DDT 12 - Second-generation platinum drugs Flashcards
(HMG) proteins
High mobility group protein
havea very highaffinity for cisplatin-modified DNA
function of HMG proteins
increase cisplatin cytotoxicity by bindingat sites of modification and obstructing cellular excision repair.
how do some cancers develop a resistance to cancer cells
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
What qualities of cisplatin are needed in complexes to help to kill cancer
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)
difference between carboplatin
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
disadvantages of carboplatin
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
when was first person treated w/ carboplatin
1982
when was carboplatin FDA approved?
1989
when was oxaliplatin approved in Europe?
1999
when was oxaliplatin approved by the FDA
2002
Oxaliplatin structure
bidentate oxygen containing chelate on RHS
Another chelating agent 1,2 diaminocyclohexane (DACH) on LHS
trans configuration
oxaliplatin mechanism of action
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.
what is oxaliplatin used in combination with
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
what cancer is oxaliplatin used for?
colorectal cancer
what 3 other platinum complexes are also used and where is it approved?
Nedaplatin (2 NH3 and a bidentate oxygen containing chelate) - approved in Japan
Heptaplatin(dicarboxylate leaving group) - approved in South Korea
Lobaplatin - approved in China
Picoplatin properties
broad spectrum of anti-cancer activity;
platinum resistant
platinum sensitive cancer
no significant nephrotoxicity
how is picoplatin administered into the body
intravenously
orally
when was first patient to be treat with picoplatin
1997
structure of picoplatin
to Cl atoms cis to eacg other
one NH3 and 2-methylpyridine
pyridine
heterocyclic hydrocarbon
benzene ring but N replaces 1 C and 1 H
what is one of the benefits of the methyl pyridine structure in picoplatin
less interactions with biomolecules and platinum core
less side effects
how was picoplatin tested in phase 2 trials
used against platinum sensitive ovarian cancer and cisplatin resistant small cell lung cacner
what is picoplatin used with to go against prostate cancer
picoplatin and docetaxel
what is picoplatin used with to go against colorectal cancer
picoplatin and 5-FU
Satraplatin structure
2 carboxylate groups (-1 charge each)
2 Cl cis to each other (-1 charge each)
NH3 - neutral
cyclohexylamine - neutral
cyclohexylamine
cyclohexane but NH2 replaces one H
C6H11NH2
how is satraplatin best administered into the body
orally - good anti-tumour activity that route
how does satraplatin react
orally active
completely saturated - less side effect
activated into platinum 2 adduct = 2 carboxylate groups are removed
binds to DNA similarly to cisplatin
when was first patient treated with orally administered satraplatin
1993
substitute for platinum in anti-cancer drugs
Ruthenium
why is ruthenium seen as s good sub for anti-cancer drugs
rate of ligand exchange is similar to Pt
range of accessible oxidation state
same group as iron in periodic table mimicking ability - low toxicity
what is different about ruthenium in comparison to cisplatin
different;
mechanism of action
biodistribution]
toxicity
2 examples of ruthenium complexes
KP 1019
NAMI -A
KP 1019 is what kind of complex and targets what kind of cancer
Ruthenium complex
colorectal cancer
what type of anti-cancer drug is KP 1019?
cytotoxic - affects cell growth and cell proliferation
what chemical reaction activates KP 1019
by reduction
who developed KP 1019
Keppler
who developed NAMI-A
Alessio
What is NAMI-A useful for?
useful for inhibiting lung metastasis formation and growth
benefits of NAMI-A
void of important organ toxicity
does not target DNA
mode of action of KP 1019
Transferrin pathway implicated
