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Pharmacology & Toxicology > PHAR8: Cancer treatment > Flashcards

PHAR8: Cancer treatment Flashcards

1
Q

Name different types of solid tumours

A

sarcomas, carcinomas, and lymphomas

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2
Q

What is metastasis?

A

Abnormal cells translocate from the primary site of the tumour to other parts of the body, whereupon secondary tumours form

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3
Q

What are the two main differences between cancerous and non-cancer cells?

A
  • Cancer cells exhibit uncontrolled growth and multiply far more (and in most cases more rapidly) than their non-cancerous equivalents. They will, therefore, have a greater demand for energy and anabolic substrates to facilitate growth (e.g. production of cell membranes, proteins, etc.)
  • Cancer cells will have a less well-regulated cell cycle and will need to duplicate their DNA far more frequently that non-cancerous equivalents. To replicate,they will rely on correctly functioning replicative processes
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4
Q

What are the hall marks of cancer?

A
  • resisting cell death
  • inducing angiogenesis
  • enabling replicative immortality
  • sustaining proliferative signalling
  • evading growth suppressors
  • activating invasion and metastasis
  • deregulating cellular energetics
  • avoiding immune destruction
  • genome instability and mutation
  • tumour-promoting inflammation
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5
Q

What drug would you use to prevent sustained proliferation signalling?

A

EGFR inhibitors

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6
Q

What drug would you use to prevent cancer cells from deregulating cellular energetics?

A

Aerobic glycolysis inhibitors

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7
Q

What drug would you use to prevent cancer cells resisting cell death?

A

Proapoptotic BH3 mimetics

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8
Q

What drug would you use to prevent genome instability and mutations?

A

PARP inhibitors

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9
Q

What drug would you use to inhibit cancer cells inducing angiogenesis?

A

VEGF signalling inhibitors

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10
Q

What drug would you use to prevent cancer cells evading growth suppressors?

A

Cyclin-dependent kinase inhibitors

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11
Q

What drug would you use to stop cancer cells avoiding immune destruction

A

Anti-CTLA4 mAb

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12
Q

What drug would you use to prevent cancer cells enabling replicative immortality?

A

Telomerase inhibitors

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13
Q

What does cancer chemotherapy traditionally target?

A

Treatments that directly exploit anabolic, replicative, and metabolic mechanisms

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14
Q

r a surgical procedure to remove as much of the tumour as possible, is called what?

A

debulking

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15
Q

What is the order of the cell cycle

A

G1
S phase
G2
M

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16
Q

What happens in G1 phase?

A

Metabolic changes prepare the cell for division. At a certain point - the restriction point - the cell is committed to division and moves into the S phase.

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17
Q

What happens in S phase?

A

DNA synthesis replicates the genetic material. Each chromosome now consists of two sister chromatids

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18
Q

What happens in G2 phase?

A

Metabolic changes produce and assemble the cytoplasmic materials necessary for mitosis and cytokinesis.

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19
Q

What happens in M phase?

A

A nuclear division (mitosis) followed by a cell division (cytokinesis).

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20
Q

What are the different types of anti-cancer drugs?

A 
Alkylating and intercalating agents
Antibiotics
Antimetabolites
Microtubule inhibitors
Hormones
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21
Q

How do alkylating agents exert their cytotoxic effect?

A

Covalently binding to particular macromolecules in the cell (most importantly is covalent binding to DNA) - This is lethal

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22
Q

Name four drugs which have a common chemical structure? and therefore mode of action

A

A) cyclophosphamide,
B) mechloethamine,
C) methchlorethamine derivative estramustine phosphate,
D) malphalan

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23
Q

What is the similarity in chemical structure for the alkylating drugs?

A

Tertiary nitrogen atom with two chloroethane groups attached

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24
Q

What are bifunctional agents?

A

can bind and react at two separate sites

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25
Q

How do alkylating agents work?

