cisplatin 1 + 2

Question 1

Rosenbergs results

Answer 1

• 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

Question 2

[Pt(Cl)6]2- is a

Answer 2

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

Question 3

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

Answer 3

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

Question 4

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

Answer 4

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

Question 5

the properties of cisplatin

Answer 5

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

Question 6

reduces the size of the tumour at lower than toxic doses

Answer 6

cisplatin

Question 7

cis platins anti tumor activity includes :

Answer 7

• 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

Question 8

cisplatin side effects

Answer 8

• 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

Question 9

cisplatin caused

Answer 9

renaissance in inorganic chemistry and its an example of serendipity

Question 10

cisplatin in combination chemotherapy

Answer 10

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

Question 11

cisplatin administration

Answer 11

-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

Question 12

cisplatin dna crosslink

Answer 12

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

Question 13

dna is the target of cisplatin which forms

Answer 13

( 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

Question 14

high mobility groups ( HMG) have

Answer 14

-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.

Question 15

why is transplstin is inactive

Answer 15

• 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.

Question 16

disadvantages of cisplatin

Answer 16

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

Question 17

some cells developed resistance to cisplatin due to:

Answer 17

• 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

Question 18

cisplatin must be neutral to

Answer 18

facilitate across the cell membrane

Question 19

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

Answer 19

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

Question 20

the non leaving ligands as nh3 in cisplatin must be

Answer 20

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

Question 21

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

Answer 21

carboplatin

Question 22

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

Answer 22

• 37 c
• 30 hours

Question 23

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

Answer 23

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

Question 24

what type of cancers can be used w/ carboplatin

Answer 24

• ovaries
• small cell lung cancer

Question 25

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

Answer 25

- bidenate ( which forms a ring structure w a metal ) - 2 - monodantate

Question 26

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

Answer 26

chelate

Question 27

The ligand which forms the chelate is a

Answer 27

chelating agent or chelator

Question 28

carboplatin or cisplatin has a chelating ring

Answer 28

carboplatin hence the stability so its a chelate

Question 29

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

Answer 29

- trans - RR chiral centres

Question 30

is used for colorectal cancer

Answer 30

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

Question 31

how many chelating agents oxiplatin has

Answer 31

2

Question 32

oxaliplatin mode of action

Answer 32

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.

Question 33

drug that has no clinically significant nephrotoxicity or neurotoxicity

Answer 33

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

Question 33

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

Answer 33

picoplatin

Question 34

Originally developed to be an orally-active alternative to cisplatin

Answer 34

satraplatin

Question 34

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

Answer 34

- oral - intravenously

Question 35

Ruthenium well suited in terms of biological application:

Answer 35

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

Question 36

ruthenium complexes:

Answer 36

- 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 -

Question 37

is the oral alternative to cisplatin

Answer 37

saraplatin

Question 38

-- is used for sensitive ovarian cancer and is effective

Answer 38

picoplatin

Question 39

--- is cytotoxic and is used for preventing metastasis and growth

Answer 39

ruthenium complexes