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Pharm Decks > Lecture 13 - Bleomycins and Platinums > Flashcards

Lecture 13 - Bleomycins and Platinums Flashcards

1
Q

What is bleomycin and what did it originate from?

A
  • mixture of cytotoxic glycopeptide antibiotics
  • isolated from Streptomyces verticillus
  • soluble in water
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2
Q

What is the structure/key features of bleomycin?

A
  • Metal binding domain, with coordinated nitrogen atoms
  • Linker region and bithiazole tail
  • Disaccharide R
  • +charged polyamine tail
  • hydrophilic molecules, unable to cross cell membrane
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3
Q

How are bleomycins used in clinics?

A
  • in combination chemotherapy
  • against lymphomas, squamous-cell carcinomas and germ-cell tumours
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4
Q

What are the side effects of bleomycins?

A
  • dose-dependent
  • lung inflammation –> lung fibrosis
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5
Q

How do Bleomycins work as drugs?

A
  • bind transition metals (Fe(II) or Cu(I)) and oxygen
  • in the presence of a one-electron reductant, can catalyze formation of ssDNA and dsDNA breaks
  • cause damage similar to ionizing radiation
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6
Q

What is an essential feature for dsDNA cleavage by bleomycins?

A
  • The linker between the metal and the bithiazole DNA-binding domain
  • flexibility of the bithiazole moeity
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7
Q

What are the most common outcomes of bleomycin treatment to cells?

A
  • Extended cell-cycle arrest
  • apoptosis
  • mitotic cell death
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8
Q

Do we have a bleomycin synthesised?

A
  • Not fully, we rely on natural products
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9
Q

What different cuts can bleomycins cause?

A

Staggered or blunt end cuts

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10
Q

Where do ssDNA cuts occur for bleomycins?

A
  • cleavage at pyrimidines (Py) 3′ to a guanine
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11
Q

Where do secondary sites of cleavage occur for bleomycin and what cut do they cause?

A
  • Depends on the residue 3′ to the primary cleavage site
  • 5′-G-Py-Pu-3′, 5′-staggered ends,
  • 5′-G-Py-Py-3′, blunt ends
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12
Q

Mechanism of interaction with DNA by bleomycin to cut DNA

A
  • Bleomycin associates with DNA threading its bithiazole tail through the DNA bound by partial intercalation
  • long polyamine tail interacts with the major groove on other side
  • get cut event
  • then regeneration
  • rotation around the bond between two thiazole rings in the tail of bleomycin with other motions, make the peroxide available for interaction with second DNA strand - flips over the DNA and second cut occurs on the other side
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13
Q

What is the 3rd mechanism of DNA repair, for dsDNA?

A

Recombination

  • for these reagents where we cut the DNA on both strands
  • applies to agents which alkylate both strands of DNA, inter-strand crosslinkers, have to adopt this type of repair
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14
Q

Steps of Recombination to repair dsDNA break

A
  1. Recombination initiated by dsDNA break
  2. DNA processed at site of break to yield regions of ssDNA
  3. Rad51 and replication protein A (RPA), coats ssDNA to form a filament that searches for homologous sequences (on the homologous chromosome or the sister chromatid) and initiates the formation of a joint molecule
  4. Break is repaired by DNA synthesis using the intact strands as templates.
  5. Following branch migration and resolution, repaired recombination products are released.
  • The final product contains cross over of both DNA material used
  • Only way of repairing if have dsDNA breaks
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15
Q

What are platinum drugs?

A
  • Antibiotics and antitumour drugs
  • Interfere with DNA, react with individual bases
  • forms duplex adducts crosslinking bits of DNA
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16
Q

Example of a platinum drugs

A
  • Oxaliplatin
  • Cisplatin
  • Carboplatin
  • Aroplatin
17
Q

What is the mechanism of action of cisplatin?

A
  • Reacts with water to form the hydrolysis product
  • which reacts with N7 of guanine to form bridge links within the major groove
18
Q

What crosslinks can cisplatin form?

A
  • intrastrand crosslinks between 2 guanines on same strand
  • or interstrand crosslinks between 2 on opposite strands
19
Q

How does cisplatin cause DNA damage?

