Cancer therapy Flashcards

1
Q

Anti-cancer drug classes

A

Anti-metabolites

Cytotoxic antibotics

Alklating drugs

Alkaloids and taxans

Anti-neoplastic drugs

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2
Q

Action of cell cycle specific drugs

A

Usually target a specific cell cycle phase. Most effective in rapidly proliferating cancer cells.

Drugs which are cell cycle non-specific kill tumour cells in cycling and resing phases of the cell cycle.

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3
Q

How does resistance to anti-cancer drugs develop?

A

Increased rate of DNA repair: e.g. when alkylating agents are used

Formation of trapping agents for ROS

Change in target enzymes

Reduced prodrug activation

Drug inactivation

Transporter

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4
Q

Adverse effects of cancer drugs

A

Tissue necrosis

Targets rapidly dividing normal cells: skin, gut, marrow, germ cells

Death of large numbers of cancer cells causes hyperuricaemia, renal failure

Immunosuppression, leads to infection or secondary tumours

Drug specific effects e.g. renal toxicity.

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5
Q

Role of drug combinations

A

Provides a maximal cell kill within a range of toxicity tolerated by the host.

Provides a broader range of interaction between drugs and tumour cells with different genetic abnormalities in a heterogenous tumour population.

Helps prevent against development of resistance.

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6
Q

Alkylating agents

A

Exert their effects by transferring alkyl groups to DNA (and other parts of the cell). This causes cross-linking of the DNA which leads to mis-pairing and subsequent DNA breaks in the DNA backbone.

Replicating cells are most susceptible to these drugs.

Cells may become resistant by increasing their capacity to repair DNA lesions, reduce transport of the drug into the cell or by conjugating the drug which reduces its activity.

Adverse effects are dose-related. Primarily occurs in rapidly dividing tissues. Increased risk of secondary malignancies.

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7
Q

Anti-metabolites

A

Utilises differences in metabolism between cancer cells and normal cells. They mimic endogenous compounds and have anti-cancer and immunosuppressant effects.

Antagonise folate, purine and pyrimidines

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8
Q

Antifolates

A

Folic acid antagonists. e.g. methotrexate

MTX is a folate analog that binds to dihydrofolate reductase. This enzyme converst dihydrofolate to tetrahydrofolate, which is required for purine and amino acid synthesis (Met, Ser). Inhibition prevents formation of DNA, RNA and cellular proteins.

Action of MTX is increased by polyglutamates which are selectively retained in cancer cells. Drug is excreted renally. Therefore needs to be monitored carefully in renal impairment.

Used in acute leukemia, lymphomas, psoriasis, Rh disease.

Folinic acid (form FH4) reduces side effects of MTX

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9
Q

Purine analogues

A

Purine analogues e.g. AZT, mercaptopurine, thioguanine reduce DNA and RNA synthesis. However, they have low efficacy as a single treatment.

Drugs are metabolised by HGPRT (hypoxanthine-guanine phosphoribosyl transferase) to form toxic nucleotides which inhibits several enzymes involved in purine synthesis.

Used in acute leuekemias and CML.

Adverse effects: liver necrosis and cholestasis.

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10
Q

Factors that affect response to cancer treatment

A

Cell type

Early diagnosis

AIDS/Immunosuppression

Genetics

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11
Q

Main mechanisms of anti-cancer drugs

A

Prevents DNA synthesis (low toxicity for patient)

Inhibits replication of preformed DNA e.g. cytotoxic antibodies/ alkylating agents (more toxic)

Prevent microtubule formation (stops the cell dividing)

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12
Q

Two examples of pyrimidine analogues

A

Cytarabine: similar to cytidine.

5-Fluorouracil:
Converted by enzymes into nucleotide metabolites. FdUMP forms a covalent complex with theymidylate synthase which results in inhibition of DNA synthesis. 5-FU is also converted into FUTP/FdUTP which is incorporated into RNA and DNA respectively.

Drug used for colorectal, breast, bladder and liver cancers.

