Cancer chemotherapy Flashcards Preview

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Flashcards in Cancer chemotherapy Deck (51)
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1
Q

what makes cancer cells special?

A
  • uncontrolled proliferation
  • loss of original function (anaplasia)
  • invasiveness
  • metastasis (malignant cells)
2
Q

what are the treatments available for cancer?

A
  • surgical removal
  • irradiation
  • chemotherapy with anticancer drugs
3
Q

when is surgery used as a cancer therapy?

A

only:

  • for solid tumours
  • if non-metastasised
4
Q

when is irradiation used as a cancer therapy?

A

only if localised

5
Q

what is required to use chemotherapy as a cancer treatment?

A

selective toxicity

6
Q

can the treatments be combined?

A

yes

7
Q

what happens to a single cells after 30 doublings?

A

it gives a cell mass of 10^9 cells - 2cm in diameter

  • detectable in skin or breast (80%)
  • non-detectable in liver
8
Q

how do normal cells become cancer cells?

A

through a change in DNA

9
Q

what two main categories of genetic change are there?

A
  • inactivation of tumour suppressor genes

- activation of photo-oncogenes to oncogenes

10
Q

what is apoptosis of transformed cells?

A
  • failed check points at cell division

- programmed cell death

11
Q

what do most anticancer drugs do not do?

A
  • de-differentiation
  • invasiveness
  • metastasis
12
Q

what do cell cycle drugs attack?

A

only a subpopulation of the cancer cells

13
Q

what are cell-cycle specific drugs?

A

drugs that are active only on dividing cells

14
Q

what are cell-cycle non-specific drugs?

A

drugs also active on resting cells

15
Q

what do solid tumours consist of?

A
  • dividing cells - progressing through cell cycle
  • resting cells - not dividing but could do so
  • cells which can no longer divide but contribute to tumour size
16
Q

what are dividing cells sensitive to?

A

cell-cycle specific drugs

17
Q

what are resting cells insensitive to?

A

many drugs

also causes many relapses

18
Q

how many chemotherapy drugs are there?

A

more than 90

19
Q

what do chemotherapy drugs mainly affect?

A

cell division

20
Q

what do anti-cancer drugs affect?

A

all rapidly dividing normal tissue

21
Q

what are the general toxic effects?

A
  • bone marrow suppression (red and white blood cells)
  • loss of hair
  • damage to gastrointestinal epithelium
  • liver, heart, kidney
  • in children, depression to growth
  • sterility
  • teratogenicity (damage to embryo)
22
Q

what happens if a dose of chemotherapy drug kills 99.999% of all dividing cells in a tumour of 10^9 cells?

A

it still leaves 10,000 cells

23
Q

what does chemotherapy drugs aim to?

A

total kill of these cells

24
Q

why is it required a prolonged treatment?

A

to reduce chance of relapse from resting cells –> severe cumulative toxicity

25
Q

what are the main classes of drugs?

A
  • alkylating agents
  • antimetabolites
  • cytotoxic antibiotics
  • microtubule
  • steroid hormones and antagonists
26
Q

what are alkylating agents?

A
  • form covalent bonds with DNA
  • interfere with both transcription and replication
  • most alkylating agents have two reactive groups
  • allow the drug to cross-link
    · with one strand DNA
    · across 2 strands of DNA
27
Q

what are the types of alkylating agents?

A
  • nitrogen mustards - derived from mustard gases
  • cysplatin
  • lomustine - can penetrate brain
  • busulphan
28
Q

what is mechlorethamine?

A

type of nitrogen mustard

  • first anticancer chemotherapy drug
  • blister agent
  • used to treat Hodgkin’s lymphoma, non-Hodgkins lymphoma
  • highly reactive- must be given in vivo
29
Q

what is melphan?

A
  • fusion of mechlorethamine with phenylalanine (precursor of melanin)
  • might accumulate specifically in melanomas
  • more stable
  • absorption and distribution possible without extensive alkylation
    used to treat multiple myeloma, ovarian and breast cancer
30
Q

what is cyclophosphamide?

