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Therapeutic Pharmacology 2 > Anticancer Treatments > Flashcards

Anticancer Treatments Flashcards

1
Q

What are the characteristics common to most cancer cells?

A

Genetic and acquired mutations lead to abnormal signal transduction regulating:

  • Uncontrolled cellular proliferation
  • Loss of apoptosis

The tumour produces MMPs and breaks through the basement membrane:

  • Tissue invasion
  • Angiogenesis
  • Metastasis
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2
Q

What are the main categories of anti-cancer drugs?

A

Cytotoxic drugs
Hormones/anatagonists
Monoclonal antibodies
Protein kinase inhibitors (Tyrosine kinase inhibitors)
Others (Antisense oligonucleotides (anti-Bcl-2), stapled p53 mimetic peptides

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3
Q

How do most current anti-cancer drugs work?

A

Most current anticancer drugs, particularly cytotoxic agents, affect only one characteristic aspect of cancer cell biology – cell division.

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4
Q

List the different types of cytotoxic drugs

A

Alkylating agents
Antimetabolites
Cytotoxic antibiotics
Plant derivatives

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5
Q

Explain the general principles of cytotoxic anti-cancer drugs

A

The pharmacological principles of cytotoxic drugs are based on perturbing cell division

Target events that occur during phases of the cell cycle

Proliferating cells are therefore targeted

In many cases, the anti-proliferative effects result from and action during the S Phase and the resultant damage to DNA initiates apoptosis

Because their main target is cell division, cytotoxic anti-cancer drugs will affect all rapidly dividing normal tissues

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6
Q

What are the toxic effects of cytotoxic anti-cancer drugs?

A

Bone marrow toxicity (myelosuppression) with decreased leucocyte production and thus decreased resistance to infection

Impaired wound healing

Loss of hair (alopecia)

Damage to the GI epithelium (including oral mucous membranes)

Depression of growth in children

Sterility

Teratogenicity

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7
Q

Describe the features of alkylating agents

A

The nitrogen at position 7 (N7) of guanine, being strongly nucleophilic, is probably the main molecular target for alkylation of DNA.

Most alkylating agents are “bifunctional” and react with two groups to cause intra-chain or inter-chain cross-linking.

This interferes not only with transcription, but also DNA replication (S Phase)

Their main impact is seen during the S Phase, when some zones of the DNA are unpaired and susceptible to alkylation.

There is a block at G2 and subsequential apoptotic cell death

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8
Q

Give examples of 2 alkylating agents

A

Cyclophosphamide (nitrogen mustard) has a pronounced effect on lymphocytes (also used as an immunosuppressant)

Cisplatin (a platinum compound) has low myelotoxicity, but causes severe nausea and vomiting

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9
Q

Describe the features of antimetabolites

A

Structurally similar to naturally occurring metabolites which are required for the synthesis of DNA and RNA

Anti-metabolites act on the S phase

They exert their effects by competing with or substituting for normal metabolites

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10
Q

Give examples of 3 types of antimetabolites

A

Folate antagonists
Purine analogues
Pyrimidine analogues

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11
Q

Give examples of 3 types of antimetabolites

A

Folate antagonists
Purine analogues
Pyrimidine analogues

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12
Q

Describe the features of folate antagonists

A

The main folate antagonist ismethotrexate

One of the most widely used antimetabolites in cancer chemotherapy.

Folates are essential for the synthesis of purine nucleotides and thymidylate, which in turn are essential for DNA synthesis and cell division.

Folates act as coenzymes, with thymidylate synthetase to produce thymidylate

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13
Q

Describe the mechanism of action of methrotrexate

A

Folates are actively taken up into cells, where they are converted to polyglutamates.

In order to act as coenzymes for thymidylate synthetase, folates must be reduced to tetrahydrofolate (FH4).

This two-step reaction is catalysed bydihydrofolate reductase, which converts the substrate first to dihydrofolate (FH2), then to FH4.

Methotrexatehas a higher affinity for dihydrofolate reductase than FH2 and thus competes with FH2, inhibits the enzyme and depletes intracellular FH4

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14
Q

Describe the mechanism of action of purine analogues e.g. Mercaptopurine

A

Mercaptopurine is converted to a fraudulent nucleotide

By substituting for purines, these analogues interfere with DNA and RNA synthesis

Works on S phase

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15
Q

Describe the mechanism of action of pyramidine analogues, e.g. 5-fluorouracil

A

An analogue of uracil converted to a fraudulent nucleotide.

