Chemotherapy Of Cancer And Infections

Front 1

Name the three classes of biochemical reactions

Back 1

- Phase 1 = Generation of energy and small compounds ( Not great targets as common in all organisms - e.g. glucose metabolism as energy source and bacteria can use amino acids and lactate)
-Phase 2 = Generation of necessary small molecules e.g. amino acids, nucleotides, phospholipds, amino sugars and carbohydrates - (folate synthesis pathway)
-Phase 3 = Generation of macromolecules e.g. proteins, RNA, DNA, Polysacchardies and peptidoglycan (cell wall)

Front 2

Why is folate a good target for chemotherapy against bacteria?

Back 2

-Folate is oxidised into tetrahydrofolate which is required as a cofactor to thymidylate synthetase for uracil to be converted to thymine.
-Folate synthesis occurs in bacteria but not man, humans derive folate from folic acid in diet and have transporters to transport into cell ;bacteria does not have transporters
- Sulphonamides inhibit folate synthesis - (Sulfamethoxazole, Sulfadoxine, Sulfadimidine are examples - all have Sulfa as prefix when antimicrobials)

Front 3

Name some features unique to bacteria

Back 3

- Peptidoglycan cell wall
-No nucleus
-No mitochondria as energy genration occurs in plasma membrane
-Have 50s and 30s subunit ribosomes as opposed to the 60s and 40s subunits - (allowing protein synthesis to be a target for therapy)

Front 4

Name three drug classes which inhibit nucleotide synthesis

Back 4

- sulphonamides
-dihydrofolate reductase inhibitors
-pyrimidine and purine analogues

Front 5

How can the base-pairing properties of a nucleic acid be changed?

Back 5

-the DNA can be intercalted in order to cause frame shift mutations - e.g. proflavine and acriflavine are used as anti-septics

Front 6

Name some DNA/RNA polymerase inhibitors and there mechanisms of action

Back 6

- Actinomycin D blocks moverment of RNA polmerase in man and is used in cancer chemo
_ rifamycin and rifampicin inhibit bacterial RNA polymerase
-Acyclovir is a analogue of guanine which is turned into acyclovir triphophate by herpes virus proteins which selectively inhibits DNA polymerase of the herpes virus
-Cytarabine is a inihibitor of mammalian DNA polymerase

Front 7

What is another name for topoisomerase 2, what is its function and name some drugs which target it?

Back 7

-Topisomerase 2 is also known as DNA gyrase, it relieves tension from a positively supercoiled DNA as it is being unwound by inserting a negative supercoil by slicing the DNA strand on both sides , think of the string animation.
-fluorquinolones inhibit bacterial DNA gyrase
-Doxorubicin inhibits mammalian DNA gyrase

Front 8

Name some agents which directly effect DNA and how they are used?

Back 8

Alkylating agents form covalent bonds with bases and prevent DNA replication , they are used in cancer chemotherapy

Front 9

Name the 7 hallmarks of cancer

Back 9

-uncontrolled proliferation
-Dedifferentiation and loss of function
-Invasiveness
-Metastasis
_evasion of apoptosis (cell suicide)
-Induction of angiogenesis
-Failure to senesce (grow old)

Front 10

Name two main categories of genetic changes that can cause cancer and how they occur ?

Back 10

- activation of proto-oncogenes into oncogenes
-Inactivation of tumour suppressor genes
-They ocur by point mutations, Gene amplification, chromosomal translocation and can be triggered by viruses or chemical carcinogens

Front 11

Name the 4 stages of the cell cycle

Back 11

-G1 phase - Cell grows
-S phase - DNA synthesis
-G2 phase - interval between DNA syntehsis and mitosis
-M phase - mitosis

Front 12

How does the G1 phase checkpoint regulate cell proliferation?

Back 12

-G1 (restriction) phase checkpoint - Makes the decision of whether the cell should divide and is controlled by cycle kinase p16 which inhibits CDK4/6 preventing it interacting with cyclin d1 which would normally cause cell growth
-

Front 13

Name three cell cycle checkpoints

Back 13

-G1 restiction phase checkpoint
-end of G2 checkpoint - triggers metaphase
- Metaphase checkpoint

Front 14

What leads to uncontrolled proliferation?

