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Y2 MCD Cancer > clinical oncology > Flashcards

clinical oncology Flashcards

cancer treatment: explain the main chemotherapeutic and targeted approaches to treating cancer, explain why many cancer treatments cause side effects and recall approaches to minimise this. Explain the rationale for developing new targets and new drugs in cancer therapy

1
Q

4 main anti-cancer treatment modalities

A

surgery, radiotherapy, chemotherapy, immunotherapy

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2
Q

types of genetic mutations causing cancer (can be inherited)

A

chromosome translocation, gene amplification (copy number variation), point mutations within promoter or enhancer regions of genes, deletions or insertions, epigenetic alterations to gene expression

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3
Q

systemic chemotherapy: cytotoxic chemotherapy treatments

A

alkylating agents, antimetabolites, anthracyclines, vinca alkaloids and taxanes, topoisomerase inhibitors

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4
Q

systemic chemotherapy: targeted therapies

A

small molecule inhibitors, monoclonal antibodies

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5
Q

how do cytotoxics work

A

“select” rapidly dividing cells by targeting their structures (mostly the DNA)

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6
Q

what to alkylating agents, antimetabolites, anthracyclines and topoisomerase inhibitors target

A

DNA

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7
Q

what do vinca alkaloids and taxanes target

A

mitotic microtubules

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8
Q

how is cytotoxic chemotherapy administered

A

i.v. or occasionally orally

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9
Q

what does cytotoxic chemotherapy target

A

non targeted, so affects all rapidly dividing cells in body

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10
Q

4 occasions when cytotoxic chemotherapy given

A

post-op (adjuvant to destroy any remaining cancer cells), pre-op (neoadjuvant to downsize prior to surgery), as monotherapy or in combination, with curative or palliative intent

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11
Q

what do alkylating agents do to prevent DNA from uncoiling at replication

A

add alkyl groups to guanine residues in DNA, causing cross-linking (intra, inter, DNA-protein) between DNA strands and preventing DNA from uncoiling at replication

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12
Q

what do cells do when they can’t uncoil at replication following alkylating agent use

A

undergo apoptosis via checkpoint pathway

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13
Q

what do alkylating agents encourage

A

miss-pairing - oncogenic, but risk of relapse cancer (benefits>risk)

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14
Q

what do pseudo-alkylating agents add instead of an alkyl group to guanine

A

platinum (same mechanism of action)

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15
Q

3 examples of pseudo-alkylating agents

A

carboplatin, cisplatin, oxaliplatin

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16
Q

4 examples of alkylating agents

A

chlorambucil, cyclophosphamide, dacarbazine, temozolomide

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17
Q

9 side effects of alkylating and pseudo-alkylating agents

A

hair loss (not carboplatin), nephrotoxicity, neurotoxicity, ototoxicity (platinums), nausea, vomiting, diarrhoea, immunosuppression, tiredness

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18
Q

how do anti-metabolites cause apoptosis

A

masquerade as purine (adenine / guanine) or pyrimidine (thymine / uracil / cytosine) residues, or folate antagonists, leading to inhibition of DNA synthesis, DNA double strand breakage and apoptosis

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19
Q

what do anti-metabolites block

A

DNA replication and transcription

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20
Q

what do anti-metabolite folate antagonists do

A

inhibit dihydrofolate reductase, which is required to make folic acid (used in all nucleic acids, especially thymine)

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21
Q

7 examples of anti-metabolites

A

methotrexate (folate), 6-mercaptopurine, decarbazine and fludarabine (purine), 5-fluorouracil, capecitabine, gemcitabine (pyrimidine)

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22
Q

7 side effects of anti-metabolites

A

hair loss (alopecia; not 5FU or capecitabine); bone marrow suppression causing anaemia, neutropenia and thrombocytopenia; increased risk of neutropenic sepsis or bleeding; nausea and vomiting (dehydration); mucositis and diarrhoea; palmar-plantar erythrodysesthesia (PPE; red hand and feet with peeling skin); fatigue

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23
Q

3 things that anthracyclines do

A

inhibit transcription and replication by intercalating (inserting between) nucleotides within DNA/RNA strand, block DNA repair (mutagenic), create DNA and cell membrane damaging free oxygen radicals

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24
Q

2 examples of anthracyclines

A

doxorubicin, epirubicin

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25
Q

7 side effects of anthracyclines

A

cardiac toxicity (arrhythmias, heart failure due to free radical damage), alopecia (hair loss), neutropenia, nausea and vomiting, fatigue, skin changes, red urine

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26
Q

how do vinca alkaloids work

A

inhibit assembly of mitotic microtubules

27
Q

how do taxanes work

A

inhibit disassembly of mitotic microtubules

28
Q

what do vinca alkaloids and taxanes cause dividing cells to undergo

A

mitotic arrest

29
Q

7 side effects of vinca alkaloids and taxanes

A

nerve damage (peripheral neuropathy, autonomic neuropathy), hair loss, nausea, vomiting, bone marrow suppresion (neuropenia, anaemia, thrombocytopenia), arthralgia (joint pain), allergy

