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PHAR > PHAR8 - Cancer Drug Therapy > Flashcards

PHAR8 - Cancer Drug Therapy Flashcards

1
Q

Define alkylation.

A

Transfer of an alkyl group from one molecule to another.

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2
Q

Define anti metabolite.

A

Substances that are structurally related to normal cellular components, and interfere with normal metabolic processes.

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3
Q

Define bifunctional.

A

A molecule with two functional groups.

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4
Q

Define cancer.

A

An abnormal growth of cells with proliferate in uncontrolled manner. Contain the ability to metastasise.

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5
Q

Define dermopathy.

A

Skin condition characterised by red swollen skin.

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6
Q

Define growth fraction.

A

Percentage of cells engaged in proliferative phases of the cell cycle, relative to cells engaged in resting phases of the cell cycle.

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7
Q

Define tumour.

A

Abnormal, benign or malignant growth of tissue. No physiological function. Arises from uncontrolled cellular proliferation.

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8
Q

Define metastasis.

A

Process by which a cancer spreads from its initial location (primary tumour) to another location (secondary tumour).

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9
Q

Discuss the difference between morbidity and mortality.

A

Morbidity refers to the state of the disease whereas mortality is the rate of death caused by the disease.

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10
Q

What are three general pathways or functions that cancers affect?

A

Metabolic pathway.
Signalling pathways.
Physiological functions.

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11
Q

Are all cancers the same? Discuss the similarities and differences.

A

Similarities - caused by uncontrolled cell growth and proliferation.
Differences - location meaning that phenotype and clinical endpoint can be different. Biochemical features also differ.

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12
Q

What are the two types of tumour?

A

Non-cancerous - benign.

Cancerous - malignant.

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13
Q

Give three examples of solid tumours. Give brief description of each.

A

Sarcoma - connective tissue tumour.
Carcinoma - skin/lining tissue tumour.
Lymphoma - blood tumour.

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14
Q

Are all tumours solid? Give example if yes/no.

A

No all tumours are not solid.

Example - leukaemia.

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15
Q

What are the two main factors that differentiate cancerous and non-cancerous cells?

A

Cancerous cells - uncontrolled cell proliferation and less regulated cell cycle.

Non-cancerous cells - controlled cell proliferation and well regulated cell cycle.

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16
Q

When considering the uncontrolled cell growth of cancerous cells, what specifically is uncontrolled?

A

Frequency of cell division.

Speed of cell division.

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17
Q

What is required for cell division to occur?

A

Metabolic energy e.g. ATP.

Various anabolic substrates e.g. lipids and proteins in cell membranes, nucleic acid precursors.

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18
Q

Do cancerous cells use more/less metabolic energy/anabolic substrates? Explain answer.

A

More metabolic energy and anabolic substrates required. Both are components required for cell division. Cancerous cells undergo multiple rounds of cell division.

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19
Q

Discuss the less regulated cell cycle in cancerous cells.

A

Cell cycle is less regulated meaning that it fires more often, resulting in the characteristic uncontrolled cell proliferation.

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20
Q

Give a definition for the hallmarks of cancer.

A

Key characteristics that are common to different types of cancer.

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21
Q

Give the six main hallmarks of cancer.

A 
Cell death resistance. 
Angiogenesis is induced. 
Enabling of replication immortality. 
Sustaining of proliferative signalling. 
Evading growth suppressors. 
Activating invasion and metastasis.
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22
Q

What are the four emerging hallmarks of cancer?

A

Deregulation of cellular energetics.
Avoiding immune destruction.
Genome instability and mutation.
Promotion of inflammation.

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23
Q

What is the key feature that must be maintained during cancer chemotherapy?

A

Destruction of cancerous cells with limited damage to non cancerous cells.

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24
Q

In case of large tumour, would chemotherapeutic drugs be offered as the initial line of treatment? If yes/no, why is this the case?

A

No. Surgical removal initially done to remove bulk of tumour. If not done, large dosages of drug would be required to kill the large bulk of tumour cells which can lead to severe adverse side effects.

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25
Q

Define debulking in the case of tumours.

A

Surgical removal of large bulks of tumour tissue, prior to chemotherapeutic treatment.

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26
Q

What are the six phases of the cell cycle?

A 
Gap phase 1.
Synthesis. 
Gap phase 2/gap phase 0.
Mitosis.
Cytokinesis.
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27
Q

Which phases of the cell cycle constitute the following: interphase, prophase, anaphase and telophase?