Back 14

-Growth factors and their receptors
-Growth factor signalling pathways
-Cell cycle transducers: Cyclins and cyclin dependent kinases
-Anti-apoptotic mechanisms
-Telomerase expression
-Tumour directed angiogenesis( growth of new blood vessels)

Front 15

How can growth factor signalling be increased in a cancer?

Back 15

-Automnous production of growth factors
-Increased growth factor receptor expression (HER2 is expressed in 20-30% of breast cancers) which can lead to ligand independent signalling (no growth factor needed to activate) and enhanced growth factor sensitivty.
- Mutated receptors which become constitutively active (constantly active)
-Mutated down stream growth signalling molecules such as RAS which is in 30% of tumours

Front 16

How do cacners become anti-apoptopic?

Back 16

-cancer can inactive tumour supressors genes and p53 is a gene which is often mutated in (50% of) cancer. P53 normally triggers DNA repair in damaged cells at the G1 checkpoint or triggers apoptosis in irrepairable damage.
-bcl-2 protein is an anti-apoptotic protein which is often over expressed in cacner
-

Front 17

How does irregularities in the telomeres and telomerase induce the unlimited life potential of cancer?

Back 17

-telomeres cap the end of chromosomes and protect from DNA degradation and rearrangment. They shorten each time a cell replicates , aging the cells.
-Telomerase is an enzyme which maintains telomeres and is expressed in highly proliferating cells to ensure their long life. Telomerase is not expressed in fully differentiated somatic cells such as neuronal cells.
-95% of malignant tumours express telomerase making them immortal

Front 18

Name one feature that makes cancers invasive?

Back 18

-They often express metalloproteinases that break down collagen

Front 19

Name the 2 main classes of drugs currently used to treat cancer and the 4 subtypes of one of the classes.

Back 19

-Cytotoxic drugs target and kill the quickly proliferating cells , these include akylating agents, cytotoxic metabolites, anti-metabolites and plant derivatives
-Sex hormones

Front 20

How do alkylating agents work and name the main alkylating agents ?

Back 20

-alkylating agents covalently attach alkyl (carbon adn hydrogen groups eg methyl , ethyl ) to the DNA and RNA
- Main currently used agents are the:
nitrogen mustards (mustard gas, melphalan, chlorambucil, cyclophospamide)
-Nitrosoureas - (carmustine, losumustine)
-Busulphan
-Cisplatin

Front 21

How do alkylating agents disrupt DNA and RNA?

Back 21

-Alkylating DNA causing DNA fragmentation as repair enzymes attempt to remove the alkyl group
-cross linking DNA with an alkyl group stops separation for synthesis
-can either cross strand link or intra strand link
-Alkylating agents cause the mispairing of nucleotides leading to mutations

Front 22

How do the nitrogen mustards work?

Back 22

-They chemically form ja posistively charged carbonium ion which reacts with the electron-rich site which is normally the electron rich n-7 posistion on guanine
-Clinclly used alkylating groups tend to have two alkylating strands so they can cross link DNA

Front 23

How do the nitrosoureas work?

Back 23

--they alkylate DNA by creating alkylating groups through spontaneous, non-enzymatic degradation but other ill defined mechanisms are involved.
-Organic isocynates are also released which carbomylate lysine residues in proteins
-Very lipophillic and so cross BBB for use in brain tumuors

Front 24

Which drug alkylates the N7 of guanine, is used in chronic granulocytic leukaemia and is selective for bone marrow blocking the formation of platelets, granulocytes and red cells? What is its side effect?

Back 24

-Busulphan
-causes thrombocytopenia (low platlet count)

Front 25

Name some of the platinum based alkylating drugs and how do they work ?

Back 25

-Cisplatin, Carboplatin and oxaplatin (carboplatin is the "newer" less toxic version of cisplatin )
- Loses its chloride ions to form a reactive platinum complex which covalently bonds with the N7 groups on the purines
-The platinum disrupts hydrogen bonding
-Is used in testicular and ovarian cancer
-Side effects include severe nausea and vomiting

Front 26

What must folic acid (folates) be reducded to inorder to act as a purine and pyrimidine biosynthesis co-enzyme? What is this reaction catalyzed by?

