Ex vivo stimulation of renal tubular p-aminohippurate transport by dexamethasone and triiodothyronine in human renal cell carcinoma.
This paper is the third of a long-term planned series of papers dealing with ex vivo investigations of drug transport in human kidney. The aims of this study are (a) to investigate whether or not human renal cell carcinoma (RCC) can actively accumulate p-aminohippurate (PAH) and (b) to test the response of RCC on dexamethasone or triiodothyronine (T3) using tissue slices ex vivo. By this approach, the accumulation capacity of RCC should be stimulated as a prerequisite for an increased uptake of anti-tumour drugs. Tissue slices of RCC samples of 30 patients were incubated for 24 h in Williams medium E containing 0.01-50 microM dexamethasone or T3. Thereafter, slices were placed in PAH-containing Cross-Taggart medium, and PAH uptake into kidney tissue was measured for 2h under standardised conditions as described previously. In intact human renal cortical slices, PAH uptake capacity, expressed as slice to medium ratio (QS/M), was about 2.8 +/- 0.16 after 24 h of incubation and increased significantly in dexamethasone-containing medium in a concentration-dependent manner, up to approximately 150%, whereas T3 did not influence PAH accumulation. On the other hand, in RCC the PAH accumulation capacity was completely abolished (QsM approximately 1). However, after administration of dexamethasone, the accumulated amount of PAH increased significantly in RCC tissue in a concentration-dependent manner, up to approximately 190%. T3 was without effect in RCC, too. Surprisingly, the dexamethasone-mediated stimulation could be differentiated into responders and non-responders, with maximal effects at different concentrations for each patient. Nevertheless, the maximal transport rates remained low in RCC, even under hormone influence. In conclusion, a moderate stimulation of tubular transport capacity can be shown ex vivo in human RCC. This phenomenon is only of a relatively low degree compared with intact renal tissue. However, in principle, the response of RCC on dexamethasone could form a basis for further therapeutic strategies to overcome multi-drug resistance in RCC patients. For this purpose, additional experiments analysing the expression of transporters of the ABC cassette-type are in progress.
Fleck
C
C
Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, Germany. CFLE@mti-n.uni-jena.de
Bachner
B
B
Göckeritz
S
S
Karge
E
E
Strohm
U
U
Schubert
J
J
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D014284:Triiodothyronine / Q000494:pharmacology*; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics*
D018528:ATP-Binding Cassette Transporters; D005938:Glucocorticoids; D014284:Triiodothyronine; D003907:Dexamethasone; D010130:p-Aminohippuric Acid