30
Q

2 things that topoisomerases do

A

prevent DNA torsional strain during replication and transcription by inducing temporary single strand (topo1) or double strand (topo2) breaks in the phosphodiester backbone of DNA; protect free ends of DNA from aberrant recombination events

31
Q

cytotoxic chemotherapy drug which has anti-topoisomerase effects

A

anthracyclines

32
Q

3 specific topoisomerase inhibitors which allow permanent DNA breaks

A

topotecan, irinotecan (topo1), etoposide (topo2)

33
Q

4 side effects of topoisomerase inhibitors

A

hair loss, nausea and vomiting, fatigue, bone marrow suppression (anaemia, neutropenia, thrombocytopenia)

34
Q

side effect of irinotecan (topo1)

A

acute cholinergic type syndrome, causing diarrhoea, abdominal cramps and diaphoresis (sweating)

35
Q

what is irinotecan (topo1) given with to prevent acute cholinergic type syndrome

A

atropine

36
Q

2 most important toxicities

A

bone marrow suppression, neutropenic sepsis (as vulnerable to infection due to neutropenia)

37
Q

4 resistance mechanisms of cells to chemotherapy

A

enhanced DNA repair, remove DNA adducts by base excision repair (PARP), enhance ATP-binding cassette transporter on surface to efflux drug, heterogeneity of cells

38
Q

monogenic vs polygenic treatments

A

can stop individual processes in monogenic cancers but for others, parallel pathways or feedback cascades are activated and upregulated

39
Q

how do dual kinase inhibitors counteract polygenic upregulation, and disadvantage

A

block more pathways, preventing feedback loops but increases toxicities

40
Q

10 hallmarks of cancer cell

A

self-sufficient, insensitive to anti-growth signals, anti-apoptotic, pro-invasive and metastatic, pro-angiogenic, non-senescent, avoid immune destruction, deregulate cellular energetics, genome instability and mutation, tumour-promoting inflammation

41
Q

self-sufficiency of cancer cells

A

normal cells need growth signals to move from G0 to active proliferation (signals transmitted into cell via growth factors binding to receptors and causing downstream cascade), however cancer cells ignore as have not dismantled cell cycle machinery

42
Q

3 examples of over-expression of receptors on cancer cells

A

HER2, which is amplified and over-expressed in 25% breast cancer; EGFR, which is over-expressed in breast and colorectal cancer; PDGFR, which is over-expressed in glioma

43
Q

what does over-expression of receptors or ligands, or constitutive receptor activation, on cancer cells lead to

A

increased kinase cascade and signal amplification

44
Q

example of over-expression of ligand for cancer cells

A

VEGF ligand, which is amplified and over-expressed in prostate, kidney and breast cancers

45
Q

2 examples of constitutive (ligand independent) receptor activation

A

EGFR (lung cancer), FGFR (head and neck cancers, myeloma)

46
Q

4 types of monoclonal antibodies

A

-momab (derived from mouse antibodies), -ximbab (chimeric), -zumab (humanised), -mumab (fully human)

47
Q

humanised vs chimeric monoclonal antibodies

A

in humanised, murine regions interspersed withing light and heave chains of Fab portion, whereas in chimeric, murine component of Fab maintained integrally

48
Q

what do monoclonal antibodies do

A

target EC component of receptors and neutralise ligands, which prevents receptor dimerisation and downstream signalling, or causes internalisation of receptor

49
Q

how can monoclonal antibodies lead to an immune response

A

complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity

50
Q

what receptor does cetuximab target

A

EGFR

51
Q

what ligand does bevacizumab bind to and neutralise

A

VEGF

52
Q

what do small molecule inhibitors do

A

bind to kinase domain of tyrosine kinase within cytoplasm, blocking autophosphorylation and downstream signalling

53
Q

example of small molecule inhibitor and what it targeted

A

Gleevec (bcr-abl - Philadelphia chromosome), which targeted the ATP binding region within kinase domain

54
Q

what is oncogene addiction, and why is this in treatment not always possible

A

where a cancerous cell creates a uniquely hyperactive oncogene driving a tumour, so can target but many caner cells don’t have it

55
Q

besides receptor tyrosine kinases, what else can small molecule inhibitors act on

A

IC kinases, so affect signalling pathways

56
Q

targeted therapies vs cytotoxics

A

by acting on EC or IC receptors, targeted therapies block cancer hallmarks without toxicity observed with cytotoxics

57
Q

advantages of monoclonal antibodies

A

highly specific, generate immune response, long-lasting

58
Q

advantages of small molecule inhibitors

A

can be ligand independent, oral administration, cheap, good tissue penetration

59
Q

disadvantages of monoclonal antibodies

A

large structures so low tumour/BBB penetration, only useful if EC target, can cause allergy, usually i.v. administration

60
Q

disadvantages of small molecule inhibitors

A

shorter half life, more frequent administration

61
Q

main issue with all cancer chemotherapy

A

resistance

62
Q

4 resistance mechanisms to targeted therapies

A

mutations in ATP-binding sites, intrinsic resistance, intragenic mutations, upregulation of downstream or parallel pathways

63
Q

how do anti-sense oligonucleotides and RNAi work

A

block translation of specific mRNA

Y2 MCD Cancer (20 decks)

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