Back 26

-Tetrahydrofolate
-Dihydrofolate reductase

Front 27

Name a common folate antagonist that is used in chemotherapy

Back 27

-Methotrexate is a tetrahydrofolate antagonist that preferentially binds to dihydrofolate reductase in order to block the synthesis of tetrahydrofolate.
-Tetrahydrofolate normally provides the methyl group in order to convert dUracilMP (dUMP) to dThymineMP (dTMP)

Front 28

Name a fraudlent nucleotide that is used in chemotherapy. How does it work?

Back 28

-Fluorouracil is converted to fluorodeoxyuridine monophosphate and inhibits dTMP synthesis by inhibiting thymidylate synthetase (uses FH4 as co-factor remember?)
-Blocks DNA synthesis but not RNA or protein synth

Front 29

How does cytarabine work? Why is its effectiveness unpredicatable?

Back 29

-Is similar to deoxyribose cytosine but has a arbainose sugar instead
-Inhibits DNA polymerase
-Some people can have high levels of the enzyme cytidine deaminase which converts it into its inactive form
-Others can have low levels of deoxycytidine kindase activity

Front 30

Which chemotherapy drug is a progdrug which is phosphorylated to deoxycytidine kinase? what are its benefits?

Back 30

-Gemcitabine
-Is incorporated into DNA to block DNA strand elongation
-Is effective against pancreatic cancer with few side effects

Front 31

Name two purine analogues that are converted into fraudulent nucleotides

Back 31

-mercaptopurine and thioguanine

Front 32

Name a cytotoxic antibiotic used in the treatment of Hodgkins lymphoma and list its method of action

Back 32

-Bleomycin
-Forms a tertitary complex with oxygen and iron (2) leading to oxidation of iron and creation of reactive oxygen species
-Degrades DNA and is most effective in the G2 (pre-mitotic phase)
-Cause pulmonary fibrosis (lung tissue scarring )

Front 33

Name a topoisomerase 2 inhibitor that belongs to the anthracycline antibiotics.List its method of actions

Back 33

-Doxorubicin
-Intercalates DNA and blocks DNA/RNA polymerase movement and is used in the treatment of solid tumuors
-Daunorubicin and idarubicin are used in leukaemia treatment

Front 34

How does the cytotoxic antibiotic Dactinomycin work?

Back 34

-Dactinomycin intercalates the minor grove of DNA between adjacent G-C pairs, prevent the movement of RNA polymerase.
-This efects gene transcription (DNA -> mRNA) and all phases of the cell cycle. It may effect topoisomerase 2

Front 35

Which cytotoxic antibiotic is used in the treatment of upper gastro-intestinal and breast cancers? It can cause myelosuppression, kidney damage and lung tissue fibrosis

Back 35

-Mitomycin
-It alkylates the O6 of guanine and may also create reactive oxygen species which degrade DNA

Front 36

Name 4 classes of plant derived chemotherapy drugs

Back 36

-VInca alkaloids (Cincristine, Vinblastine, Vindesine)
-Taxanes (Taxol and docelatel)
-Etoposide
-Campothecins (Irinotecan, Topotecan)

Front 37

How do bacteria become resistant to the beta lactam antibiotics? How can this resistance be overcome?

Back 37

-Bacteria can either develop the ability to produce beta-lactamase or modify its pencillin binding proteins so that a beta-lactam antibiotic can no longer bind there - MRSA does this
- A beta lactamase inhibitor can be administered in order to overcome metabolic adaptaions and an example of this is Clavulanic acid

Front 38

How do the Vinca alkaloids work? What do they treat?

Back 38

-Vinca alkaloids bind to tubulin in order to block microtubule polymerization, preventing the mitotic spindle from forming (metaphase arrest)
-Is relatively non toxic and is used in the treatment of non-hodgkins lymphoma

Front 39

Which cytotoxic drug class derived from the yew bark and pine needles binds to tubulin and stablises the microtubules in order to prevent mitosis?

Back 39

The taxanes are derived from yew bark and are used in the treatment of ovarian cancer, breast cacner and non-small-cell lung cancer
-Are neuropathic and can cause bone marrow supression (serious side effects)

Front 40

Which drug class is derived from a screaming root in harry potter? What are its mechanisms of action and what does it treat?

