cancer part 4 Flashcards by Okemadu Christian Ukachukwu

State the first metal complex used in cytotoxic therapy

Cis platin

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Are metal-based cytotoxic compounds cell cycle non-specific therapeutics?

Yes

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State facts about Cis platin

the most powerful/effective antitumour compound in use.
But its only effective against a limited range of tumours.
Accidental discovery by Rosenberg in 1960 - medical use delayed due to scepticism.

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What the mode of action of cis platin?

Diffuses into cells
Two Cl atoms aquated, leads to alkylation of N7 and O6 of guanine:-
Intra-strand breaks
Inter-strand breaks
Cross-link between DNA and associated protein

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Facts about HMG-domain protein

An HMG-domain protein (HMGB1; domain A shown as gray ribbon) inserts a phenyl group (yellow) into the groove created when cisplatin (platinum shown in red) forms a complex with DNA, causing it to bend.

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Describe how cis platin binding occur

Aquated cisplatin binds with high affinity to
nuclear DNA, esp nucleophilic N7 sites on purines, thereby promoting the activation of the DNA damage response.
cytoplasmic nucleophiles such as mitochondrial DNA (mtDNA) as well as multiple mitochondrial and extramitochondrial proteins

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State the uses of Cis platin

V. effective-vs-certain rare tumours with poor alternative treatment options
Sometimes cures - often increased survival
Testicular - v. effective vs lung mets from testicular
Effective vs a broad range of cancers - Prostate, ovarian, cervical, bladder, thyroid, head/neck/ oesophageal cancers, breast cancer
Often in combo with vinblastin & bleomycin

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Facts about Cis Platin’s toxicity

V. long 1/2 life (days) - protein binding, tissue accumulation (esp kidney, liver)
Biphasic clearance, not cross BBB
Nephrotox - dose limiting
Fractionate dose ie 5x iv daily not single iv bolus
N and V is severe
Ototoxicity, peripheral neuropathy, metal complexes
Regular testing - renal, auditory

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State how to limit nephrotoxicity when using Cis Platin?

Pre-treatment forced diuresis - iv mannitol/saline

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List an example of Metal complexes with reduced toxicity

Carboplatin
oxaliplatin

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Antitumour antibiotics are cell cycle——

Non specific agents

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The cytotoxic effect of anti-tumour antibiotics is due to what ?

to interaction with DNA - leads to disruption of cell function

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list examples of antitumour antibiotics

Anthracyclines
Actinomycin-D
Bleomycin

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State the indication of Doxorubicin

widely used and improve cancer drug for sarcomas, breast, lung, ALL and lymphomas

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state the indication of Aclarubicin & Idrarubicin

Similar spectrum with Doxorubicin

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What is Epirubicin & mitozantrone indicated for

Breast cancer

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What is Daunorubicin indicated for

ALL ( Acute LYmphoblastic Leukaemia ) and AML( Acute myeloid Leukaemia)

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State the mechanism of action of Anthracyclines

Bind to DNA causing adducts
Intercalation with DNA between adjacent base-pairs/cross links (interferes with DNA repair) blocks topo II

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Anthracyclines binds to cell membrane proteins leading to altered transport functions. True/False

True

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State how Anthracyclines cause the DNA strand to rupture

Generation of oxygen radical by lipid peroxidation - P450 reductase catalyses reduction to semiquinone free radicals - yields superoxide radicals and hydrogen peroxide - strand rupture

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Cardiotoxicity of Doxorubicin is minimized by

The use of liposomal Doxorubicin

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State the adverse effects of Anthracyclines

Dose-dependent irreversible cardiotoxicity due to free radical generation
Extravasation
Severe alopecia
Transient bone marrow suppression, GI disturbance
cardiotoxicity

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Describe Bleomycin?

Mix of different metal chelating glycopeptides

State the uses of Bleomycin

Testicular cancer - almost 100% effective in combo with cisplatin and vinblastin/etoposide
Squamous cell carcinomas
Lymphomas

State the mechanism of action of Bleomycin

Fe2+ complex Oxidation to Fe3+ Free radicals Strand breaks Cytotoxicity blocked progression

State how Topoisomerase inhibitors work?

Active in S-phase – inhibition of DNA ‘unwinding’

What are Antimetabolites

They are Analogues of natural substrates

Describe how Antimetabolite work

Competitive antagonist of enzymes involved in anabolic metabolism Affects production of nucleotides needed for ‘de novo’ synthesis of DNA Incorporation into a metabolic pathway Formation of defective products False feedback (allosteric) antagonism of initial rate limiting steps in pathway Mimic feedback inhibitory action of a normal regulatory metabolite

State the mode of action of Methotrexate

V polar molecule Enters cell by active transport Kept in cell by polyglutamylation

Methotrexate and derivatives inhibit ..........

DHFR(Dihydrofolate reductase) in all species. Need 1000 fold xs of folate to overcome inhibition Methotrexate also indirectly inhibits folate dependent enzymes (eg thymidylate synthase) Accumlation of MTX polyglutamates Accumulation of dihydrofolate polyglutamates

Methotrexate also indirectly inhibits folate dependent enzymes called

thymidylate synthase

State how folate pool is replenished

By giving a patient folinic acid (Leucovorin)

State the role of Thymidylate synthase

To synthesise thymidine from Uracil

Facts about Raltitrexed(Tomudex)

more specific to TS( Thymidylate synthatase) dvanced colon cancer Combo with irinotecan (Topo inhibitor) and oxaliplatin (cytotoxic agent)

List the three enzyme targeted by Pemetrexed

DHFR TS Glycinamide ribonucleotide formyl transferase (GARFT)

Pyrimidine analogue such as 5FU can follow various uracil pathways such as

Incorporation in RNA via FUTP - 2 ways Incorporation into DNA

Describe how FdUMP acts as a metabolite?

