveness Metastasis Invasiveness Normal cells, other than those of the blood and lymphoid tissues, are not generally found outside their ‘designated’ tissue of origin This is because, during differentiation and tissue or organ growth, they develop certain spatial relationships with respect to each other These relationships are maintained by various tissuespecific survival factors that prevent apoptosis. In this way, any cells that escape accidently lose these survival signals and die The pathogenesis of cancer Cancer cells manifest, to varying degrees, four characteristics that distinguish them for normal cells. These are: – – – – Uncontrolled proliferation De-differentiation and loss of function Invasiveness Metastasis Metastasis Metastases are secondary tumours formed by cells that have been released from the initial or primary tumour and which have reached other sites through blood vessels or lymphatics Often, the primary tumour is asymptomatic and it is not until the cancer spreads that the secondary tumours cause symptoms leading to diagnosis of illness As such, metastases are the principal cause of mortality and morbidity in most solid tumours and constitute a major problem for cancer therapy Evolution of cancer treatments Falzone L, Salomone S, Libra M. Evolution of Cancer Pharmacological Treatments at the Turn of the Third Millennium. Front Pharmacol. 2018 Evolution of cancer treatments Falzone L, Salomone S, Libra M. Evolution of Cancer Pharmacological Treatments at the Turn of the Third Millennium. Front Pharmacol. 2018 The goals of cancer chemotherapy Cure Control Palliate Kill cancer cells Prolong remission Relieve symptoms Complete remission Decrease rate of relapse Improve quality of life Depend on selectivity ? Selectivity and cytotoxic cancer chemotherapy Estimated that 3 x 109 normal cells divide each day in an adult Cells proliferate by completing a series of highly organized steps called the “cell cycle” Cancer a disease of cell proliferation Selectivity through targeting rapidly proliferating cells S G1 G2 M Cytotoxic chemotherapy vs targeted therapies Cytotoxic drugs Targeted drugs They typically react with cellular They have a pharmacological mode macromolecules of action (binding a target) Act on normal and cancerous Act on specific molecular targets cells that are proliferating that are associated with cancer (limited selectivity) Were identified because they kill Are deliberately chosen or designed cells to interact with their target Cancer Chemotherapy Targeting Proliferation Targeting proliferation Purines Pyrimidines 6-mercaptopurine Methotrexate Ribonucleotides Hydroxyurea 5-Fluorouracil Camptothecins Epipodophyllotoxins Antibiotics Deoxyribonucleotides DNA replication DNA RNA Cytarabine Fludarabine Alkylating agents Platinum compounds L-Asparaginase Proteins Vinca alkaloids Taxenes e.g. Kinase inhibitors Cell behaviours/processes Chromosome segregation Protein homeostasis Cell survival signalling After Goodman and Gilman’s the Pharmacological Basis of Therapeutics, 11 th ED Bortezomib Cytotoxic chemotherapy S-phase specific Doxorubicin Etoposide 5-FU S Selectivity through targeting rapidly proliferating cells Some therapies target specific phases, some do not G1 Act in all phases Cisplatin Cyclophosphamide G2 M M-phase specific Vincristine Vinblastine Taxol Main classes of cytotoxic chemotherapy Alkylating agents and related compounds, which act by forming covalent bonds with DNA and thus impeding replication – Cyclophosphamide – Cisplatin Antimetabolites which block or subvert one or more of the catabolic pathways i.e. supply chain) involved in DNA synthesis – 5-Fluorouracil Natural products – Vincristine – Etoposide – Doxorubicin Alkylating agents The effects of bifunctional alkylating agents on DNA. Note the cross-linking of two guanines. A, adenine; C, cytosine; G, guanine; T, thymine. Nitrogen mustards Nitrogen mustards are an important type of alkylating agent, discovered early in the history of cancer chemotherapy (and related to the ‘mustard gas’ used in World War I) In the body, each 2-chloroethyl side-chain undergoes an intramolecular cyclisation with the release of a Cl −. The highly reactive ethylene immonium derivative so formed can interact with DNA and other molecules Ethylene immonium R-N-bis-[2-chloroethyl Nitrogen mustards Drug names Diseases Cyclophosphamide Broad application Mechlorethamine Hodgkin’s disease; non Hodgkin’s lymphoma Chlorambucil Chronic lymphocytic lymphoma Melphalan Multiple myeloma, ovarian and breast Mechanism of action Alkylating agents Alkylating agents Cyclophosphamide Alkylates proteins – – – – BIS-2-chloroethylamino group is essential for drug activity Chloro atom provides maximum activity Amino groups Carboxyl groups Sulphydryl Imidazole groups Nucleic acids alkylated – Alkylation of N7 of guanine appears most pharmacologically relevant http://www.slideshare.net/ganeshmote1/medicinal-chemistry-of-anticancer-agents Structure-activity relationships Side chain (R) affects the reactivity of the mustard R -N CH2-CH2-Cl Mechlorethamine CH2-CH2-Cl Basic formula of a nitrogen mustard Chlorambucil Increasing reactivity Melphalan Cylcophosphamide Structure-activity relationships Reactivity limits routes of administration and clinical usefulness Drug Route of admin Plasma half-life Mechlorethamine Iv (not im or sc) 1 min Chlorambucil Oral 90 mins Melphalan Oral 90 mins Cyclophosphamide Oral or iv 7 hours Drug Acute Delayed Mechlorethamine Vesicant (cause blistering), severe nausea, vomiting, phlebitis, local reaction Bone marrow depression (myelosuppression) Amenorrhea Chlorambucil Nausea, vomiting Myelosuppression Melphalan Mild nausea Myelosuppression Cyclophosphamide Nausea, vomiting, Myelosuppression, haemorrhagic cystitis, alopecia, neurotoxicity, water retention Cyclophosphamide metabolism Hepatic cytochrome P450 4-hydroxycyclophosphamide non enzymatic Aldophosphamide Phosphoramide + acrolein Nornitrogen mustard* 4-ketocyclophosphamide Carboxyphosphamide Aldehyde dehydrogenase Cyclophosphamide metabolism Normal tissues such as liver may be protected from cyclophosphamide by high levels of – Aldehyde dehydrogenase – Glutathione and Glutathione transferases Aldophosphamide Aldehyde dehydrogenase Nornitrogen mustard Glutathione-S-transferases Reaction with glutathione Carboxyphosphamide N7 guanine alkylation Insensitive cells Controlling the side effects of cyclophosphamide Haemorrhagic cystitis – Due to the metabolite acrolein (while anti-tumour activity is due to phosphoramide and Nornitrogen mustard) Control acrolein toxicity – Reduced by increase fluid intake – Prevented by administration of N-acetyl cysteine or mesna – Long term treatments always accompanied by mesna to mitigate against a bladder cancer risk