A

Interphase - g1, S, g2 (and g0)

Prophase/metaphase/anaphase/telophase- M and C phases.

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28
Q

Give brief overview of gap phase 1.

A

Metabolic changes within cell occur, to prepare for cell division. Organelle numbers increased. Changes result in high rate of biosynthetic processes. Culminates in ‘restriction point’ which ensures it passes into S phase.

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29
Q

Give brief overview of S phase.

A

DNA synthesis - replication of genetic material. Chromosome is composed of two sister chromatids. Rate of other biosynthetic processes is low.

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30
Q

Give brief overview of gap phase 2.

A

Metabolic changes within the cell, meaning that rate of biosynthetic processes is high. Mitotic spindle components (microtubules) begin to form. Ensures passage into M phase.

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31
Q

Give brief overview of M phase.

A

Include prophase, metaphase, anaphase and telophase. Nuclear division occurs - referred to as karyokinesis.

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32
Q

Give brief overview of the C phase of the cell cycle.

A

Refers to cytokinesis where the cell divides to form two new daughter cells.

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33
Q

What are the two main classes of anticancer drugs? Give brief description of each.

A

Cell cycle specific - targets specific phases of the cell cycle.
Cell cycle non specific - target any phase of the cell cycle.

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34
Q

What is the growth fraction?

A

Growth fraction refers to the proportion of cells in proliferative phases of the cell cycle (either S or M phase) compared to those that are in resting phases (G0 phase).

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35
Q

What is the link between growth fraction of cancerous cells and the efficacy of anticancer drugs?

A

Anticancer drugs generally target proliferative phases of the cell cycle. If fewer cells are in proliferative phases, the drug is unlikely to have enough of an effect.

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36
Q

Give example of tissues with high growth fraction.

A

Hair.

Enterocytes of the gut lining.

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37
Q

Give examples of tissues with a low growth fraction.

A

Some neurons.

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38
Q

What class of anticancer drug should be used for the treatment of cancers with a high growth fraction?

A

Both cell-cycle specific and non-specific drugs can be used for high growth fraction cancers.

39
Q

What class of anticancer drug should be used for the treatment of cancers with a low growth fraction?

A

Cell cycle non specific drugs should be used as specific ones are unlikely to have an effect due to few cells being in proliferative phases.

40
Q

What are the five main groups of anticancer drugs?

A 
Alkylating and intercalating agents.
Antibiotics.
Antimetabolites.
Microtubule inhibitors. 
Hormones and their antagonists.
41
Q

Give examples of common alkylating agents.

A

Cyclophosphamide.
Mechlorethamine.
ESTRAMUSTINE phosphate.
Malphalan.

42
Q

What is the general process by which alkylating agents act?

A

Cause chemical modifications to the DNA. Prevents DNA synthesis being completed. Initiates programmed cell death.

43
Q

Why are alkylating agents considered bifunctional agents?

A

Contain two functional groups that bind to two different locations.

44
Q

Discuss how alkylating agents that contain a tertiary nitrogen atom with two chloroethyl side groups is able to act as an anticancer drug.

A

Chloroethyl side chain bonds with nitrogen 7 atom on nearby guanine residues. This results in cross linking which prevents the entire DNA molecule being replicated. Programmed cell death/apoptosis is initiated resulting in death of cancerous cells.

45
Q

Are side effects of alkylating agents common? Explain.

A

Yes common. Can cause cross linkages in DNA of non cancerous cells, initiating their programmed cell death. Side effects are variable and can be severe.

46
Q

What are two examples of antibiotics used as anticancer drugs?

A

Dactinomycin.

Doxorubicin.

47
Q

Give an overview of the mechanism of action of dactinomycin.

A

Binds to DNA forming dactinomycin-DNA complex by interaction of guanine cytosine base pair minor groove.
Prevents action of RNA polymerase enzymes, preventing transcription, translation and protein synthesis.
Without proteins required for cell growth , cancer cells will die.

48
Q

Does dactinomycin interfere with DNA synthesis?

A

Not at usual dosages, as it affects RNA synthesis not DNA synthesis. At higher dosages, can affect DNA synthesis.

49
Q

How does dactinomycin result in single stranded breaks?

A

Not confirmed but potential mechanisms are:
Interference with action of topoisomerase II.
Generation of free radicals.

50
Q

What are common side effects of dactinomycin?

