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Cancer - MDT + AT > AT - Bleomycins > Flashcards

AT - Bleomycins Flashcards

1
Q

What are bleomycins?

A

A family of glycopeptide antibiotics that have potent antitumour activity against a range of lymphomas, head and neck cancers and germ-cell tumours.

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2
Q

The therapeutic efficacy of the bleomycins is limited by

A

the development of lung fibrosis.

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3
Q

The cytotoxic and mutagenic effects of the bleomycins are thought to be related to their ability to mediate

A

Both single-stranded and double-stranded DNA damage, which requires the presence of specific cofactors (a transition metal, oxygen and a one-electron reductant).

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4
Q

The ability of bleomycins to cause both SS and DS DNA damage requires the presence of specific cofactors, what are they? [3]

A
  1. A transition metal.
  2. Oxygen
  3. A one-electron reductant
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5
Q

What were the bleomycins isolated from?

A

Streptomyces verticillus

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6
Q

As part of a regimen with cisplatin and etoposide, bleomycins are __% curative for testicular cancer.

A

90%

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7
Q

Why are bleomycins attractive therapeutics?

A

They exhibit both low myelosuppression and low immunosuppression.

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8
Q

The therapeutic efficacy of the bleomycin is limited by their dose-dependent _________, which can affect up to 46% of the total patient population, of which 3% die.

A

Pneumonitis

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9
Q

The bleomycin family members share the same core structure but differ in their decoration with _______ and _________ charged tails.

A

Sugars, positively charged tails.

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10
Q

Bleonoxane, the clinically administered form of the drug is composed of 60% bleomycin __ and 30% bleomycin __.

A

60% bleomycin A2

30% bleomycin B2

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11
Q

The bleomycins require a reduced transition metal (__(II) or __(II)), ______ and a ___-electron reductant to generate an ‘activated’ bleomycin.

A

Fe(II) or Cu(II)
Oxygen
One-electron reductant.

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12
Q

dsDNA cleavage is initiated by an activated ______-conjugated form of bleomycin and this cleavage and its biological consequences are responsible for tumour necrosis.

A

metal-conjugated form of bleomycin

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13
Q

What are the 5 different domains of bleomycin?

A

(1) Metal binding region which is attached to a (2) disaccharide and a (3) linker region which links the metal binding region to the (4) bithiazole tail which has a (5) positively charged tail.

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14
Q

The damage caused by bleomycins is similar to that caused by

A

ionising radiation

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15
Q

Studies have shown that a single molecule of bleomycin is sufficient to generate lesions on _____ strands of DNA.

A

Both strands of DNA.
Hot spots for dsDNA cleavage have been identified and have led to empirical rules about the sequences leading to dsDNA lesions.

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16
Q

Studies on a large number of bleomycin molecules have indicated that the whole molecule is what?

A

Greater than the sum of its parts.

The linker between the metal and the bithiazole DNA-binding region and the flexibility of the bithiazole moiety itself are essential for efficient dsDNA cleavage.

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17
Q

Which part of the bleomycin structure is responsible for DNA binding?

A

The pyrimidine moiety, interacting in combination wth the bithiazole tail is responsible for DNA binding.

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18
Q

What are the most common cellular responses to belomycin treatment?

A

Extended cell-cycle arrest
Apoptosis
Mitotic cell death

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19
Q

Why are bleomycins unable to cross the cell membrane via free diffusion?

A

They are hydrophillic molecules.

They require active transport as a result of the positively charged tail.

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20
Q

Why is it beneficial that biosynthetic genes for bleomycin have been identified and some of the proteins in the pathway characterised?

A

Combined with partial chemical synthesis = cheaper, easier production of bleomycin analogues for research and treatment.

21
Q

The postively charged groups on the bithiazole tail enhance the binding of bleomycin to DNA via __________ _________.

A

Electrostatic interactions.

22
Q

What is the role of the sugars in bleomycins?

A

remains unknown, removing them results in less affinity for DNA in some studies.

23
Q

Flexibility of the bithiazole is required so that bleomycin can reorganise and do what?

A

Cleave the second strand of DNA

24
Q

Recent studies have demonstrated that activated bleomycin can catalyse RNA cleavage with high specificity in vitro. What are the implications for this in practice?

A

Not that great, the evidence supporting RNA as a therapeutic target is limited.

25
Q

Bleomycin induced DNA damage is dependent on what cellular function?

A

The cell cycle.
Bleomycin has been found to cause 2-3 times fewer dsDNA breaks in S-phase cells than in G1 or G2/M phase cells.

Consitent with previous studies that bleomycin does not directly interfere with DNA replication.

26
Q

Bleomycin has been found to cause 2-3 fewer dsDNA breaks in - phase cells than in __ or __/ phase cells.

A

Less in S-phase,

More in G1/G2/M phase.

27
Q

Bleomycin-generated ssDNA lesions result in the production of either a ____ and an _______ ______ site or a base propenal and a gap with a 3’-phosphoglycolate/5’-phosphate ends.