A

The drug binds with guanines or adenine bases leading to cross-linkages between guanine residues in the DNA chain which facilitates DNA strand breakage. This interferes with transcription and replication of DNA.

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26
Q

How do anti-tumour antibiotics work?

A

Interactions with DNA, leading to disruption of DNA function.

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27
Q

Name two anti-tumour antibiotics

A

dactinomycin and doxorubicin: owe their cytotoxic action primarily to their interactions with DNA, leading to disruption of DNA function.

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28
Q

Why might alkylating agents’ side effects be: severe, variable and related to many aspects of the body?

A

DNA damage may not be targeted well -> interfering with DNA in normal cells

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29
Q

Explain the mechanism of Dactinomycin?

A

It intercalates into the minor groove of the double helix between guanine-cytosine base pairs of DNA, forming a stable dactinomycin-DNA complex. The complex interferes primarily with DNA-dependent RNA polymerase, although at high doses, dactinomycin also hinders DNA synthesis. The drug also causes single-strand breaks, possibly due to action on topoisomerase II or by generation of free radicals.

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30
Q

What are the major dose limiting toxicities of dactinomycin?

A

Bone marrow depression: nausea, vomiting, diarrhoea and alopecia

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31
Q

What are the three different mechanisms of doxorubicin?

A

1) Intercalation of DNA: The drugs insert non-specifically between adjacent base pairs and bind to the sugar-phosphate backbone of DNA. This causes local uncoiling and, thus, blocks DNA and RNA synthesis.
2) Binding to cell membranes: This action alters the function of transport processes.
3) Generation of oxygen radicals: Cytochrome P450 reductase (POR; present in cell nuclear membranes) catalyses reduction of the anthracyclines to semiquinone free radicals. These in turn reduce molecular O2, producing superoxide ions and hydrogen peroxide, which mediate single-strand scission (cutting) of DNA.

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32
Q

What does cytochrome P450 reductase catalyse the production of?

A

Superoxide and hydrogen peroxide from molecular oxygen, whilst doxorubicin is converted to doxorubicin metabolite

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33
Q

What do superoxide and hydrogen peroxide do to DNA

A

They cause double stranded breaks in DNA

34
Q

How can doxorubicin be used to treat cancer?

A

There is evidence to suggest that giving this antibiotic in large doses or for a prolonged period can cause irreversible, dose-dependent cardiotoxicity, thought to result from the generation of free radicals and association lipid peroxidation.

35
Q

What are antimetabolites?

A

Structurally related to normal cellular components and interfere with normal metabolic processes. ypically, antimetabolites have a very similar chemical structure to the substrates for the metabolic processes they inhibit

36
Q

How do antimetabolites work in the context of cancer chemotherapy?

A

Affect the availability of the normal purine or pyrimidine nucleotide precursors by inhibiting their synthesis, and therefore more specifically affect proliferating cells.

37
Q

Name the three main types of antimetabolites used in cancer chemotherapy

A 
Folate antagonists (e.g. methotrexate)
Pyrimidine analogues (e.g. 5-fluorouracil)
Purine analogues (e.g. mercaptopurine)
38
Q

What is Methotrexate (antimetabolite) structurally related to?

A

Folic acid which plays an important role in a variety of metabolic reactions

39
Q

What is the difference between methotrexate and folic acid structure?

A

Folate has an oxygen double bonded to left ring whereas methotrexate has an amine group. in the middle of the structure folate has a methyl group whereas methotrexate has an ethyl group

40
Q

What is the mechanism of action of methotrexate?

A

Methotrexate blocks the dihydrofolate reductase enzyme leading to deficiency of numerous coenzymes that play important roles in the synthesis of purine. (dUMP: deoxyuridine monophosphate, dTMP: deoxythymidine monophosphate, MTF: methyltetrahydrofolate, THF: Tetrahydrofolate).

41
Q

What is the end result once the dihydrofolate reductase enzyme is blocked?

