35 research outputs found
Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies
Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) and its Na+ analogue (KP1339) are two of the most prominent non-platinum antitumor metal complexes currently undergoing clinical trials. After intravenous administration, they are known to bind to human serum albumin (HSA) in a noncovalent manner. To elucidate their HSA binding sites, displacement reactions with the established site markers warfarin and dansylglycine as well as bilirubin were monitored by spectrofluorimetry, ultrafiltration-UV-vis spectrophotometry, and/or capillary zone electrophoresis. Conditional stability constants for the binding of KP1019 and KP1339 to sites I and II of HSA were determined, indicating that both Ru(III) compounds bind to both sites with moderately strong affinity (log K (1)' = 5.3-5.8). No preference for either binding site was found, and similar results were obtained for both metal complexes, demonstrating low influence of the counter ion on the binding event
The mechanism of resistance to platinum drugs and strategies to overcome this phenomenon
Platinum drugs belong to one of the oldest [2] and best investigated groups of
cytotoxic drugs. On account of their high efficacy and alkylating-like action [14] they
are used in a treatment of various types of neoplasms [3–5]. Despite investigators’
best efforts survival time of patients diagnosed with cancer is still short. Responsible
for the fact is high toxicity of used therapeutic methods and development of
resistance to them [3–5, 19]. In this paper authors review reasons behind decreased
sensitivity of neoplastic cells to platinum treatment and discuss the newest promising
trends in its overcoming.
Due to different properties of neoplastic cells, availability of a chemotherapeutic
agent inside a tumour is limited [9–12]. Moreover continuous development
of resistance to platinum drugs further decreases their cellular concentration and
inactivates their functions. Also owing to increased activity of DNA repair systems,
higher tolerance to genome deformations and numerous mechanisms that lead to
impaired apoptosis, drug efficacy is reduced [3-5, 19].
In order to increase a potency of platinum agents new therapeutic strategies are
investigated. Coadministration with resistance modulators [20, 22, 23] and combination
therapy with other antineoplastic drugs [8, 24–30] have already proved
their effectiveness. Additionally, newer generations of platinum drugs are developed
[15–18]. Mostly platinum(IV) prodrug complexes often releasing axial ligands with
their own pharmacological action [5, 6, 31], but also multi-nuclear platinum compounds
that form more complex DNA-adducts [32–35]. Other strategies include
the development of innovative dosage forms such as single walled carbon nanotubes
(SWCNTs), multiwalled carbon nanotubes (MWCNTs) [38, 39] or encapsulation
[36, 37]. Finally utilisation of oncolytic viruses could be a way to selectively destroy
neoplastically transformed cells [40]
Ruthenium(II) Tetradentate Schiff Base Complexes: Synthesis, Characterization, DNA Binding, and Antioxidant Studies
Kinetic Interactions between Cyclolinopeptides and Immobilized Human Serum Albumin by Surface Plasmon Resonance
Hemoglobin–albumin cross-linking with disuccinimidyl suberate (DSS) and/or glutaraldehyde for blood substitutes
An NMR Protocol for In Vitro Paclitaxel Release from an Albumin-Bound Nanoparticle Formulation
Syntheses and characterization of vitamin B12-Pt(II) conjugates and their adenosylation in an enzymatic assay
Aiming at the use of vitamin B12 as a drug delivery carrier for cytotoxic agents, we have reacted vitamin B12 with trans-[PtCl(NH3)2(H2O)]+, [PtCl3(NH3)](-) and [PtCl4](2-). These Pt(II) precursors coordinated directly to the Co(III)-bound cyanide, giving the conjugates [(Co)-CN-(trans-PtCl(NH3)2)]+ (5), [(Co)-CN-(trans-PtCl2(NH3))] (6), [(Co)-CN-(cis-PtCl2(NH3))] (7) and [(Co)-CN-(PtCl3)](-) (8) in good yields. Spectroscopic analyses for all compounds and X-ray structure elucidation for 5 and 7 confirmed their authenticity and the presence of the central "Co-CN-Pt" motif. Applicability of these heterodinuclear conjugates depends primarily on serum stability. Whereas 6 and 8 transmetallated rapidly to bovine serum albumin proteins, compounds 5 and 7 were reasonably stable. Around 20% of cyanocobalamin could be detected after 48 h, while the remaining 80% was still the respective vitamin B12 conjugates. Release of the platinum complexes from vitamin B12 is driven by intracellular reduction of Co(III) to Co(II) to Co(I) and subsequent adenosylation by the adenosyltransferase CobA. Despite bearing a rather large metal complex on the beta-axial position, the cobamides in 5 and 7 are recognized by the corrinoid adenosyltransferase enzyme that catalyzes the formation of the organometallic C-Co bond present in adenosylcobalamin after release of the Pt(II) complexes. Thus, vitamin B12 can potentially be used for delivering metal-containing compounds into cells