L14 - Anti-cancer 2: Targeting DNA replication, transcription & cell division Flashcards by Micro Bio

Aims of palliative chemotherapy?

extend survival but patient will eventually die

symptoms recur between treatments

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Aims of curative chemotherapy for solid tumours?

tumour reduced by surgery/radiation

treatment of micrometastases continued

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Aims of curative chemotherapy for disseminated cancers?

combination drug therapy (reduce drug resistance)

each drug has different cellular site of action

each drug has diff. organ toxicity

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How is the cell cycle different in cancer cells?

cancer cells go through cell cycle much faster

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What are antimetabolites?

structurally related to normal compounds

inhibit/interfere with DNA/RNA synthesis

S-phase specific

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What is MTX structurally related to?

folic acid

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What is methotrexate (MTX)?

antimetabolite

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What is MTX retained in cells as?

MTX-polyglutamate compounds

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How can MTX be rescued?

Leucovorin - produces tetrahydrofolate in cells

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Where does MTX target?

cells in S phase

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What cancers is MTX used against?

ALL
Breast
Head and neck

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How does MTX work?

inhibits dihydrofolate reductase (DHFR) and stops production of tetrahydrofolate - stops production of precursors for DNA synthesis

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What does DHFR usually do?

catalyses folate into tetraphydrofolate - used for synthesis of precursors of DNA synthesis

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Is MTX toxic?

potentially - may block stem cell replication

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Can MTX treat other diseases?

Yes - low dose treatment of rheumatoid arthritis

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How is MTX administered?

oral
IV
IM
intrathecally

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What is the fate of MTX?

unchanged drug appears in urine

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What is 6-mercaptopurine?

nucleotide anlogue

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What does 6-Mercaptopurine do?

inhibits purine biosynthesis

converted into thio-IMP by HGPRT

blocks synthesis of other nucelotide precursors

blocks phospho-ribosylamine synthesis

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How does 6-Mercaptopurine lead to non-functional molecules?

incorporated into DNA and RNA

ribosomes cannot translate chemically modified RNA

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How is there resistance to 6-Mercaptopurine?

inherited mutations - do not make HGPRT

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What is 5Fluorouracil (5FU)?

uracil analogue

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What does 5FU do?

block production of dTMP by thymidylate synthetase, needed for DNA synthesis and cell growth

deplete intracellular nucleotide pools

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What is 5FU often given in combo with?

MTX

they target diff enzymes - 2 diff aspects of DNA and RNA synthesis in cancer cells

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What is Gemcitabine?

analogue of deoxycytidine

What does Gemcitabine do?

inhibit DNA synthesis can be phosphorylated deaminated to non-toxic products & excreted in urine

What is Gemcitabine used to treat?

advanced metastatic pancreatic cancer

how is Gemcitabine administered?

infused IV

Side effects of Gemcitabine?

myelosuppression | depressed WBC count

What is Cytarabine (cytosine arabinoside/AraC)?

chain terminator of DNA synthesis inhibit DNA polymerases competes with normal deoxyribose precursors

side effects of Cytarabine

myelosuppression

Fate of cytarabine?

excreted in urine

What does Dactinomycin do?

binds to DNA minor groove - interferes with transcription AND DNA replication DNA double strand breaks

What is dactinomycin used in combination with?

MTX

Why is there resistance to dactinomycin?

P-glycoprotein - major mediator against cancer drugs

why is the double strand break system of dactinomycin not that effective?

enzyme system repairs breaks

Why are antibiotics used as cancer therapy?

to block the life of cancer cells

Fate of dactinomycin?

urine and bile doesn't cross blood-brain barrier

What are the 2 anthracyclines?

Doxorubicin | Daunorubicin

How do anthracyclines work?

intercalate into DNA generate free radicals - break up DNA strands interfere with DNA breakage repair system - apoptosis can be activated oxidise lipids in membranes

What cell cycle stage to anthracyclines target?

S and G2 phase

What are anthracyclines used to treat?

breast lung leukaemia (in combo)

What is the fate of anthracyclines?

bile and urine

What do alkylating agents do?

transfer alkyl groups to DNA act on adjacent G bases in DNA

What type of cells do alkylating agents target?

rapidly dividing cells

What do alkylating agents need for transformation into active drug?

cytochrome p450 - hydroxylates and activate

What are alkylating agents used to treat?

solid and lymphatic tumours

original use of alkylating agents?

mutagens to create mutations in organisms

Why can alkylating agents be used for brain cancer?

cross blood-brain barrier

2 examples of alkylating agents?

Temozolomide | Decarbazine

How are aklylating agents administered?

orally (temozolomide) | IV (decarbazine)

What are platinum coordination complexes?

cisplatin carboplatin oxaliplatin

How do platinum coordination complexes work?

form intra- and inter-strand crosslinks interferes with transcription AND DNA replication

What cell cycle stage to platinum coordination complexes target?

G1 and S phase

What does cisplatin treat?

solid tumours testicular (VBL and bleomycin combination) bladder

What are topoisomerase I inhibitors?

bind to enzyme-DNA intermediate and prevent re-ligation of DNA strand by Topo I

What are the topoisomerase I inhibitors?

Topetecan | Irinotecan

What is Topetecan used to treat?

metastatic ovarian cancer lung cancer

What is Irinotecan used to treat?

Colon & rectal cancer (combo with 5FU and leucovorin)

How are Topo I inhibitors administered?

What does Topo II usually do?

breaks and reseals DNA strands

What are Topo II inhibitors?

Daunorubicin Doxorubicin Etoposide teniposide

What do Etoposide and teniposide do?

bind to transient cleavable form of enzyme-DNA complex = double strand breaks

How are daunorubicin and Doxorubicin Topo II inhibitors

intercalate DNA prevent topo II catalysed breakage/reuinion - DNA strands NOT repaired

What cell cycle stage do topo Inhibitors target?

S phase

What is Etoposide used to treat?

testicular cancer | bleomycin, cisplatin

What is teniposide used to treat?

ALL gliomas neuroblastomas

How are topo II inhibitors administered?

IV and oral

What do Vinca alkaloids do?

block mitosis in METAPHASE bind to tubulin - inhibit microtubule formation induce spindle dysfunction

What do taxanes do?

block mitosis in METAPHASE bind b-tubulin subunit promote polymerisation BUT microtubules are non-functional and "frozen"

What are the 2 Vinca alkaloids?

Vincristine (VX) | Vinblastine (VBL)

What are vinca alkaloids isolated from?

Vinca rosea

Side effects of VX?

neurotoxic

Side effects of VBL?

myelosuppressant

What are Vinka alkaloids used to treat?

rapidly dividing tumours

What are the 2 taxanes?

Paclitaxel | Docetaxel

What are taxanes used to treat?

advanced ovarin & breast cancers non-small cell lung

Side effect of taxanes?

neutropenia

What can help reduce neutropenia from taxane treatment?

Filgrastim