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MD2002 Lucas > Cancer Chemotherapy > Flashcards

Cancer Chemotherapy Flashcards

1
Q

What is Cancer?

A
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2
Q

What is the percentage of cancerous cells which should ideally be killed by treatment ?

A

Enough for a clinical response

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3
Q

Describe the main treatment options for cancer.

A

1) Surgical excision
2) Radiotherapy
3) Chemotherapy

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4
Q

Identify the main groups of drugs used in chemotherapy.

A
  • Alkylating agents
  • Antimetabolites
  • Cytotoxic antibiotics
  • Plant derivatives
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5
Q

Identify the most commonly used group of drug in chemo.

A

Alkylating agents

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6
Q

Describe the mechanism of action of Alkylating agents.

A
  • Have properties of forming covalent bonds with suitable nucleophillic substances in the cell under physiological conditions.
  • Intrastrand crosslinking of DNA:
  • Normally guanine residues in DNA exist predominantly in the keto tautomer.
  • This allows them to hydrogen bond with cytosine.
  • When the 7 nitrogen of guanine is alkylated it becomes more acidic and the enol tautomer is formed. (i.e. keto to enol)
  • This modified guanine can mispair with thymine residues during DNA synthesis. i.e. G-T not G-C
  • Alkylation of the 7 nitrogen destabilises the imidazole ring causes ring cleavage
  • This leads to depurination (excision of guanine residues)
  • The resulting damage triggers cell death by apoptosis.
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7
Q

Identify the major groups of alkylating agents. Give one or two examples for each group.

A
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8
Q

Describe the mechanism of action of cyclophosphamide.

A
  • Cyclophosphamide (inactive) activated by P450 mixed function oxidases.
  • Converted into hydroxycyclophosphamide, which forms aldophosphamide reversibly
  • Aldophosphamide transported to other tissues where it forms phosphoramide (cytotoxic) + Acrolein (cytotoxic, responsible for unwanted effect)
  • Mesna counteracts effects of acrolein (haemorrhagic cystitis)
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9
Q

Identify mesna and describe its importance in chemotherapy treatment.

A

Medication used in those taking cyclophosphamide to counteract effects of acrolein (to avoid haemorrhagic cystitis).

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10
Q

Describe the specific features of Busulphan.

A
  • Selective effect on the bone marrow
  • Depresses the formation of granulocytes and platelets in low dosage and red cells in higher dosage.
  • Used in chronic granulocytic leukaemia
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11
Q

Describe the specific features of Nitrosoureas.

A

e. g. lomustine, carmustine
- Lipid soluble

  • Can cross the blood-brain barrier, may be used against tumours of the brain and meninges
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12
Q

Describe the specific features of Cisplatin.

A
  • water-soluble planar coordination complex containing a central platinum atom surrounded by two chlorine atoms and two ammonia groups.
  • its action is analogous to that of the alkylating agents. When it enters the cell, Cl- dissociates leaving a reactive complex that reacts with water and then interacts with DNA
  • causes intrastrand cross-linking- probably between N7 and O6 of adjacent guanine molecules-which results in local denaturation of the DNA chain.
  • Used for ovarian cancer
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13
Q

Identify the main groups of antimetabolites. Give one or two examples for each group.

A

1) Antifolates – e.g. methotrexate
2) Antipyrimidines – e.g. 5-FU, gemcitabine, Cytarabine
3) Antipurines – e.g. mercaptopurine, thioguanine, fludarabine

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14
Q

Describe the specific features of Methotrexate.

A
  • Folate analogue (structurally similar) so antifolate
  • Usually given orally but can also be given
    intramuscularly, IV or intrathecally.
  • Low lipid solubility so does not cross the blood brain barrier easily.
  • Polyglutamated which means it can be retained within cells for weeks.
  • Targets DHFR
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15
Q

Describe the specific features of Fluorouracil.

A

Fluorouracil (5-FU) interferes with thymidylate synthesis (DTMP).

  • It is converted into a fraudulent nucleotide FDUMP. Cannot be converted into DTMP
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16
Q

Describe the specific features of Cytarabin.

A
  • Analogue of cytosine but has arabinose and not ribose attached.
  • Undergoes phosphorylation to give cytosine arabinoside triphosphate.
  • This inhibits DNA polymerase.
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17
Q

Describe the specific features of Gemcitabine.

A

• Analogue of cytarabine.

18
Q

Describe the specific features of Mercaptopurine.

A
  • Converted to 6- mercaptopurine-ribose phosphate, called “Lethal Synthesis”.
  • 6 mercaptopurine-ribose-phosphate inhibits a number of enzymes in the de novo synthesis of purines.
  • Results in fraudulant nucleotide
19
Q

Describe the main features of Fludarabine.

A

In its triphosphate form, inhibits DNA polymerase.

20
Q

Describe the structure of the following antimetabolites:

  • 5-FU
  • Gemcitabine
  • Mercaptopurine
  • Fludarabine
A
21
Q

Identify the main groups of Cytotoxic antibiotics.

A
  • Anthracyclines
  • Dactinomycin
  • Bleomycin
  • Mitomycin
22
Q

Identify the main Anthracyclines.

A

Doxorubicin

23
Q

Describe the mechanism of action of Doxorubicin.

