Q: What are the 3 major approaches to treating common solid tumours? A: Surgery Radiotherapy Chemotherapy Q: True or false? Cancer drugs specifically recognise and target cancer cells. A: False. Cancer drugs are cytotoxic to all proliferating cells in cycle. Q: What are 7 mechanisms of resistance to cancer chemotherapy? A: * Permeability mutants (contain plasma membrane proteins which pump drugs out of the cell) * Up-regulation of target proteins (side-stepping metabolic blocks) * Mutation of target proteins (uncommon) * Down-regulation of target genes (e.g. hormon dependent tumours stop expressing hormone receptor and are no longer hormone dependent) * Repair of DNA lesions (made by the anticancer drugs) * Chemical inactivation of the drugs * Deregulation of apoptosis (particularly p53 and BCL2) Q: What are the 4 main classes of drugs used in cancer treatment? A: * Antimetabolites (anti-folates, purine and pyrimidine analogues) * Hormones and Hormone antagonists * Mitotic spindle inhibitors * DNA binding agents (intercalating and alkylating agents) Q: How does methotrexate work? A: Methotrexate is a derivative analogue of folic acid which antagonises the enzyme dihydrofolate reductase. This leads to a depletion of tetrahydrofolic acid and an inhibition of purine nucleotide and thymidylate synthesis. These are required for DNA synthesis and cell division. Q: What is the main toxicity of methotrexate? A: Myelosuppression. Q: What are the 2 major pyrimidine inhibitors of DNA synthesis? A: * 5-fluorouracil (5FU) * Cytarabine (cytosine arabinoside) Q: How does 5-fluorouracil (5FU) work? A: 5FU is converted into the fraudulent nucleotide fluorodeoxyuridine monophosphate (FdUMP) which inhibits a critical enzyme in DNA synthesis, Thymidylate synthase. Q: How does cytosine arabinose (cytarabine) work? A: Cytarabine is an analogue of cytidine. It is partially incorporated into DNA and RNA but its main cytotoxic action is to inhibit DNA polymerase. Q: What are the main toxicities of 5FU? A: * Myelosuppression * Gut epithelial damage Q: What are the main toxicities of cytosine arabinose? A: * Bone marrow * Gut Q: What are 3 purine inhibitors of DNA synthesis? A: * Mercaptopurine * Thioguanine * Hydroxyurea Q: How do mercaptopurine and thioguanine work? A: They are converted into fraudulent nucleotides which inhibit various steps in de novo purine synthesis and antagonise the enzyme ribonucleotide reductase (a key enzyme in DNA synthesis). Q: What are the side effects of mercaptopurine, thioguanine and hydroxyurea? A: * Bone marrow toxicity * Gut toxicity Q: How are glucocorticoids useful in cancer therapy? A: Glucocorticoids have inhibitory effects on lymphocyte proliferation and are used in treating lymphomas and leukamias. They also play a supportive role in the treatment of other cancers because of their positive effects on calcium metabolism. Q: What types of cancer are oestrogens used in the treatment of? A: Oestorgens are used to block the effects of androgens in androgen dependent prostatic tumours. Q: What types of cancer are progestogens used in the treatment of? A: Endometrial tumours. Q: What is tamoxifen and what is it used to treat? A: Tamoxifen is an oestrogen-receptor antagonist and has been very effective in treating some cases of pre-menopausal hormone-dependent breast cancer and endometrial tumours. (Being explored as a prophylatic agent in the prevention of breast cancer.) Q: What are flutamide and cyproterone and what are they used to treat? A: Flutamide and cyproterone are androgen receptor antagonists. They are effective in the treatment of prostate cancer. Q: What types of cancer are hormone synthesis inhibitors used in the treatment of? A: Several agents which inhibit the synthesis of adrenal hormones have effects in post menopausal breast cancer. Q: What is Formestane? A: Formestane is a late stage sex hormone synthesis inhibitor which acts by inhibiting aromatase, which is the enzyme that converts androgens to oestrogens. Q: What are trilostane and aminoglutethimide? A: Trilostane and aminoglutethimide are early stage hormone synthesis inhibitors which inhibit the conversion of cholestreol into corticosteroids. Q: Name 3 examples of the vinca alkaloids. A: * Vincristin * Vinblastin * Vindesin Q: How do the vinca alkaloids work? A: The vinca alkaloids are inhibitors of tubulin polymerisation and therefore inhibit spindle formation during mitosis. They also inhibit other cellular activities involving microtubles such as leukocyte phagocytosis and chemotaxis as well as axonal transport in neurones. Q: What are the side effects of the vinca alkaloids? A: The vinca alkaloids are relatively non toxic, generally having a mild myelosuppressive activity but they cause sensory changes and neuromuscular abnormailities fairly frequently. Q: What are