A

Nausea, vomiting, diarrhoea, alopecia.

51
Q

Give one toxic severe side effect of dactinomycin.

A

Bone marrow depression - decreased number of haematopoietic stem cells. Leads to haematological and immunological complications.

52
Q

What are the three ways in which doxorubicin functions as an anti cancer drug?

A

DNA intercalation.
Cell membrane binding.
Oxygen radical generation.

53
Q

Discuss how doxorubicin acts as an anti cancer drug by DNA intercalation.

A

Drug binds to sugar phosphate backbone via non specific insertion between adjacent base pairs. DNA uncoils around this area. DNA synthesis prevented. RNA synthesis prevented.

54
Q

Discuss how doxorubicin acts as an anti cancer drug by cell membrane binding.

A

Binds to cell membrane at different locations. Prevents transporter processes across membrane. Cell function is inhibited. Can lead to cell death.

55
Q

Discuss how doxorubicin acts as an anti cancer drug by oxygen radical generation.

A

Cytochrome reductase enzymes metabolise doxorubicin into its metabolites whilst simultaneously converting oxygen into superoxide ions and hydrogen peroxide. These cause single stranded breaks to the DNA - DNA damage - programmed cell death.

56
Q

Give a toxic side effect of doxorubicin and when it occurs.

A

Cardio toxicity. Caused by large doses and prolonged exposure.

57
Q

Why is doxorubicin thought to contribute to cardio toxicity?

A

Free radicals generation. Associated lipid peroxidation.

58
Q

What are antimetabolites roles within anticancer therapy?

A

Contain structural similarities to molecules involved in normal metabolic processes however disrupt the process. Commonly affect purine or pyrimidine nucleotide precursors availability.

59
Q

What are the three main types of antimetabolites?

A

Folate antagonists.
Pyrimidine analogues.
Purine analogues.

60
Q

What type of antimetabolite is methotrexate?

A

Folate antagonist.

61
Q

Give a brief overview of the mechanism of action of methotrexate.

A

Methotrexate prevents the formation of dihydrofolate from folate and blocks the dihydrofolate reductase enzyme, preventing the production of tetrahydrofolate from dihydrofolate.

62
Q

What type of antimetabolite is 5-fluorouracil?

A

Pyrimidine analogue.

63
Q

What are the pyrimidines?

A

Cytosine
Thymine
Uracil.

64
Q

Discuss how 5-FU is converted into 5-FdUMP.

A

5-FU converted to 5-FUMP by phosphoribosyl transferase enzyme.

5-FUMP converted to 5-FUDP by uridine kinase enzyme.

5-FUDP converted to 5-dUMP by ribonucleotide reductase enzyme.

65
Q

How does the 5-FdUMP produced by 5-FU affect DNA synthesis and cancer cells?

A

5-FdUMP prevents dTMP formation from dUMP. This is because it blocks the thymidylate synthase enzyme by forming a ternary complex with it and co-enzyme 5,10-MTHF.

Reduced synthesis of thymidine. DNA synthesis affected. Cells die.

66
Q

What type of antimetabolite is mercaptopurine?

A

Purine analogue.

67
Q

What compound is merceptopurine initially converted into?

A

Initially converted into 6-thioinosic acid (thio-IMP)

68
Q

How does thio-IMP inhibit purine ring synthesis?

A

Thio IMP converted into thio-GMP by dehydrogenation.
Thio-GMP converted into disphosphates and triphosphate via phosphorylation reactions.
Metabolites become incorporated into RNA/DNA - prevent normal synthesis.

69
Q

Discuss the role of microtubules in cell cycle.

A

Microtubules are used during cell division to ensure separate of the sister chromatids, ensuring two daughter cells with equal genetic information are produced.

70
Q

How does the mitotic spindle normally form?

A

Tubulin monomers polymerise to form microtubules which form the mitotic spindle.

71
Q

Why does inhibition of microtubule formation result in cell death?

A

Without microtubules, the sister chromatids are unable to separate. This prevents Cell division.

72
Q

Discuss the mechanism of vinca alkaloids as anticancer drugs.

A

Vinca alkaloid drugs bind to tubulin monomers using GTP. This forms tubulin dimers NOT polymers. Dimers form para-crystalline aggregates prevent mitotic spindle formation. Sister chromatids unable to separate. Programmed cell death occurs.

73
Q

What are the two types of interactions between tumours and hormones?