FdUMP can also act as an antimetabolite of dUMP and block TS responsible for conversion of dUMP to dTMP required for synthesis of DNA

State the other mechanism of action of 5-FdUMP?

Not only does 5-FdUMP compete with dUMP for TS TS, FdUMP and an active folate cofactor covalently bind to form a complex which causes a sustained inhibition. Dependent on cofactor concentration - use leucovorin to boost cofactor concentrate and 5-FU activity

Is 5-FU a pro-drug?

5-FU is a pro-drug - only activated in cells expressing enzymes for 5-FdUMP and 5-FUMP

State why 5-FU is used in colorectal cancer

5-FU is a pro-drug - only activated in cells expressing enzymes for 5-FdUMP and 5-FUMP These enzymes are highly expressed in GI tract - use for colorectal cancer

Facts about 5-FU metabolism

80-90% degraded by dihydropyrimidine dehydrogenase (DPD) DPYD gene product 10-20% activated to anticancer agent

state how to overcome cytotoxicity in 5FU

genotyping for DPD using a prodrug such as capecitabine

Describe the Mechanism of action of Capecitabine(xeloda)

prodrug Oral admin Metabolised in cancer cells by thymidine phosphorylase (2), to 5-FU

Describe the mode of action of Tegafur with uracil(Uftoral)

Metabolised in cancer cells by thymidine phosphorylase (2), to 5-FU Uracil inhibits 5-FU breakdown – higher target tissue concentration than with 5-FU alone oral administration

A pyrimidine analogue that is cell cycle specific phosphorylated to d-araCTP - competes with dCTP for DNA, Blocks strand elongation and repair mechanisms and Inhibits reduction of CDP to dCDP is known as

Cytosine arabinoside (araC)

facts about Gemcitabine(GEMZAR)

Chain termination as araC

Gemcitabine is indicated for

Breast, lung, ovarian, pancreatic

Facts about Purine antimetabolites

needed for RNA and DNA De novo pathway preferred via IMP (inosinic acid) But salvage route exists for bases and nucleosides

Thioguanine is incorporated into the DNA which leads to strand breaking. true/False

True

Fludarabine is a purine analogue indicated for

Given iv for leukaemia (esp chronic lymphocytic)

State what happens when Fludarabine is given orally

GIT bacteria split off the sugar to give v.toxic fluoroadenine

List the adverse reaction of Fludarabine

N/V/D, myelosuppression, fever, neurological toxicity - blindness, encephalopathy, death

Mr K, a 65 year old man, has a recent diagnosis of multiple myeloma. His treatment begins with the cytotoxic chemotherapy regimen BCD (Bortezomib, cyclophosphamide and dexamethasone). Cyclophosphamide is a cell cycle non-specific agent that affects cell both in G0 and in passing through the cell cycle. Which of the following mechanisms is the BEST match for the described therapeutic? a). Incorporation into DNA leading to chain termination. b). Intercalates into the DNA structure preventing DNA unwinding, transcription and DNA synthesis. c). An orally bioavailable prodrug of a bifunctional nitrogen mustard d). An interaction with the enzyme reverse transcriptase e). Readily crosses the blood brain barrier to target cancer cells seeking ‘pharmacological sanctuary’

Mrs B has bladder cancer and is being treated with cytotoxic chemotherapy in the neoadjuvant setting to shrink the tumour prior to surgery. One of the cytotoxic agents acts as a biochemical mimic antagonising the function of dihydrofolate reductase and thymidylate synthase. Which of the following therapeutics is the BEST match for the described mechanism? a). mechlorethamine. b). bleomycin c). methotrexate d). capecitabine e). bendamustine

Miss S has a diagnosis of advanced colorectal cancer and has enrolled in a trial comparing FOLFOX (5-FU, folinic acid and oxaliplatin) to OX-CAP (oxaliplatin and capecitabine). Capecitabine cytotoxicity is mediated by Select the MOST appropriate mechanism for the therapeutic indicated above. a). Incorporation into DNA leading to chain termination. b). Forming a GG intra-strand DNA cross link which ‘bends’ the DNA slightly c). Acting as an orally bioavailable prodrug of 5-FU d). An interaction with the enzyme thymidine kinase e). The addition of glutamyl groups to proteins

Mrs B has bladder cancer and is being treated with cytotoxic chemotherapy in the neoadjuvant setting to shrink the tumour prior to surgery. One of the cytotoxic agents acts as a biochemical mimic impacting the function of DNA polymerase leading to chain termination. Which of the following therapeutics is the BEST match for the described mechanism? a). mechlorethamine. b). bleomycin c). methotrexate d). cytarabine e). bendamustine

(d) cytarabine

Ms S has a diagnosis of advanced colorectal cancer and has enrolled in a trial comparing FOLFOX (5-FU, folinic acid and oxaliplatin) to OX-CAP (oxaliplatin and capecitabine). Folinic acid activity is mediated by Select the MOST appropriate mechanism for the agent indicated above. a). Incorporation into DNA leading to chain termination. b). Forming a GG intra-strand DNA cross link which ‘bends’ the DNA slightly c). Acting as an orally bioavailable prodrug of 5-FU d). An interaction with the enzyme thymidine kinase e). Acting as an activated folate providing methyl groups for biosynthetic reactions

e). Acting as an activated folate providing methyl groups for biosynthetic reactions