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Bioinorganic, take 2 > Section 7 - Platinum based Anti-Cancer Drugs > Flashcards

Section 7 - Platinum based Anti-Cancer Drugs Flashcards

1
Q

When was cis platin approved for clinical use?

A

1978

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2
Q

What cancers does cis platin treat?

A
  • 95% successful for testicular and ovarian cancer
  • Used for head and neck, bladder, lung, cervical cancers
  • lymphoma, melanoma and osterosareoma
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3
Q

What are the loose ‘rules’ for anti cancer activity?

A
  • For (PdL2X2)
  • cis leaving groups
  • neutral complex with Pt(II) and Pt(IV) systems
  • Leaving groups are moderately bound, too labile and the drug is toxic, too strong and the drug has reduced activity
  • non LG is also crucial, amine groups with at least one N-H group
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4
Q

How are anti-cancer drugs tested?

A
  • first in vitro on mouse leukaemia cell lines
  • testing on animals
  • several stages of clinical trials
  • only 1 in 10000 drugs make it to approved clinical use
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5
Q

How is the active form of cis-platin formed?

A
  • slow addition of one water molecule
  • reversible
  • 2-3 hours
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6
Q

What is the structure of cis platin?

A

PtCl2(NH3)2

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7
Q

How was the active species of cis platin determined?

A
  • Pt and N NMR studies
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8
Q

What is mono aqua cis platin attracted to?

A
  • positive charge means the complex is attracted to the negatively charged surface of DNA
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9
Q

What causes the delay in Cis Platin sensitisation?

A

due to the slow formation of the mono aqua complex

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10
Q

Where is the mono aqua complex of cis platin most likely to form?

A
  • in plasma [Cl]= 100 mM and a slow exchange of Cl for H2O
  • the molecule crosses the cell membrane by passive diffusion
  • in the cytoplasm [Cl]= 4 mM so a slow ligand exchange occurs
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11
Q

Why is Pt-DNA binding the main focus of studies?

A
  • diseases where DNA processes are deficient are hypersensitive to cis-platin
  • Correlations have been shown between Pt-DNA adducts in blood cells and disease response in cis-platin patients
  • Treatment of HeLa cells with a high dose of 195Pt(metastable) radiolabelled cis platin shows:

1 Pt per 10^5 protiiens
1 Pt per 100 RNA
1 Pt per 1 DNA

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12
Q

What mononucleotides does Pt bind the most strongly to?

A

G(N7)>A(N7)>A(N1)>C(N3)

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13
Q

Why is the Pt G(N7) bond so strong?

A
  • the most electron rich centre
  • bond can only be broken by a strong nucleophile e.g. cyanide
  • possible H-Bonding also stabilises the adduct
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14
Q

How is the Pt-G(N7) adduct detected spectroscopically?

A
  • Proton NMR
  • Guanune C8-H singlet at 7.8
  • Adduct singlet at 8.8 and Pt satellites
  • large shift means that NMR is very useful in more complex systems
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15
Q

What are oligonucleotides?

A
  • very short duplexes that are 2 to 15 nucleotides long

- used for model studies

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16
Q

Where does cis platin bind in oligonucleotides?

A
  • G(N7)-p-G(N7) almost exclusively
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17
Q

Describe a typical experiment for studying cis-platin binding to DNA

A

1) in vitro incubation of DNA and cis platin
2) extraction of DNA from cells
3) digestion of DNA with enzymes
4) separation by HPLC
5) characterisation by NMR

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18
Q

What percentage of cis platin is cis[Pt(NH3)2(GpG)]?

A
  • 60-65%
  • G,G 1,2 intrastrand
  • hard to cleave due to cycle
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19
Q

What percentage of cis platin is cis[Pt(NH3)2(ApG)]?

A
  • 20 to 25%

- G,A 1,2 intrastrand

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20
Q

What percentage of cis platin is cis[Pt(NH3)2(GMP)2]?

A
  • 5-10%
  • G,G 1,3 intrastrand
  • or interstrand (1,3 most likely)
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21
Q

What percentage of cis platin is cis[Pt(NH3)2(GMP)(OH)]?

A
  • 2-5%
  • monoadduct
  • time dependent
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22
Q

What percentage of cis platin is cis[Pt(NH3)2(GMP)(protein)]?

A
  • less than 1%
  • whole cell studies only
  • DNA protein binding
  • can lead to side effects
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23
Q

Why are 1,2- intrastrand crosslinks important to anti cancer activity?

