Ex vivo stimulation of renal transport of the cytostatic drugs methotrexate, cisplatin, topotecan (Hycamtin) and raltitrexed (Tomudex) by dexamethasone, T3 and EGF in intact human and rat kidney tissue and in human renal cell carcinoma.
Previous experiments have shown that both in vivo and in vitro pre-treatment with various hormones increases the renal transport capacity for weak organic acids, such as PAH, in rats. The aim of the present study was to test whether or not accumulation of the anticancer drugs methotrexate (MTX), cisplatin (CP), raltitrexed (Tomudex) and topotecan (Hycamtin) can be increased in intact, healthy rat and human renal cortical slices and in human renal cell carcinoma (RCC). Intact, healthy human tissue was obtained from tumour bearing kidneys of patients suffering from RCC. Experiments were intended as a new approach to overcome so-called multidrug resistance. Kidney tissue slices were incubated for 24 h in William's medium E containing various concentrations of dexamethasone, T(3), or EGF. Thereafter slices were placed in anticancer drug containing Cross-Taggart medium and the drug uptake into kidney tissue was measured for 2 h. In intact rat and human renal tissue slices, the uptake of p-aminohippurate (PAH = reference substance) increased significantly after incubation in dexamethasone containing medium (134% and 156%, respectively). There were no stimulating effects of either T(3) or EGF on PAH accumulation. On the other hand, only the accumulation of MTX, but not of CP, raltitrexed or topotecan, was significantly enhanced after hormone pre-treatment both in intact renal tissue and in RCC. A stimulation of renal PAH accumulation can be performed ex vivo, as reported previously, both in intact rat and human renal cortical slices and in RCC. Discrepancies between the effects of dexamethasone and T(3) or EGF indicate different modes of action of these substances at the cellular level. Unfortunately, with the exception of MTX, the uptake of anticancer drugs can not be stimulated effectively ex vivo in human RCC tissue by the substances used. Evidently the transport of these anticancer drugs out of the kidney cells is more effective than their uptake.
Institute of Pharmacology and Toxicology, University of Jena, 07740 Jena, Germany. CFLE@mti-n.uni-jena.de
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C
Fleck
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Hilger
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Jurkutat
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Karge
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Merkel
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Schimske
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Schubert
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D002945:Cisplatin / Q000493:pharmacokinetics; D003907:Dexamethasone / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism*; D008727:Methotrexate / Q000493:pharmacokinetics; D011799:Quinazolines / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013876:Thiophenes / Q000493:pharmacokinetics; D019772:Topotecan / Q000493:pharmacokinetics; D014284:Triiodothyronine / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D005938:Glucocorticoids; D011799:Quinazolines; D013876:Thiophenes; D014284:Triiodothyronine; D004815:Epidermal Growth Factor; D019772:Topotecan; D003907:Dexamethasone; C068874:raltitrexed; D002945:Cisplatin; D008727:Methotrexate