This “decoy” (fluorodeoxyuridine monophosphate/FDUMP) interacts with thymidylate synthetase and results in the inhibition of DNA, but NOT RNA or protein synthesis

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16
Q

Describe the features of cytotoxic antibiotics

A

Eg. The Anthracyclines

Anthracyclines that are derived from bacteria belonging to the genus Streptomyces

Extensive clinical studies have demonstrated that they are active against a wide variety of tumours.

However, the clinical use of anthracyclines has been limited because of a significant risk of cardiac damage.

The chances of this life-threatening side effect depend on cumulative dosage, and can occur decades after exposure (Kremer et al., 2001).

Many proposed mechanisms of action, including generation of semiquinone free radicals and oxygen free radicals.

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17
Q

Give 2 examples of cytotoxic antibiotics

A

Doxorubicin

Daunorubicin

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18
Q

Describe the mechanisms of action for cytotoxic antibiotics

A

Intercalates with DNA and inhibits both DNA and RNA synthesis

Cytotoxic action also thought to be mediated through its effect on topoisomerase II (a DNA gyrase), the activity of which is markedly increased in proliferating cells

During replication of the DNA helix, Type IItopoisomerasecuts both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils.

Doxorubcin intercalates into the DNA and stabilises the DNA-topoisomerase II complex after the strands have been nicked, thus halting the process at this point.

Denard, Lee and Ye (2012) also report that doxorubicin produces ceramide formation which ultimately leads to increased expression of several genes which inhibit cellular proliferation

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19
Q

Describe the mechanism of action of plant derivatives

A

Act on the Mitotic (M) Phase

Bind to tubulin (microtubules) stabilizing them in the polymerized state (freezing them)

The mitotic spindle forms, but fails to breakdown (depolymerisation)

Chromosomes therefore fail to segregate.

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20
Q

Give examples of plant derivatives

A

Taxanes, such as docetaxel and paclitaxel

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21
Q

Describe the features of hormones/anatgonists used in cancer treatment (endocrine therapy)

A

Tumours arising in hormone-sensitive tissue (breast, uterus, prostate gland) may be hormone-dependent, an effect related to the presence of hormone receptors in the malignant cells

Endocrine therapies are widely used and have a favourable adverse-event profile for the treatment of women with hormone receptor-positive metastatic breast cancer (MBC)

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22
Q

Give examples of hormones/antagonists used in cancer treatment

A

Selective Oestrogen Receptor Modulators (SERMs)

Aromatase inhibitors

Selective Oestrogen Receptor Downregulators (SERDs)

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23
Q

Give examples of hormones/antagonists used in cancer treatment

A

Selective Oestrogen Receptor Modulators (SERMs)

Aromatase inhibitors

Selective Oestrogen Receptor Downregulators (SERDs)

24
Q

Give 2 examples of SERMs

A

Tamoxifen

Toremifine

25
Q

Describe the mechanism of action of SERMs

A

SERMs compete with estrogen for binding to the estrogen receptor (ER ) and reduce estrogen signalling within the tumour

ERs bound by SERMs can still form dimers and have some residual agonist activity.

This residual activity has been attributed to the increased risk of thromboembolitic events and endometrial CA

26
Q

Describe the mechanism of action of aromatase inhibitors

A

Aromatase inhibitors disrupt estrogen signalling in the breast cancer tumour by reducing the amount of estrogen circulating in the bloodstream.

These targeted agents inhibit the aromatization of circulating androgens into estrogen.

27
Q

Where are aromatase inhibitors most effective?

A

Most effective for inhibition of peripheral estrogen production (from fat, muscles, liver, and the tumour)

28
Q

When are aromatase inhibitors contraindicated?

A

Because of high estrogen production in the ovaries, aromatase inhibitors are not indicated in premenopausal women

29
Q

Describe the mechanism of action of SERDs

A

SERDs bind to and accelerate the degradation of the estrogen receptor (ER), diminishing the signal.

Estrogen receptors bound by a SERD cannot form dimers with other estrogen receptors.