A
  • Generally, binds to DNA and inhibits both DNA and RNA synthesis.
  • During replication of the DNA helix, reversible swivelling needs to take place around the replication fork in order to prevent the daughter DNA molecule becoming inextricably entangled during mitotic segregation.
  • The swivel is produced by topoisomerase II, which nicks both DNA strands and subsequently reseals the breaks. Hence, the activity of topoisomerase II is markedly increased in proliferating cells.
  • Doxorubicin intercalates in the DNA and its effect is to stabilise the DNA-topoisomerase II complex after the strands have been nicked, thus causing the process to seize up at this point.
24
Q

Describe the mechanism of action of Dactinomycins.

A
25
Q

Describe the mechanism of action of Bleomycin.

A
  • Group of metal-chelating glycopeptide antibiotics that degrade preformed DNA, causing chain fragmentation and release of free bases
  • Action on DNA involves chelation of ferrous iron and interaction with oxygen, resulting in the oxidation of the iron and generation of superoxide and/or hydroxyl radicals
  • Most effective in the G2 phase of the cell cycle and mitosis, but it is also active against non-dividing cells
26
Q

Describe the mechanism of action of Mitomycins.

A
  • After enzymic activation in the cells, functions as a bifunctional alkylating agent, alkylating preferentially at O6 of guanine.
  • Cross-links DNA and may also degrade DNA through the generation of free radicals.
27
Q

Briefly explain how plant derivatives generally work.

A

Spindle poisons – affect microtubule function and prevent mitotic spindle formation

28
Q

Identify the main groups of plant derivatives. Give a couple of examples for each group.

A
  • Vinca alkaloids (e.g. Vincristine, Vinblastine)
  • Taxanes (e.g. Paclitaxcel (taxol), docetaxel)
  • Camptothecins (e.g. irinotecan)
  • Etoposide
29
Q

Describe the mechanism of action of Vinca alkaloids, e.g. Vincristine, vinblastine

A

Bind tubulin and prevent polymerisation into microtubules

30
Q

Describe the mechanism of action of Taxanes - Paclitaxel (taxol), docetaxel

A

Stabilise (freeze) microtubules

31
Q

Describe the mechanism of action of Camptothecins, e.g. irinotecan

A

Bind to and inhibit topoisomerase I

32
Q

Describe the mechanism of action of Etoposide.

A

Inhibits mitochondrial function, nucleoside transport and topoisomerase II

33
Q

Identify the main novel targeted agents.

A
  • Rituximab
  • Trastuzumab (Herceptin)
  • Imatinib (Gleevec)
34
Q

Describe the function of the following novel targeted agents and the cancer they are usually used against.

  • Rituximab
  • Trastuzumab (Herceptin)
  • Imatinib (Gleevec)
A
  • Rituximab- Targets a B cell surface protein and is used for B cell lymphomas
  • Trastuzumab (Herceptin)- Targets epidermal growth factor receptor and is used for breast cancer.
  • Imatinib (Gleevec)- Inhibits bcr-abl gene signaling pathways and is used for chronic myeloid leukaemia.
35
Q

What are the main drawbacks of current chemotherapy of cancer ?

A
  • target cell proliferation not the more lethal properties of invasiveness and metastasis
  • non-specific cell killers rather than being aimed at the particular changes which make a cell malignant.
  • the development of resistance (particularly multi-drug resistance) to anticancer drugs
  • remaining cells (tumour stem cells), since total elimination of malignant cells is not possible using therapeutic doses, and the host’s immune response is often not adequate to deal with the remainder
  • Patient compliance due to side-effects (risk of not completing the therapy regimen)
  • Healthy cells which have a high rate of growth and multiplication include cells of the bone marrow, hair, GI mucosa and skin therefore side-effects often relate to these body systems
36
Q

Identify other approaches to cancer therapy, besides the traditional ways (i.e. traditional chemotherapy, radiation, surgery).

A
  • Kill or remove malignant cells: cytotoxic drugs, surgery & irradiation
  • Targeted cytotoxic agents (e.g.antibody-linked toxins or radioactive agents)
  • Specifically inactivate components of oncogene signalling pathway, mAbs etc
  • Employ tissue-specific proliferation inhibitors: estrogens, anti-estrogens, androgens, anti- androgens, glucocorticoids, gonadotrophin- releasing hormone analogues.
  • Enhance host immune response; cytokine-based therapies, gene therapy-based approaches, cell- based approaches (e.g. anti-tumour T cells).
  • Reverse drug resistance; inhibitors of multidrug resistance transport
  • Antisenseoligonucleotides
  • Restore function of tumour suppressor genes: gene therapy.
  • Inhibit tumor growth, invasion, metastasis: inhibitors of angiogenesis, matrix metalloproteinase inhibitors.
  • Inhibitors of anti-apoptotic factors or stimulators of pro-apoptotic factors
37
Q

True or False: Cancer treatment may involve a combination of chemotherapy, radiotherapy and surgery

A

True.

38
Q

Explain the general aim of chemotherapy.

A

“Killing cancer cells”

39
Q

What are the causes of cancer?

A
40
Q

What is Tumour Lysis Syndrome?

A
41
Q

What are other specific side-effects ?

A
42
Q

Summary: mechanisms of action

A

MD2002 Lucas (111 decks)

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