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13
Q

Action of cytotoxic antibiotics

A

Intercalates DNA bases which blocks transcrption.

Stimulates topoisomerase II induced dsDNA breaks

Causes free radical production which damages DNA

Binds to cell membranes to alter fluidity and transport

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14
Q

Examples of 3 cytotoxic antiboiotics

A

Doxorubicin and daunorubicin: Metabolised to free radicals, cause DNA breaks by stimulating topoII. Maximum effect in S-phase. Both are cardio-toxic. Doxyrubicin active for lymphomas and solid tumours. Daunorubicin active for lymphomas and leukemias.

Bleomycin: Binds to DNA and generates free radicals which cause ss and ds breaks. This stops DNA synthesis. Arrests cells in G2 of the cell cycle. Used for treatment of HL and NHL. Causes pigementation of the skin and pulmonary fibrosis.

Etoposide: Stimulates topoII which causes DNA breaks. Clinical activity against germ cell tumours. HL and NHL and Kaposi’s sarcoma. Targets rapidly diving cells.

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15
Q

Examples of alkylating agents

A

Cyclophosphamide: Oral drug activated by P450 enzymes in the liver. Alkylate nucleotide bases of DNA causing cells to arrest in G2 as DNA cannot divivde. Has maximum effect in S phase. Used in combination against lymphoma, leukemia, choriocarcinoma. Causes harmorrhagic cystitis because by-product of metabolism acrolein has bladder toxicity.

Platinum analogues (cisplatin, carbiplatin): Kill cells at all stages of the cell cycle (most effective S phase). Forms links between DNA strands. Used against solid tumours. Cleared by the kidneys - nephrotoxic, causes peripheral neurophathy.

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16
Q

Topoisomerase 1 inhibitors

A

Topo1 normally produces a ss DNA break which is then re-ligated. Inhibitors prevent religation, which increases the sensitivity of cells to radiotherapy.

17
Q

Drugs used in breast cancer

A

Aromatase inhibitor: useful in the early stage of breast cancer following/instead of tamoxifen.

Anti-oestrogens: tamoxifen suppresses oestrogen dependent breast tumours. Risk of thrombosis and menopausal symptoms

Inhibit growth factors: herceptin, used in aggressive breast cancer

Drop in oestrogens may predispose to osteoporosis. Rist of thrombosis and menopausal symptoms.

18
Q

Use of corticosteroids in cancer treatment

A

Used in leukemia and lymphona.

Reduces oedema and relieves vomiting

Suppresses other hormone depended tumours e.g. thyroid, prostate

19
Q

Name three chemotherapy drugs derived from plants

A

Vinca alkaloids

Podophyllotoxins

Taxanes

20
Q

Action of vinca alkaloids

A

e.g. Vincristine and vinblastine.

Inhibits tubule polymerisation which disrupts the assembly of microtubules. Inhibiting the mitotic spindle arrests the cell in metaphase.

Used in lekemias, lymphoma, nephroblastoma,. Vincristine is neurotoxic, usually presents as peripheral neuropathy but can affect the CNS.

21
Q

Uses of taxanes in chemotherapy

A

Paclitaxel is an alkaloid that binds to microtubules and enhances polymerisation. However there are no microtubule associated proteins so the cell cycle in inhibited.

Broad range of activity in solid tumours

Side effects include hypersensitivity, neuropathy, arrhythmias and myalgia

22
Q

How can drug delivery be targeted to cancer cells?

A

Direct:
target proteins on the cancer cell surface
target cancer cell genes to activate pro-drugs or damage tumour DNA/mRNA

Indirect: target cancer blood supply

23
Q

Commonest limit to the dose of chemotheray drugs

A

Bone marrow toxicity.

Can be reduced by co-treatment with G-CSF/GM-CSF which stimulate BM, allowing maximum doses to be given.

Blood or platelet transfusions may also be needed.

24
Q

Complication of alkylating agents is haemorrhagic cystitis. How can this be avoided?

A

Giving a second drug - mesna which binds to acrolein and prevents unwanted effects.