A
  • high phophoramidase activity in some tumours
  • specific in situ activation in tumour cells
  • prodrug, activated in liver
  • much less toxic
  • aldehyde dehydrogenase protects against drug - in bone marrow, hepatocytes and intestinal epithelium
  • used to treat many cancers of tissues low in aldehyde dehydrogenase
31
Q

what is cisplatin?

A
  • targets N7 of purine nucleotides
  • resistance from
    · nucleotide excision repair mechanism
    · efflux transporters for Copper
32
Q

what are antimetabolites?

A

drugs that interfere with nucleotide synthesis or DNAa synthesis

33
Q

what are the nucleotide synthesis (antifolates)?

A

methotrexate, ralitrexed, pemetrexed

34
Q

what are the nucleotide analogues?

A

5-fluorouracil, cytarabine (Ara-C), gemcitabine, fludarabine, capecitabine

35
Q

what are the types of antimetabolites?

A
  • folate antagonists: methotrexate
  • pyrimidine analogues: fluoro-uracil
  • pruine analogues: mercaptopurines
36
Q

what are folate antagonists?

A
  • higher affinity for dihydrofolate reductase than folic acid
  • inhibition of tetrahydrofolate formation
  • inhibition of purine/pyrimidine synthesis
  • ultimately, halt to DNA and RNA synthesis
37
Q

what are pyrimidine analogues?

A
  • prevents thymidine biosynthesis

- stops DNA synthesis

38
Q

what are purine analogues?

A
  • converted into false nucleotides
  • disrupt purine nucleotide synthesis
  • may be incorporated into DNA, disrupting helix
39
Q

what is cytarabine?

A
  • sugar moiety of cytidine is arabinosine rather than ribose
  • isolated from the sponge cryptothethya crypto
  • cellular activation to ara-CTP
  • S phase cell cycle specific
  • inhibit DNA polymerases
  • incorporation into DNA causes chain termination
40
Q

what are cytotoxic antibiotics?

A

act mainly by a direct action on DNA as intercalates

- dactinomycin

41
Q

what is dactinomycin?

A
  • isolated from Streptomyces
  • inserts itself into the minor groove in the DNA helix
  • RNA polymerase function is disrupted
  • common adverse drug reaction includes bone marrow suppression, fatigue, hair loss, mouth ulcer, loss of appetite and diarrhoea
42
Q

what is Doxorubicin?

A
  • from Streptomyces?
  • inserts itself between base pairs
  • binds to the sugar-phosphate DNA backbone
  • local uncoiling
  • impaired DNA and RNA synthesis
  • now some 2000 doxorubicin analogues (anthracyclines) exist
43
Q

what are microtubule inhibitors?

A
  • isolated from Madagascar periwinkles
  • bind to micro tubular protein
  • block tubulin polymerisation
  • block normal spindle formation
  • disrupt cell division
44
Q

what do steroid hormones do?

A

tumour may be responsive to a specific hormone which makes it regress

  • prednisone
  • prednisolone
45
Q

what is prednisone?

A
  • synthetic adrenocortical steroid hormone

- converted in the body to active form

46
Q

what is prednisolone?

A

suppresses lymphocyte growth

47
Q

what will an antagonist of the hormone do?

A

suppress growth

e.g. tamoxifen - antagonist of oestrogen receptor

48
Q

what are some breast cancers?

A
  • oestrogen dependent
  • oestrogen stimulates their growth
  • can be treated with Tamoxifen
49
Q

what are most prostrate cancers dependent on?

A

stimulation by testosterone

50
Q

what could the prostrate cancer treatment be?

A

testosterone receptor antagonists

  • e.g. glutamine (Drogenil)
  • now replaces by bicalutamide (casodex)
51
Q

what are pituitary downregulators for prostrate cancer?

A
  • LHRH agonists inhibit release of Luteinising hormone (LH)
  • LH normally stimulates testes to produce testosterone
  • result: reduced testosterone release, reduced cancer growth