Back 40

-Etoposide
-It is a topoisomerase II inhibtor (prevents negative supercoiling, blocking DNA uncoiling for replication )
-Also inhibits mitochondrial function and inhibits nucleotide transport
-Treats small-cell luing cancer and testicular cancer
- Can cause hair-loss, myleosupression and nausea

Front 41

How does the campothecin class of drugs work?

Back 41

-They inhibit topoisomerase 1 and are used in the treatment of bowel cancer
-Have relatively few side effects but can cause diarrhoea and bone marrow supression

Front 42

Name five hormone dependent cancers

Back 42

-Testicular
-Breast
-Ovary
-Prostate
-uterus

Front 43

Name a hormone that is particularly effective in the treatment of hormone dependent breast cancers? How does it work?

Back 43

-Tamoxifen is a non-steroidal anti-oestrogen
-As a oestrogen receptor antagonist it competes with endogenous oestrogen for its receptor, preventing the transcription of oestrogen-responsive genes
-Shows mild agonist effects in the inner membrane of the uterus and bone

Front 44

How does the drug fulvestrant work?

Back 44

-It is a second gen oestrogen receptor antagonist with no agonist effects, unlike tamoxifen
-Forms a complex with the receptor that is quickly degrading , reducing amount of estrogen receptor proteins

Front 45

which hormone is used as an appetite increaser in a breast cancer sufferer?

Back 45

-Megestrol acetate is a proestrogen analogue that can also relieve cancer pain

Front 46

Name three ways in which a hormone dependent cancer can have its growth inhibited using hormone therapy?

Back 46

-Hormones with opposing actions
-Hormone antagonists (Tamoxifen)
-Inhibition of synthesis

Front 47

Name a hormone therapy treatment used in the second line treatment of post-menopausal breast cancer and how does it work?

Back 47

-Drugs which can inhibit the synthesis of adrenal hormones
-Formestane inhibits aromatase which synthesizes oestrogens from androgens
-Trilostane and aminoglutethimide can inhibit sex hormone synthesis in early stage cancer

Front 48

How do gonadotrophin-releasing hormone analogues work?

Back 48

-They are used as agonists to stimulating FSH and LH secretion
-Continued use (+10 days) desensitises the receptors and this is the therapeutic goal
-Used in treatment of prostate cancers and some breast cancers

Front 49

What is the function of Gonadotrophin-releasing hormone?

Back 49

-It controls the secretion by the anterior pituitary of both follicle stimulating hormone and luteinizing hormonhe, both of which stimulate the production of testerone and oestrogen in the testes and ovaries

Front 50

How are Glucocorticoids used in the treatment of cancer?

Back 50

-The immunosupression they create is useful in the treatment of leukaemias and lymphomas

Front 51

Name the 7 types of resistance a cell can have against anti cancer drugs

Back 51

-Increase in cellular efflux
-Decreased metabolism to the active agent
-Decrease in drug uptake
-Conversion of active agent into an inactive one by enzymes
-Rapid repair of DNA breaks and cross links
-Increased concentration of target enzyme
-Reduced affinity of the target for the drug

Front 52

Name some anti-emetics used in cotherapy to reduce chemotherapy sickness?

Back 52

-5-HT3 receptor antagonists (Ondasetron)
-Cannabis (usa)

Front 53

Which future treatmens help reduce the amount of myeleosupression (bone marrow suppression ) experienced during chemo

Back 53

-Bone marrow harvesting
-Stem cell harvesting

Front 54

Why are solid state tumours hard to treat using classical chemotherapy?

Back 54

-Solid tumour cells can be in a resting state where no cell division is taking place and then can become reactive and proliferate again

Front 55

Name 11 possible future treatment routes for cancer?

Back 55

-Monoclonal antibody therapy
-Ras protein (farnesyltransferase inhibitors)
-Tyrosine Kinase inhibitors
-Serine/threonine protein kinase inhibitors
-Cyclin adn CDK inhibitors
-Metalloproteinase inhibitors
-Telomerase inhibitors
-Angiogenesis inhibitors (Avastin)
-Antisense oligonucleotides and RNAi
-Enhancement of immune system and cancer vaccines
-Gene therapy