A

Inhibition of dihydrofolate reductase deprives the cells of the various folate coenzymes resulting in decreased biosynthesis of DNA, RNA and protein, eventually leading to cell death.

42
Q

What happens when 6-metacaptpurine penetrates target cells?

A

mercaptopurine is converted into the nucleotide 6-mercaptopurine ribose phosphate known as 6-thioinosinic acid (Thio-IMP)

43
Q

What is the active metabolite of mercaptopurine?

A

Thio-IMP

44
Q

What does Thio-IMP do?

A

blocks the synthesis of AMP, XMP and phosphoribosylamine, which are necessary for purine ring biosynthesis

45
Q

What is the mechanism of action for thio-IMP?

A

via the dehydrogenation of thio-IMP to thio-GMP, and subsequent phosphorylation to di- and tri-phosphates. These metabolites can be incorporated into RNA and DNA but trigger cell death as they do not function like a normal nucleotide.

46
Q

How does 5-Fluorouracil enter the cell?

A

Through a carrier-mediated transport system

47
Q

What happens to 5-FdUMP once it enters the cell?

A

It is converted to the corresponding deoxynucleotide (5-flurodeoxyuridine monophosphate (5-FdUMP) which competes with deoxyuridine monophosphate for thymidylate synthase.

48
Q

What does 5-FdUMP compete with for thymidylate synthase

A

deoxyuridine monophosphate

49
Q

5-FdUMP acts as a __________ and is trapped with the enzyme and its coenzyme N5, N10-methylene tetrahydrofolic acid (5,10-MTHF) in a ternary complex that cannot proceed to release products.

A

pseudosubstrate

50
Q

Why does DNA synthesis decrease, leading to imbalanced cell growth and cell death with 5-FdUMP presence?

A

Due to lack of thymidine

51
Q

Describe the flow chart of 5-FU

A

5-FU -> 5-FUMP -> 5-FUDP -> 5-FdUMP
5FdUMP inhibits conversion of dUMP -> dTMP
dUMP -> dTMP catalyses the conversion of 5,10-MTHF to DHF.

52
Q

Why are polymeric tubulins

A

The polymeric structures made from tubulin that form part of the cellular cytoskeleton, are critical for cell function and division

53
Q

What is Vincristine?

A

so-called Vinca alkaloids as they are derived from the Vinca rosea plant

54
Q

What do vinca alkaloid drugs do?

A

Block mitosis in metaphase

55
Q

How do vinca alkaloid drugs work?

A

Their binding to the microtubular protein, tubulin, is GTP-dependent and blocks the ability of tubulin to polymerize to form microtubules. Instead, paracrystalline aggregates consisting of tubulin dimers and the alkaloid drug are formed. The resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cell proliferation.

56
Q

What do vinca alkaloid drugs bind to?

A

microtubular protein, tubulin

This process is GTP-dependent

57
Q

What does vinca alkaloid binding to tubulin do?

A

Prevents tubulin from polymerising to microtubules

58
Q

Name three hormone targets for cancer treatment

A
  • Prednisone
  • Tamoxifen
  • Estrogens
59
Q

Tumours that are steroid hormone sensitive may be either

A
  • Hormone responsive, in which the tumour regresses following treatment with a specific hormone
  • Hormone dependent, in which removal of a hormonal stimulus causes tumour regression
  • Both
60
Q

Hormone treatment of responsive tumours is usually only _____, except in the case of ____?

A

Palliative

the cytotoxic effect of glucocorticoids at higher doses on lymphomas

61
Q

With regards to hormones, what can surgery accomplish?

A

Removal of hormonal stimuli from hormone-dependent tumour

62
Q

Other than surgery, how can hormones be eliminated in patients with hormone sensitive tumours

A

By drugs e.g: breast cancer, for which treatment with the antiestrogen tamoxifen is used to prevent estrogen stimulation of breast cancer cells

63
Q

Is prednisone active or inactive?