A
  • they are the major adducts formed

- clinically inactive compounds fail to form these cross links

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24
Q

Describe the kinetics of the mechanism of cis platin and DNA binding

A
  • kinetics is important
  • RDS is the formation of the mono aqua complex
  • binding of DNA and cation is very fast
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25
Q

How do 1,2- intrastrand cross-links distort DNA?

A
  • bending towards the major groove
  • unwinding of the duplex
  • distortion of Watson- Crick base-pairing
  • duplex destabilisation by 6.37 kcal per mol
26
Q

How does distorting DNA affect biological function?

A
  • blocks replication and inhibits transcription

- replication stops at sites one nucleotide before the Pt-G residue and at site opposite the two Pt-G residues

27
Q

What types of cells are sensitive to cis-platin?

A
  • cells deficient in DNA repair
  • DNA is continually checked for errors in its sequence by DNA proteins
  • Proteins can activate enzymes to prevent the errors
28
Q

What is apoptosis?

A
  • programmed cell death

- some evidence suggests it is induces by cis-platin

29
Q

How do Pt 1,2 intrastrand cross links inhibit repair?

A
  • Binding of HMG protien with the 1,2 intrastrand cis Platin DNA complex shields the DNA from repair leading to apoptosis
  • binding occurs by HMG inserting into a phenyl group protruding from its backbone into the notch created when cis Platin binds with DNA
  • increases the bend in DNA to 60-90 degrees
30
Q

What element provides potential coordination sites for Pt complexes?

A
  • Suphur

- strong soft-soft interactions

31
Q

How do platinum and sulphur bind in cells?

A
  • GSH (glutathione) is in cells at 3-10 mM concentrations
  • GSH binds to Pt and gives a polymer with a Pt:GSH ratio of 1:2
  • results in the depletion of Pt from circulation
  • GS-X pump pumps GS-Pt out of tumor cells
  • Is a way of intercepting Pt before it binds to DNA, which makes the drug less effective
  • Cancer cells grow faster and have thinner cel membranes than normal cells so are affected more than normal cells
32
Q

How do platinum and sulphur bind in kidneys?

A
  • Metllothionen (MT) is a low molecular weight protien (6-7 k)
  • 1/3 of residues are Cys
  • Cys residues bind and store metal ions and are used in the kidneys for detoxification
  • MT reacts with cis-platin to give Pt7-10MT containing PtS4 units
33
Q

What adducts does trans platin form with DNA?

A
  • The longer distance between the two Cl leaving groups (4 vs 2.8) results in trans-platin being unable to form 1,2-intrastrand DNA adducts
  • can form 1,3-intrastrand (GpNpG), 1,4-intrastrand and interstrand links as well as monoadducts.
34
Q

Why does trans platin not show any anticancer activity?

A
  • Trans-platin lesions are more easily repaired since they lead to more radical distortion of DNA. They don’t bind HMG proteins as strongly as cis-platin lesions, possibly due to the lack of an appropriate space for intercalation of the HMG protein phenyl group.
  • Trans-platin is more readily intercepted by sulphur-containing species (e.g., glutathione) leading to removal of Pt from the cancer cells, due to trans effect
  • 3.
    Trans-platin monoadducts are more easily displaced by the action of trans- labilizing nucleophiles such as glutathione or thiourea.
35
Q

What are the short term effect of cis platin?

A

Emetogensis – severe vomiting and nausea
Hair loss
Ototoxicty – hearing loss / tinnitus
Myelosupression – low white blood cell count
Nephrotoxicity – kidney damage Neurotoxicity - depression

36
Q

What are the chronic effects of cis platin?

A

Kidney damage
Hearing impaired
Peripheral neuropathy – loss of feeling in limbs
Psycho-sexual difficulties

37
Q

What causes the side effects and what does this limit?

A
  • These side effects are associated with DNA and protein bound platinum (similar to other heavy metal poisoning).
  • This limits the maximum dose of cis-platin to ~100mg per day for up to 5 consecutive days.
38
Q

How can the toxic effects of cis platin be controlled?