A

Hormone responsive - tumours regress when treated with specific hormone.
Hormone dependent - tumours regress when hormonal stimulus is removed.

74
Q

Define palliative care.

A

Treatment done with the intention of relieving symptoms of the disease not actually curing the disease.

75
Q

Discuss the mechanism of action of prednisone.

A

Prednisone is an inactive drug. Metabolised to prednisolone by 11-beta-hydroxyateroid enzymes. Presnisolone binds to intracellular receptors. Receptor dimerisation occurs. Dimer migrates to nucleus. Interacts with DNA. Gene transcription modified.

76
Q

What type of cancer is treated by prednisone? How does this occur?

A

Lymphomas. Required in high dosages to have a cytotoxic effect.

77
Q

Why is prednisone a pro drug?

A

Must be metabolised to prednisolone in order to have an effect.

78
Q

What are the two ways in which a hormonal stimulus can be removed for the treatment of a hormone dependent cancer?

A

Surgery - e.g. orchiectomy for advanced prostate cancer.

Drugs - e.g. tamoxifen treatment of breast cancer cells, as it is an anti oestrogen.

79
Q

Discuss the use of GnRH analogues in the treatment of prostate cancer.

A

Block production of leutinizing hormone. This reduces production of androgen in the tests. Inhibits growth of prostate tissue.

80
Q

Give two examples of oestrogen.

A

Ethinyl estradiol.

Diethylstilbesterol.

81
Q

What hormone is mainly used in the treatment of prostate cancer?

A

Oestrogen.

82
Q

Discuss the mechanism of action of tamoxifen.

A

It is an anti oestrogen that binds to oestrogen receptors. Tamoxifen-oestrogen receptor complex in transcriptionally unproductive. Oestrogen responsive genes are not expressed. Oestrogen receptor downregulated.

83
Q

What are the two types of resistance in cancer cells?

A

Primary - resistance from initial drug administration.

Acquired - resistance developed during drug treatment

84
Q

What are the key mechanisms in drug cancer resistance? Give ten examples.

A 
Decreased accumulation of cytotoxic drugs.
Decreased drug uptake by cell.
Insufficient drug activation.
Increased target enzyme concentration.
Increased alternative metabolic pathway utilisation.
Rapid repair of drug induced lesions.
Altered target activity.
Gene mutations.
Gene amplification. 
Drug efflux via pumps.
85
Q

Briefly discuss decreased accumulation of cytotoxic drugs as a resistance mechanism in cancerous cells.

A

Increased expression of energy dependent transport proteins can move drugs out of cancerous cells, reducing their accumulation within the cell.

86
Q

Briefly discuss decreased drug uptake by the cell as a resistance mechanism for cancer cells.

A

Drug is unable to physically enter the cell due to alterations in cell membrane therefore the cell is resistant to the drug.

87
Q

Briefly discuss insufficient activation as a resistance mechanism for cancer cells.

A

Pro-drugs need to be metabolised to become active. Less activation means less effect so cancer cell more likely to develop resistance.

88
Q

Discuss target enzyme concentration as a mechanism for resistance in cancer cells.

A

If a drug targets an enzyme and blocks it, increasing the amount of the enzyme, will reduce the effect of the drug.

89
Q

Discuss increased alternative metabolic pathway utilisation as a resistance mechanism for cancer cells.

A

Anti metabolic anticancer drugs target specific metabolic pathways. If others can be utilised, the antimetabolites are likely to have little effect.

90
Q

Discuss rapid repair of drug induced lesions as a resistance mechanism for cancer cells.

A

Rapidly repairing the lesion, reduces the effect that anticancer drugs have e,g, by damaging DNA to cause cell death. Commonly resistance mechanism for alkylating agents.

91
Q

Discuss altered target activity as a resistance mechanism for cancer cells.

A

If the target operates in a different manner, the drug may no longer have an effect on the target.

92
Q

Discuss gene mutations as a resistance mechanism.

A

Mutations within some genes can cause resistance to specific cytotoxic drugs via various mechanisms.

93
Q

Discuss gene amplification as a resistance mechanism for cancer cells.

A

The high proliferative rate of the cell can contribute to high gene application. Protein may be overproduced. Anticancer drug may be rendered ineffective.

94
Q

Discuss drug pumps as a resistance mechanism for cancer cells.

A

Some cancer cells move the anticancer drug out of the cell without allowing it to penetrate the cell at all - example of primary resistance.

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