A

a base and an oxidised abasic site.

28
Q

The ssDNA breaks caused by bleomycin can be repaired by ___ using APE1 and POLB.

A

BER using APE1 and POLB

29
Q

What are APE1 and POLB?

A

APE1: apurinic/apyrimidinic endonuclease 1

POLB: Polymerase B

Both involved with BER of ssDNA breaks caused by Bleomycins.

Also of note: TDP1 might function in repair of lesions.

30
Q

Why should the repair of ssDNA lesions lead to accurate restoration of genetic information?

A

There is a template strand opposite which is unbroken which can be used as a template.

(However, base-substitution mutations can occur if the proof reading function of POLB is altered or if APEI is mutated)

31
Q

Increased levels of APE1 in germ cell lines have been shown to correlate with what?

A

Increase bleomycin resistance.

32
Q

HeLa cells and primary fibroblasts treated with bleomycin showed an adaptive response, what happened to levels of and localisation of APE1?

A

Levels of APE1 became upregulated and APE1 was also translocated into the nucleus.

33
Q

What is the evidence to support the role of POLB in the base-excision repair pathway to repair ssDNA breaks caused by bleomycins?

A

Cultured mouse macrophage cells in which POLB is inhibited = sensitisation of the cell to bleomycin damage.

34
Q

What are the two pathways that exist in mammalian cells to repair breaks in dsDNA?

A

Non-homologous end joining NHEJ

Homologous recombination repair HRR

35
Q

In order to repair bleomycin-generated ds-breaks through NHEJ, why are exonucleases like APE1 and TPD1 needed?

A

They are needed to remove 3’-PG ends, the resulting 3’-OH can then be directly ligated.

36
Q

Why is the NHEJ pathway for repair of special interest with respect to bleomycin-induced breaks in dsDNA?

A

It has an error-prone nature.

37
Q

What is ATM?

A

ATM is a phosphatidylinositol-3-kinase-like kinase proposed to function as both a damage sensor and signal transducer with a role in bleomycin-induced DNA damage.

38
Q

How has the role for ATM in bleomycin-induced DNA damage supported?

A

Bleomycin has been shown to introduce 9.7 breaks per metaphase cell in the ATM-knockout cells, 6 times more than in the wild-type cells.

39
Q

What impact does functioning p53 have on bleomycin dsDNA breakage?

A

p53 is involved in dsDNA repair when present and functioning.

40
Q

How many distinct types of tumour-cell death are associated with bleomycin?

A

Two.

They depend on bleomycin concentration in the cell, and consequently the different amount of ds-cleavage of DNA.

41
Q

At a low therapeutic dose of bleomycin, cells accumulate in __/_ phase and a slow, mitotic cell death pathway was observed.

A

G1/M phase = low therapeutic doses of bleomycin = slow, mitotic cell death pathway.

42
Q

High dose bleomycin causes what distinct tumour-cell death?

A

At high doses, bleomycin acts as a micro-nuclease, causing extensive ds-breaks in DNA and rapidly initiates an apoptosis-like process.

The operative pathway is related to the number of ds-breaks mediated by activated bleomycin.

43
Q

Bleomycin is believed to be transported into cells in what form?

A

Bleomycin - Cu(II), once bleomycin is administered IV as the metal-free form, it rapidly picks up Cu(II) from blood plasma.

44
Q

Why does a correlation between cytotoxicity and the exact form of bleomycin in the cell remain to be established?

A

It doesnt seem to matter what form the metallobleomycin takes (zinc, copper, nickel or iron).

45
Q

Why are future studies to identify the precise mechanism by which bleomycin uptake occurs important?

A

If we can alter the bleomycin structure so that it can be more effectively incorporated into tumour cells we will be able to lower the systemic dose of bleomycin, which could potentially minimise lung toxicity.

46
Q

What has been suggested with regards to the lung toxicity caused by bleomycin? what are the implications of this?

A

Independent of cytotoxicity - if we can identify what aspect of bleomycin metabolism causes the lung toxicity we can design analogues without it which retain cytotoxic effects.

47
Q

Recently the uptake problems associated with bleomycin delivery has been addressed by conjugating tallysomycin S (a bleomycin with an additional sugar attached to threonine in the linker) to an internalising antibody BR96. The increased the potency ___-fold.

A

Recently, the uptake problem associated with
bleomycin delivery has been addressed by conjugating
tallysomycin S10b (a bleomycin with an additional
sugar attached to threonine in the linker) to an internalizing
antibody BR96 (REF. 99). The potency of this
conjugate was increased 875-fold in a panel of cell
lines relative to tallysomycin itself. T

48
Q

____ is an internalising antibody which has been conjugated to tallysomycin S (a bleomycin derivative) leading to increase in potency of ____-fold.

A

BR96

875-fold increase.

49
Q

Recent studies have begun to address the question of whether inhibiting which domain of POLB repair protein may potentiate bleomycins cytotoxicty?

A

The lyase domain.

Cancer - MDT + AT (11 decks)

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