Reversal of P-Glycoprotein-Associated Multidrug Resistance: From Bench to Bedside

Abstract

Reversal of P-glycoprotein-associated multidrug resistance (MDR1) has received much attention in recent years. A number of agents has been identified which are capable of overcoming MDR1 in experimental tumor models. The clinical effec- tiveness of such chemosensitizers (CS) has been limited to date. Nonetheless, there are data suggesting that the concept of MDR1 reversal might also function in cancer patients. It always has been a concern that inhibition of physiological P-glycoprotein function may increase chemotherapy toxicity. Recent data suggest that CS can inhibit biliary and/or renal elimination of cytotoxic agents, resulting in increased bone marrow toxicity. It seems likely that such phenomena will be more frequently observed in the future as more potent CS become available. In order to making progress in this field, future clinical studies of CS must strictly adhere to the usual standards of clinical drug development, i.e., starting with phase I and pharmacokine-tic studies and only based on these results proceeding to activity studies (phases II and III). Clinical MDR1 reversal is a complex task, and it is only through carefully conducted trials that significant progress in this area may be possible. For the time being, the clinical use of CS continues to be an experimental approach and thus should not be pursued outside the context of controlled studies.

High Quality Aluminide and Thermal Barrier Coatings Deposition for New and Service Exposed Parts by CVD Techniques

“…Since the classical pack cementation process seems to provide less oxidation resistance owing to an increased amount of refractory elements at the additive layer as well as the inclusion of some alumina particulates from the pack, the out-of-pack mode was the preferred method to establish a better comparison with "true" CVD on Pt/Al coatings. The role of platinum is mainly that of providing a barrier to aluminium [20] and refractory elements diffusion [21][22][23][24][25], although this is still a matter of controversy. The presence of PtAl 2 provides an aluminium reservoir to enhance oxidation resistance but it may modify the mechanical properties of the coating and may also embrittle the superalloy-TBC interface.…”

Methods to Detect MDR1/P-Glycoprotein in Clinical Tumor Samples

“…Fixation has been found to have a significant effect on the staining results with particular anti-Pgp antibodies [34]. [5,15,[65][66][67]. After so many years of clinical studies of MDRl/Pgp in clinical cancers, it is disturbing that so many is sues have remained unresolved.…”

Microstructural Transformation in Platinum Aluminide Coated on CMSX-4 Superalloy

“…Whilst optimised for creep resistance and high strength, alloys used in gas turbines have negligible intrinsic corrosion or oxidation resistance and therefore require protection by coatings, which are typically based on β-NiAl [1]. Platinum modified β-NiAl coatings dramatically improve the hot corrosion and oxidation resistance of the aluminide coatings [4][5][6][7][8] and there has been much development of Pt modified aluminide coatings since their original development and commercialisation in the early 1960s and 1970s [9,10]. During exposure at high temperatures in an oxidising environment, the protective coatings become aluminium depleted due to aluminium consumption by the formation of an α-alumina protective scale and due to either Al diffusion into the substrate alloy or nickel diffusion into the coating which results in the formation of Ni 3 Al (γ') regions within the coating [11,12].…”