A
  • kinks the DNA, interferes with ability of DNA to repair itself
20
Q

How do tumours acquire resistance to cisplatin/carboplatin BEFORE DNA binding?

A
  • mutations which block drug entering through copper transporters into cell
  • DNA acts as a nucleophile against the electrophilic drug, upregulating , glutathione and metallothionein levels mopping up the drug
  • Active export of platinum from the cells through copper exporters and through the glutathione S-conjugate export GS-X pump
21
Q

How do tumours acquire resistance to cisplatin and carboplatin AFTER DNA binding?

A
  • upregulate NER to remove major covalent bis-adduct that is formed with adjacent guanines on the same strand of DNA (the intra-strand crosslink)
  • Bypassing of adducts by polymerase β and η
  • Through down regulation of apoptotic pathways
22
Q

What is the best way for tumours to acquire resistance to cisplatin or carboplatin?

A
  • Upregulating NER
  • Preventing the drug getting to the DNA in the first place
23
Q

Once the platinum drug has entered the nucleus what happens?

A
  • preferential covalent binding to the nitrogen on position 7 of guanine occurs
  • major covalent bis-adduct that is formed involves adjacent guanines on the same strand of DNA (the intra-strand crosslink); a minor adduct involves binding to guanines on opposite DNA strands (the inter-strand crosslink)
24
Q

What are some ongoing strategies to avoid resistance of cisplatin and carboplatin?

A
  • increasing the levels of platinum reaching tumours e.g. liposomal platinum products
  • combining existing platinum drugs with molecularly targeted drugs (for example, bevacizumab)
  • using novel platinum drugs such as oxaliplatin
  • using other drugs either alone (TLK286) or in combination (for example, decitabine), which exploit particular cisplatin-mediated resistance mechanisms.
25
Q

What anti-angiogenic therapy can be used for renal-cell carcinoma?

A
  • bevacizumab
  • a recombinant human monoclonal anti-VEGF antibody that binds to and neutralizes all biologically active isoforms of VEGF
26
Q

Important aspects of DNA recognition and targeting to consider

A
  • secondary structures are important
  • DNA not a rigid ladder
  • Bases have properties depending on sequences around them
  • Hoogsten or Watson crick
27
Q

What do intercalators prefer to target?

A
  • form complexes, prefer to react with DNA with a protein bound to it
28
Q

How do bleomycins differ?

A
  • differ in the terminal amine substituent of the common structural unit, bleomycin acid
29
Q

What are the main components of bleomycin’s for injection

A

Bleomycins A2 and B2

30
Q

How many molecules of bleomycin were determined sufficient to induce dsDNA lesions in an in vitro study?

A

A single molecule is sufficient to generate lesions on both strands of DNA

31
Q

What structural feature of bleomycins are thought to play a role in cellular uptake?

A

Positively charged tail

32
Q

What structural components of bleomycins interact with the grooves?

A
  • +polyamine tail forms interaction in the major groove
  • sugars sit in the minor groove
33
Q

How does the bithiazole tail act?

A
  • In an intercalator manner
34
Q

What needs to happen to bleomycin in order for dsDNA cleavage to occur?

A
  • Bleomycin reactivation and reorganization
  • Must be a regeneration with this catalytic cutting centre to form the second cut
35
Q

What other forms of dsDNA break repair are there?

A
  • NHEJ
  • BIR
36
Q

What therapy are platinum drugs frequently combined with?

A
  • Bevacizumab
  • May stabilise the vasculature and reduce tissue interstitial pressure, enhancing penetration of chemotherapeutic drugs
  • improve sensitivity to cytotoxic drugs like platinum’s
  • reduce dose
37
Q

Combination of cisplatin and decitabine…

A
  • exploit cisplatin mediated resistance mechanisms
  • Such as GSH, reduced glutathione and glutathione S-transferase
  • In GASTRIC CANCER: induce Sox2 DNA demethylation to promote expression of the Sox2 gene –> anti-tumour
38
Q

Overview of development of platins

A
  • Cisplatin –>
  • Carboplatin - improved safety
  • and oxaliplatin - broader spectrum of antitumour activity
39
Q

What is Aroplatin and the rationale for making it?

A
  • an attempt to formulate liposomal preparations of cisplatin like agents

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