A

inactive

64
Q

What is prednisone reduced to, to become active? What is this catalysed by?

A

prednisolone by 11-β-hydroxysteroid dehydrogenase (prodrug)

65
Q

How does prednisolone act within the body?

A

1) The steroid binds to intracellular receptor
2) The receptor then dimerises
3) It then migrates to the nucleus
4) It interact with DNA to modify gene transcription, inducing synthesis of some proteins and inhibiting synthesis of others

66
Q

Name two types of oestrogen that used to be used in prostate cancer therapy

A
  • ethinyl estradiol

- diethylstilbestrol

67
Q

What has estrogen treatment for prostate cancer been replaced with?

A

GnRH (gonadotrophin releasing hormone) analogs because of fewer adverse effects

68
Q

How do estrogens work as anti-cancer treatment in prostate cancer patients?

A

Estrogens inhibit the growth of prostatic tissue by blocking the production of luteinizing hormone, thereby decreasing the synthesis of androgens in the testis. Thus, tumours that are dependent on androgens are affected.

69
Q

How does Tamoxifen function?

A

Tamoxifen binds to the estrogen receptor, but the complex is transcriptionally not productive. That is, the complex fails to induce estrogen-responsive genes, and RNA synthesis does not ensue. The result is a depletion (down-regulation) of estrogen receptors, and the growth-promoting effects of the natural hormone.

70
Q

How does 5-fluorouracil function?

A

Antimetabolite
Folate antagonist/mimic
Blocking the synthesis of DNA and/or RNA

71
Q

How does Cyclophosphamide function?

A

Alkylating agent

Intrastrand cross-linking of DNA

72
Q

List the different types of mechanisms for anticancer drug resistance

A

Decrease accumulation of cytotoxic drugs in cells due to increase expression of cell surface, energy-dependent drug transport proteins (e.g. doxorubicin, vinblastine and dactinomycin).

A decrease in the amount of drug taken up by the cell (e.g. methotrexate).

Insufficient activation of the drug (e.g. mercaptopurine and 5-fluorouracil). Some drugs require metabolic activation to produce antitumour activity. If not, they may be unable to block the metabolic pathways required to exert their effects.

Increased concentration of target enzyme (methotrexate).

Increased utilisation of alternative metabolic pathways (antimetabolites).

Rapid repair of drug-induced lesions (alkylating agents).

Altered activity of target, for example modified topoisomerase II (doxorubicin).

Mutations in various genes, giving rise to resistant target molecules. For example, the p53 gene and overexpression of the Bcl-2 gene family (several cytotoxic drugs).

Gene amplification. A cancer cell may produce hundreds of copies of a particular gene. This gene triggers an overproduction of protein that renders the anticancer drug ineffective.

Cancer cells may pump the drug out of the cell as fast as it is going in using a drug efflux pumps such as p-glycoprotein.

73
Q

Define alkylation

A

The transfer of an alkyl group from one molecule to another

74
Q

Define antimetabolite

A

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

75
Q

Define bifunctional

A

A molecule with two functional groups

76
Q

Define cancer

A

An abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasise (spread).

77
Q

Define dermopathy

A

A skin condition characterized by red, swollen skin.

78
Q

Define growth fraction

A

The percentage of cells engaged in proliferative versus resting phases at a given point in time.

79
Q

Define tumour

A

An abnormal, benign, or malignant new growth of tissue that possesses no physiological function and arises from uncontrolled usually rapid cellular proliferation.

80
Q

Define metastasis

A

The process by which cancer spreads from the place at which it first arose as a primary tumour to distant locations in the body.

81
Q

What are the different anti-cancer drugs discussed in the emodule?

A 
Methotrexate
5-Fluorouracil
Cyclophosphamide
Doxorubicin
Vincristine
Tamoxifen

Pharmacology & Toxicology (8 decks)

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