There is no known agonist activity associated with SERDs.

30
Q

Give an example of a SERD

A

Fulvestrant

31
Q

What is the result of the lack of oestrogen-agonist activity displayed by SERDs?

A

Since fulvestrant has no known estrogen-agonist activity, this agent has not been associated with the increased incidences of endometrial cancer or cardiovascular events as has been reported with tamoxifen

32
Q

Describe the features of growth factor receptors

A

Ligand binding domain located on the extracellular side of the membrane

Single transmembrane spanning helix

Cytoplasmic tail possesses intrinsic catalytic activity (tyrosine kinase)

Ligand binding induces dimerisation of the receptors resulting in autophosphorylation on tyrosine residues located in the cytoplasmic domains

33
Q

What are the features of monoclonal antibodies (mAbs)?

A

mAbs are a relatively recent addition to the arsenal of anti-cancer drugs.

Unlike the majority of the cytotoxic drugs, they offer the prospect of highly targeted therapy without many of the side effects associated with conventional chemotherapy.

This advantage is offset by the fact that they are given in combination with more traditional therapies

34
Q

Describe the mechanisms of action of monoclonal antibodies

A

Either bind to its target and activates the host’s immune response and the cancer cell is killed by complement-mediated lysis or by killer T cells

Or attach to and inactivate growth factor receptors on cancer cells (inhibiting the binding of the endogenous agonist), thus inhibiting the survival pathway and promoting apoptosis

Or targets and neutralizes circulating VEGF, thereby preventing angiogenesis and tumour survival

35
Q

Give examples of monoclonal antibodies

A

Avastin
Cetuximab
Herceptin

36
Q

Give examples of monoclonal antibodies

A

Avastin
Cetuximab
Herceptin

37
Q

Describe the features of Avastin

A

Humanised monoclonal Ab against VEGF.

Targets and neutralizes circulating VEGF, thereby preventing angiogenesis and tumour survival

Licenced for the treatment of metastatic colorectal cancer and metastatic breast cancer

Given by IV infusion

38
Q

Describe the features of Cetuximab

A

Chimeric Ab binds directly to the Epidermal Growth Factor Receptor (EGFR, a receptor tyrosine kinase)

Competitively inhibits the binding of EGF to its cognate receptor)

Licenced for the treatment of metastatic colorectal cancer in patients with tumours expressing epidermal growth factor receptor.

Given by IV infusion

Patients must receive an anti-histamine and a corticosteroid before infusion

39
Q

Describe the features of Herceptin

A

Humanised murine monoclonal antibody which binds to the oncogenic protein HER2 (human epidermal growth factor receptor-2 – a receptor tyrosine kinase)

Licenced for the treatment of early breast cancer which over-expresses human HER2. (Over 25% of breast cancer patients over-express this receptor and proliferation is rapid)

Metastatic gastric cancer in patients with HER2-positive tumours

40
Q

Describe the suggested mechanisms of Herceptin

A

HER2 internalization and degradation

Antibody-dependent cellular cytotoxicity (mAb attracts/recruits immune cells such as Natural Killer cells to the tumour site which over-expresses HER2)

Interference with HER2 dimerization and inhibition of downstream pathways (p42/44 MAPK and PI3-kinase)

41
Q

Describe the mechanism of action of Pertuzumab

A

Pertuzumab is a HER2-”directed” humanised monoclonal Ab

HDIs bind to the HER2 receptor to block dimerization of HER2 with other HER family members (HER1, HER3, HER4)

This prevents HER2-mediated tumour cell survival and proliferation

Pertuzumab is designed to bind to domain 2 of HER2 to block ligand-activated pairing of HER2 with other HER2 family members (eg. HER3)

42
Q

Describe the features of Pertuzumab

A

HER2 dimerization inhibitors (HDIs): a new class of agents which target HER2

Pre-clinical studies indicate that inhibiting HER2/HER3 dimerization interrupts both the MAPK cellular proliferation pathway and the PI3 Kinase cell survival pathway which ultimately inhibits tumour growth.

