Transport, cisplatin

As a predictor of the concentration of cisplatin in normal peritoneal tissues, these data indicate a steady-state penetration depth (distance to half the surface layer concentration) of about 0.1 mm (100 tm). If this distance applied to tumor tissue, penetration even to three or four times this depth would make it difficult to effectively dose tumor nodules of 1- to 2-mm diameter. Fortunately, crude data are available from proton-induced X-ray emission studies of cisplatin transport into intraperitoneal rat tumors, indicating that the penetration into tumor is deeper and is in the range of 1-1.5 mm (10). Such distances are obtained from Equation 9.5 or 9.5 only if k is much smaller than in normal peritoneal tissues — that is, theory suggests that low permeability coefficient-surface area products in tumor (e.g., due to a developing microvasculature and a lower capillary density) may be responsible for the deeper tumor penetration. 

Further evidence that links the kidney s vulnerability to its role in cisplatin transport is provided by autoradiographic studies that show greater uptake of radiolabeled cisplatin in the S3 segments of the proximal nephron [13]. As the S3 segment of the proximal tubule is the principle site of cell toxicify of cisplatin and contains the most platinum, these studies provide further evidence that the particular vulnerability of this cell type depends on its ability to accumulate cisplatin. 

Kawakami, M., Kagotani, K., Okumura, K., Akiyama, S., Kuwano, M., A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation, Cancer Res. 1996, 56, 4124-4129. 

Uchiumi T, Hinoshita E, Haga S, Nakamura T, Tanaka T, Toh S et al. Isolation of a novel human canalicular multispecific organic anion transporter, cMOAT2/MRP3, and its expression in cisplatin-resistant cancer cells with decreased ATP-dependent drug transport. Biochem Biophys Res Commun 1998 252(1)703-110. 

Williams, P.D. and Hottendorf, G.H. (1985). Effects of cw-dichlorodiamineplatinum-II (Cisplatin) on organic ion transport in membrane vesicles from rat kidney cortex. Cancer Treat. Rep. 69 875-880. 

G. Ciarimboli, T. Ludwig, D. Lang, H. Pavenstadt, H. Koepsell, H. J. Piechota, J. Haier, U. Jaehde, J. Zisowsky, and E. Schlatter. Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. Am J Pathol 167 1477-1484... 

A. Yonezawa, S. Masuda, K. Nishihara, I. Yano, T. Katsura, and K. Inui. Association between tubular toxicity of cisplatin and expression of organic cation transporter rOCT2 (Slc22a2) in the rat. Biochem Pharmacol 70 1823-1831 (2005). 

Fujii R, Mutoh M, Sumizawa T, Chen Z, Yoshimura A, