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cisplatin 1 + 2 Flashcards

1
Q

Rosenbergs results

A
  • under normal condition, the e coli rods were short
  • when the field was turned on, bacteria appeared w very long filaments ( 300 times their usual length )
  • cell division was inhibited but cell growth wasn’t aka the rna and protein synthesis were functional
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2
Q

[Pt(Cl)6]2- is a

A

-octahedra metal complex of pt (IV) and pt (ii ) is square planer and both are 3rd raw d block.

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3
Q

[Pt(Cl)6]2- is formed bc

A

cl2 oxidised the pt electrode
the cis [Pt(Cl)6]2- what caused the inhibition of cell division

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4
Q

Where did [Pt(NH3)2(Cl)4]2- come from and what is it?

A

In the presence of light and NH4+ the following reaction
occurs:
[Pt(Cl)6]2- + NH4+ cis-[Pt(NH3)2(Cl)4 ] + 2HCl

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5
Q

the properties of cisplatin

A
  • square planer
  • 2 cl- ligands and 2 nh3 ligands in cis
  • overall complex is neutral
  • oxidation state : 2
  • lipophilic to cross the cell membrane .
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6
Q

reduces the size of the tumour at lower than toxic doses

A

cisplatin

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7
Q

cis platins anti tumor activity includes :

A
  • active for chemically, virally, and transplanted tumours
  • tumors in mice to be cured
  • broad spectrum of anti cancer activities as: testicular, ovarian, head, neck, and bladder
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8
Q

cisplatin side effects

A
  • nausea
  • alopecia aka hair loss
  • myelosupperssion (25-30%) - bone marrow and toxic to blood
  • the WORST : nerphotoxicty aka kidney damage
  • ototoxisty - ear and neural component
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9
Q

cisplatin caused

A

renaissance in inorganic chemistry and its an example of serendipity

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10
Q

cisplatin in combination chemotherapy

A

cisplatin ( platinol ) used w combination of drugs as vinblastin and bleomycin.

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11
Q

cisplatin administration

A

-administered intravenously every 3-4 weeks in single doses of 50-120 mg per m2 body surface
or 15-20 mg per m2 daily for 5 days.
Lower doses are required in combination chemotherapy.
- It is injected in 2 litre NaCl (0.9%) or Glucose (4%) + NaCl
(0.18%) solutions and infused over 6-8 hours. These are
isotonic saline solutions.
- Mannitol (a diuretic) is added to protect the kidneys and
the patient is usually hydrated before administration of cisplatin

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12
Q

cisplatin dna crosslink

A
  • intrastrand
    ( 65%) w/ g and g
    (25%) guanine w Adenine
    -monoaducts w one g
  • interstrand ( less than 1%) w 2 guanines
  • protein dna crosslink
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13
Q

dna is the target of cisplatin which forms

A

( mechanism of action ) intrastrand crosslink , after cisplatin enters the cell the cl ligand ( since cl is low inside of the cell) will be replaced w aqueous ligand aka the hydrolysis and then they will be replaced by nitrogen base of dna. this causes a kink in the dna which is not recognised by dna repair proteins = apoptosis

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14
Q

high mobility groups ( HMG) have

A

-high affinity for cisplatin modified dna
- affinity is up to 100 times that for unmodified due to the structural resemblance of modified dna double helix as binding site for these proteins
- HMG increases cisplatin cytotoxicity by binding at the site of modification and obstructing the cellular excision repair.

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15
Q

why is transplstin is inactive

A
  • Hydrolysis of ‘transplatin’ like cisplatin involves replacement of the Cl- ligands by H2O but not the NH3 ligands (these are very difficult to replace).
  • When one of the H2O ligands is replaced by the guanine (DNA) nitrogen (red) the other H2O ligand is not in the correct position to be replaced by the second guanine N to form an intrastrand adduct similar to that formed by cisplatin. There is an NH3 in the way.
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16
Q

disadvantages of cisplatin

A
  • some cancer cells have developed resisiatxne
  • highly toxic to kidney and GI tract
  • inactive against some cancer as: breast, colon, lungs
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17
Q

some cells developed resistance to cisplatin due to:

A
  • decreased intracellular accumulation of cisplatin
  • increased intracellular levels of entrain sulphur containg macromoliucules as: metallothionein which bind to cisplatin or its hydrolytic metabolites and inactivates them
  • increased dna repair
18
Q

cisplatin must be neutral to

A

facilitate across the cell membrane

19
Q

cisplatin must contains ligand as —- and — which are rapidly replaced by — and then —

A
  • cl- or oxygen ( they are age leaving ligands and must be in cis )
  • h20
  • dna
20
Q

the non leaving ligands as nh3 in cisplatin must be

A
  • unreactive amines
  • should form hydrogen bonds w dna an stabilize the dna adduct ( dna recognition and adduct stabilisation )
21
Q

is devoid of nephrotoxity, less toxic to GI tract, myelosupression is dose limiting , more stable leaving grop which lowers the toxitity without affecting the anti tumour efficiency

A

carboplatin

22
Q

at —- degrees the retention half-life of carboplatin in blood plasma is— hrs while for cisplatin it is only 1.5-3.6 hrs.

A
  • 37 c
  • 30 hours
23
Q

how many folds are required for carboplatin and rate of adduct formation is —

A

-20-40 fold higher concentration
- 10 folds slower leads to stability

24
Q

what type of cancers can be used w/ carboplatin

A
  • ovaries
  • small cell lung cancer
25
Q

cyclobutane-1,1 decarboxylate is a —- and forms — dative bonds, so cl and nh3 are —-

A
  • bidenate ( which forms a ring structure w a metal )
  • 2
  • monodantate
26
Q

A metal complex in which the metal ion is part of a ring structure is called a

A

chelate

27
Q

The ligand which forms the chelate is a

A

chelating agent or chelator

28
Q

carboplatin or cisplatin has a chelating ring

A

carboplatin hence the stability so its a chelate

29
Q

in oxaliplatin it has 2 amino groups in —- and the configuration in —-

A
  • trans
  • RR chiral centres
30
Q

is used for colorectal cancer

A

oxiplatin , can be used w/ 5-flurouricl for anti-metabolite that prevents the biosynthesis for normal cells metabolites

31
Q

how many chelating agents oxiplatin has

A

2

32
Q

oxaliplatin mode of action

A

The bulky DACH moiety may interact differently with DNA furnishing DACH-containing adducts with different biological properties, notably that equivalent cytotoxicity is seen with lower levels of DNA adducts induced by oxaliplatin compared with cisplatin.

33
Q

drug that has no clinically significant
nephrotoxicity or neurotoxicity

A

picoplatin
- has Steric bulk
- reduction in inactivation by thiols such as metallothionein
- Trials also ongoing for picoplatin in combination with docetaxel (Taxotere – Sanofi-Aventis) against prostate cancer and with 5-FU against colorectal cancer (Poniard Pharmaceuticals)
- used for sensitive ovarian cancer and resistant small cell lung cancer

33
Q

Broad spectrum of anti-cancer activity
including platinum-resistant and
platinum-sensitive cancers.

A

picoplatin

34
Q

Originally developed to be an
orally-active alternative to cisplatin

A

satraplatin

34
Q

Clinical studies demonstrated that it
possessed good anti-tumour activity by the — route, at lease comparable to —– administered cisplatin or carboplatin in mice with human ovarian cancer xenografts

A
  • oral
  • intravenously
35
Q

Ruthenium well suited in terms of biological application:

A

-favourable rate of ligand exchange (similar to Pt)
-range of accessible oxidation states
-iron mimicking ability (low toxicity)

36
Q

ruthenium complexes:

A
  • targets colorectal cancer
  • cytotoxic
  • activation by reduction
  • transferring pathway implicated
  • extremely effective in inhibiting lung metasistais and growth
  • devoid of important organ toxicity
  • ## inhibition of matrix metalloproteases is thought to be important
37
Q

is the oral alternative to cisplatin

A

saraplatin

38
Q

– is used for sensitive ovarian cancer and is effective

A

picoplatin

39
Q

— is cytotoxic and is used for preventing metastasis and growth

A

ruthenium complexes

ddt (22 decks)

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