the taxanes and how do they work? A: The taxanes (of which Taxol is the best known example) are inhibitors of tubulin depolymerisation. Microtubules are dynamic structures that have to be assembled and dismantled again during mitosis. The taxanes are generally more toxic than the vinca alkaloids and side effects includemyelosuppression and sensory perturbation. Q: What are 2 examples of clinically used basic aminoacridines? A: * 9-aminoacridine * Provflavine Q: What are 2 examples of clinically used quaternary phenanthridines? A: * Ethidium * Propridium Q: What are 2 examples of clinically used anthracyclins? A: * Daunomycin * Adriamycin Q: What is an example of a clinically used anilinoacridine? A: Mitoxantrone. Q: What is an example of a clinically used phenoxazone depsipeptide? A: Antinomycin D. Q: How do anticancer intercalating agents work? A: Intercalating agents are flat planar molecules that insert themselves in between DNA basepairs. Intercalators stabilise the DNA duplex to thermal melting because they bind more tightly to double stranded DNA than single stranded DNA. They inhibit RNA polymerase activity but not DNA polymerase and their main action but their MAIN ACTION IS TO POISON THE ACTIVITY OF TOPOISOMERASE II. Q: What is the notable feature of anthracyclines in relation to the heart? A: Anthracyclines have a peculiar dose-limiting irreversible and lethal cardiomyopathy. Q: What are the main toxicities of the DNA intercalating agents? A: * Myelosuppression * Damage to gut epithelium Note: Anthracyclines have a peculiar dose-limiting irreversible and lethal cardiomyopathy. Q: How do alkyating agents work? A: Alkylating agents bing irreversibly to DNA and function by cross linking the two Watson-Crick strands, thereby inhibiting strand separation and preventing replication. Q: What are the 3 types of alkylating agents studied in UNSW med III pharmacology? A: * Nitrogen mustards * Nitrosoureas * Cisplatin Q: What are nitrogen mustards? A: Nitrogen mustards are chemically reactive chloroethylamines that prinicpally bind to the N7 nitrogen atom of guanine bases in the DNA major groove. Q: How are the nitrogen mustards used in cancer therapy thought to act? A: Nitrogen mustards with antitumour activity are bifunctional compounds and work by forming an interstrand crosslink between two guanines of opposing strands. This lesion inhibits DNA replication and induces the cell to engage in apoptosis. Q: Why is it said that clinically effective nitrogen mustards are somewhat "deactivated"? A: Simple nitrogen mustard are very chemically reactive and are de-activate by rapid hydrolysis and by binding to amine and sulfur groups on proteins. Therefore, clinically effective agents are somewhat "deactivated" so that they are less reactive and hence more of them reach the DNA in an active form. Q: What are the 3 major clinically used nitrogen mustards? A: * Melphalan * Chlorambucil * Cyclophosphamide Q: Why might cyclophosphamide not work well to destroy dividing cells in vitro? A: Cyclophosphamide is a prodrug that is activated in the liver by cytochrome p-450 to produce the active compound phosphoramide mustard. Q: How do cells become resistant to alkylating agents? A: * Repairing the DNA lesion (a variety of mechanisms) * Upregulating thiol containing compounds (such as glutathione and metallothiones) Q: What are the main toxicities of the nitrogen mustards? A: Bone marrow and gut suppression. Q: What are the two best know chloronitrosoureas? A: * Carmustine * Lomustine Q: How do chloronitrosoureas work? A: Chloronitrosoureas are composed of a cholorethyl group and a nitrosourea which spontaneously decompose in water to yield a chloroethonium ion, nitrogen gas and an isocyanate. The chloroethonium ion reacts first react with the N7 of guanine in DNA then the adduct rearranges and alkylates the N3 of the basepaired cytosine. This forms an interstrand crosslink inhibiting DNA replication and inducing the cell to engage in apoptosis. Q: True or false? The Nitrosoureas cross the blood-brain barrier but are not active against brain tumours because of the high levels of thiol compounds present in neural tissue. A: False. The Nitrosoureas cross the blood-brain barrier and *are* active against brain tumours. Q: How does cisplatin work? A: Cisplatin hydrolyses in water to yield a positively reactive charged diamino aquo species that resembles alkylating mustards. It attacks the N7 atoms of guanineforming interstrand and intrastrand crosslinks. Note: Hydrolysis of cisplatin is suppressed in blood by saline and the drug passes uncharged into cells where the lower chloride level permits hydrolysis. Q: What are the main toxicities of cisplatin? A: * Kidney * Ear Note: Patients should where possible by hydrated before administration of cisplatin to minimise kidney damage.