DDT 12 - Second-generation platinum drugs

Question 1

(HMG) proteins

Answer 1

High mobility group protein

havea very highaffinity for cisplatin-modified DNA

Question 2

function of HMG proteins

Answer 2

increase cisplatin cytotoxicity by bindingat sites of modification and obstructing cellular excision repair.

Question 3

how do some cancers develop a resistance to cancer cells

Answer 3

decreased intracellular accumulation of cisplatin
increased intracellular levels of certain sulfur-containing macromolecules (e.g. metallothionein) which bind to cisplatin or its hydrolytic metabolites, and inactivate them
increased DNA repair

Question 4

What qualities of cisplatin are needed in complexes to help to kill cancer

Answer 4

Neutral - allows for passive diffusion across cell membrane
leaving ligands are Cl- or oxygen containing ligand
leaving ligands must be in cis configuration
Pt must be in II or IV oxidation state
non leaving ligands must be unreactive amines, preferrably primary (2 hydrogens attached to Nitrogen)

Question 5

difference between carboplatin

Answer 5

more stable - Cyclobutane-1,1-dicarboxylate bidentate ligand/ chelate is attached
reaches target DNA w/o breaking down first
Less side effect - lower toxicity
longer half life in blood plasma
less toxic to GI tract
Myelosuppression is dose-limiting

Question 6

disadvantages of carboplatin

Answer 6

20-40 times greater concentration of carboplatin is required than cisplatin
rate of adduct formation is 10 times slower
same survival rates as cisplatin for ovarian cancer

Question 7

when was first person treated w/ carboplatin

Answer 7

1982

Question 8

when was carboplatin FDA approved?

Answer 8

1989

Question 9

when was oxaliplatin approved in Europe?

Answer 9

1999

Question 10

when was oxaliplatin approved by the FDA

Answer 10

2002

Question 11

Oxaliplatin structure

Answer 11

bidentate oxygen containing chelate on RHS
Another chelating agent 1,2 diaminocyclohexane (DACH) on LHS
trans configuration

Question 12

oxaliplatin mechanism of action

Answer 12

diamine cyclohexane interact differently with DNA
Thus DNA containing platinum-adducts formed are different biological properties in comparison to cisplatin, notably that equivalent cytotoxicity is seen with lower levels of DNA adducts induced by oxaliplatin compared with cisplatin.

Question 13

what is oxaliplatin used in combination with

Answer 13

5-FU (fluorouracil) acts in several ways but principally as an anti-metabolite - compounds that prevent the biosynthesis of normal cell metabolites for colorectal cancer

Question 14

what cancer is oxaliplatin used for?

Answer 14

colorectal cancer

Question 15

what 3 other platinum complexes are also used and where is it approved?

Answer 15

Nedaplatin (2 NH3 and a bidentate oxygen containing chelate) - approved in Japan
Heptaplatin(dicarboxylate leaving group) - approved in South Korea
Lobaplatin - approved in China

Question 16

Picoplatin properties

Answer 16

broad spectrum of anti-cancer activity;
platinum resistant
platinum sensitive cancer
no significant nephrotoxicity

Question 17

how is picoplatin administered into the body

Answer 17

intravenously

orally

Question 18

when was first patient to be treat with picoplatin

Answer 18

1997

Question 19

structure of picoplatin

Answer 19

to Cl atoms cis to eacg other

one NH3 and 2-methylpyridine

Question 20

pyridine

Answer 20

heterocyclic hydrocarbon

benzene ring but N replaces 1 C and 1 H

Question 21

what is one of the benefits of the methyl pyridine structure in picoplatin

Answer 21

less interactions with biomolecules and platinum core

less side effects

Question 22

how was picoplatin tested in phase 2 trials

Answer 22

used against platinum sensitive ovarian cancer and cisplatin resistant small cell lung cacner

Question 23

what is picoplatin used with to go against prostate cancer

Answer 23

picoplatin and docetaxel

Question 24

what is picoplatin used with to go against colorectal cancer

Answer 24

picoplatin and 5-FU

Question 25

Satraplatin structure

Answer 25

2 carboxylate groups (-1 charge each)
2 Cl cis to each other (-1 charge each)
NH3 - neutral
cyclohexylamine - neutral

Question 26

cyclohexylamine

Answer 26

cyclohexane but NH2 replaces one H

C6H11NH2

Question 27

how is satraplatin best administered into the body

Answer 27

orally - good anti-tumour activity that route

Question 28

how does satraplatin react

Answer 28

orally active
completely saturated - less side effect
activated into platinum 2 adduct = 2 carboxylate groups are removed
binds to DNA similarly to cisplatin

Question 29

when was first patient treated with orally administered satraplatin

Answer 29

1993

Question 30

substitute for platinum in anti-cancer drugs

Answer 30

Ruthenium

Question 31

why is ruthenium seen as s good sub for anti-cancer drugs

Answer 31

rate of ligand exchange is similar to Pt
range of accessible oxidation state
same group as iron in periodic table mimicking ability - low toxicity

Question 32

what is different about ruthenium in comparison to cisplatin

Answer 32

different;
mechanism of action
biodistribution]
toxicity

Question 33

2 examples of ruthenium complexes

Answer 33

KP 1019

NAMI -A

Question 34

KP 1019 is what kind of complex and targets what kind of cancer

Answer 34

Ruthenium complex

colorectal cancer

Question 35

what type of anti-cancer drug is KP 1019?

Answer 35

cytotoxic - affects cell growth and cell proliferation

Question 36

what chemical reaction activates KP 1019

Answer 36

by reduction

Question 37

who developed KP 1019

Answer 37

Keppler

Question 38

who developed NAMI-A

Answer 38

Alessio

Question 39

What is NAMI-A useful for?

Answer 39

useful for inhibiting lung metastasis formation and growth

Question 40

benefits of NAMI-A

Answer 40

void of important organ toxicity

does not target DNA

Question 41

mode of action of KP 1019

Answer 41

Transferrin pathway implicated