Pre-clinical studies have demonstrated that combining the anti-HER2 activity of Tratstuzumab (Herceptin) with the anti-HER2 dimerization activity of Pertuzumab offers a more comprehensive blockade of HER2-driven signalling pathways than with either agent alone

Synergistic anti-tumour effect

43
Q

Give 2 examples of a protein kinase inhibitor

A

Gefitinib

Sunitinib

44
Q

Describe the mechanism of action of protein kinase inhibitors

A

A small molecule inhibitor selective for EGFR intrinsic tyrosine kinase activity

Inhibits EGFR tyrosine kinase by binding to the ATP-binding site of the enzyme

Tyrosine residues on the intracellular component of the EGFR are NOT phosphorylated therefore are unable to act as docking sites for proteins integral to cellular proliferation pathways (MAPK) and cell survival/anti-apoptotic pathways (PI3-kinase)

45
Q

When is Gefitinib used?

A

This tyrosine kinase inhibitor is licenced for the treatment of locally advanced or metastatic non-small cell lung cancer with activating mutations of the epidermal growth factor receptor (the receptor is constitutively active)

46
Q

Describe the features of Sunitinib

A

Sunitinib maleate interacts selectively with the intracellular ATP-binding sites of multiple receptor tyrosine kinases (RTKs) including:

  • Vascular endothelial growth factor receptors 1–3 (VEGFR1–3),
  • Platelet-derived growth factor receptors (PDGFRs),
  • Stem-cell growth factor receptor (KIT),
  • Fms-related tyrosine kinase 3 (FLT3)
  • Colony-stimulating factor 1 receptor (CSF1R).

Receptor inhibition has multiple effects on cellular processes including:

  • Tumour cell survival and proliferation
  • Angiogenesis
  • Lymph angiogenesis (involvement of the lymphatic vasculature in metastatic tumour spread)
47
Q

What are the final anti-tumour effects of sunitinib?

A

Tumour cell death

Anti-angiogenic effects leading to growth delay and/or tumour regression by inhibition of new blood-vessel formation

Vascular disruption by inhibition of existing VEGF/VEGFR-dependant tumour blood vessels leading to central tumour cell necrosis.

48
Q

What are the final anti-tumour effects of sunitinib?

A

Tumour cell death

Anti-angiogenic effects leading to growth delay and/or tumour regression by inhibition of new blood-vessel formation

Vascular disruption by inhibition of existing VEGF/VEGFR-dependant tumour blood vessels leading to central tumour cell necrosis.

49
Q

When is sunitinib used?

A

Sunitinib is used in gastrointestinal stromal tumours, cancer of the pancreas and renal cell carcinoma.

50
Q

Give examples of anti-cancer therapies being researched

A 
Antisense Oligonucleotides (anti-Bcl-2) 
Stapled helical peptide derived from p53
51
Q

Give an example of an Antisense Oligonucleotide

A

Augmerosen

52
Q

Describe the mechanism of action of Augmerosen

A

Augmerosen, down-regulates the anti-apoptotic protein Bcl-2

An early clinical trial demonstrated that Augmerosen (Genta) sensitized malignant melanoma to standard anti-cancer therapy

53
Q

Describe the features of Antisense Oligonucleotides

A

Synthetic sequences of single stranded DNA complementary to specific coding regions of mRNA, which can inhibit gene expression

54
Q

Describe the features of the anti-apoptotic protein Bcl-2

A

Exerts its anti-apoptotic effect by blocking mitochondrial release of cytochrome c, thereby preventing or delaying the onset of cell death.

Tumour cells which overexpress Bcl-2 are relatively resistant to the cytotoxic effect of current anticancer therapy.

55
Q

Describe the features of p53

A

A tumour suppressor protein

Part of our apoptotic machinery which disposes of abnormal cells

Scans the DNA in search of damage

If damage is irreparable, p53 will switch on the apoptotic machinery of the cell

56
Q

Describe the mechanism of action of staple p53 mimetic peptides

A

MDM2 is a negative regulator of the tumour suppressor protein p53

MDM2 binds to p53 and mediates its degradation by the Ubiquitin-mediated pathway

There is a binding cleft in the MDM2 protein which binds a helical region of p53

Synthetic stapled helical peptides corresponding to this helical region of p53 inhibit the degradatory activity of MDM2

P53 activity is therefore enhanced

Therapeutic Pharmacology 2 (7 decks)

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