A
  • by inhibiting the formation of Pt- protein complexes

- by ‘rescuing’ Pt from these Pt-protein complexes

39
Q

Give examples of how to control cis platin side effects

A
  • RS-, RSH complexation is inhibited by high Cl- concentration. Hence cis-platin is administered in a saline drip. This reduces kidney damage dramatically.
  • Rescue agents can be administered 3-4 hours after cis-platin treatment. These agents displace Pt from sulphur containing biomolecules but do not affect Pt-DNA complexes.
40
Q

What are the three major mechanisms of cis platin resistance

A

A - Decreased intracellular transport
B - Increase interception by thiol rich species
C - Improved repair

41
Q

How can cis platin resistance be overcome?

A

1) Develop new Pt drugs
2) increase the dosage of Pt drugs
3) use combination chemo with other active anti-tumor drugs
4) use in combination with other agents know to modulate the mechanisms of cis platin resistance

42
Q

What is carboplatin? Draw its structure

A
  • the first of the second generation anti-cancer drugs
43
Q

What are the effects of carboplatin compared to cis platin?

A
  • less toxic than cis platin
  • higher dosage can be used
  • ## can still cause myelosupression
44
Q

Why is carboplatin less toxic than cis platin?

A
  • added stability in the bloodstream

- prevents binding to proteins

45
Q

What are the disadvantages of carboplatin?

A
  • less potent than cis platin (4x the dose required)

- 10x more expensive

46
Q

How is carboplatin administered?

A
  • intravenous infusion
47
Q

What is carboplatin effective against?

A
  • the same cancers as cisplatin as it forms the same adducts to DNA
48
Q

Describe Nedaplatin and draw its structure

A
  • similar clinical properties to carboplatin

- used in Japan for testicular, ovarian and cervical cancers

49
Q

Describe oxaliplatin and draw its structure

A
  • recently approved
  • used to treat stage 3 colorectal cancers after surgery
  • administered in combination with 5-fluorouracil and leucovorin for increased effectiveness
50
Q

What are third generation anti cancer drugs?

A
  • decreased toxicity, increased activity against resistance and the ability to be taken orally
  • new Pt compounds with decreased reactivity towards nucleophiles, new biodistribution and different boding modes to DNA
51
Q

Why are new sterically hindered complexes being formed?

A
  • leads to decreased substitution reaction rates
  • slower reaction with sulphur containing biomolecules
  • fewer side effects and can overcome type B resistance
52
Q

Describe an example of a sterically hindered complex and draw its structure

A
  • ZD0473
  • treats lung and ovarian cancers
  • the 2-methyl group sits above the plane of the molecule leading to axial steric hinderance
  • forms 1,2- intrastrand links with the DNA similar to cis platin
53
Q

Why are Pt(IV) complexes being developed

A
  • more inert to ligand substitution than Pt(II)
  • less likely to react with biomolecules so they have fewer side effects
  • ## active against some resistant cells
54
Q

How do Pt(IV) complexes bind to DNA?

A
  • Some studies show Pt(IV)-DNA complexes resulting in large kinks
  • more likely that intra and extracellular agents reduce them to Pt(II) to form cis platin like adducts
55
Q

Give examples of Pt (IV) complexes, draw their structures

A
  • Satraplatin, tetraplatin and iproplatin

-

56
Q

Describe Satraplatin

A
  • orally administered
  • water and lipid soluble
  • treats prostate, lung and ovarian cancers
57
Q

Why are complexes with a second DNA binding function being developed?

A
  • by attaching DNA-intercalators such as doxorubicin and anilioarinide the compounds could localise on DNA before aquation
  • can also stabilise adducts
58
Q

What is an alternative approach to DNA binding functions?

A
  • adding hydrogen bonding groups to the complex
  • bind to the DNA phosphate backbones
  • or attachment of proteins that bind in the minor grove of DNA
59
Q

Why are trans Pt complexes being developed?

A
  • statically hindered ligands reduce the kinetic activity of trans platinum
  • aquation rates approach those of cis platin
  • overcomes the problem of trans molecules reacting with biomolecules
  • result in activity against improved repair
60
Q

Why are multinuclear Pt complexes being developed?

A
  • initially dinuclear Pt complexes were found to be active
  • make a hair pin structure with B-DNA
  • too toxic for clinical trials
  • more Pt nuclei added
61
Q

Give an example of a Pt multinuclear complex

A
  • BBR3464
  • phase II trials for melanoma, lung cancer and pancreatic cancer
  • 10 x more potent than cis platin
  • active against resistant cells
  • forms long range interstrand and intrastrand crosslinks (up to 6 base pairs apart)
  • significant duplex unwinding

Bioinorganic, take 2 (5 decks)

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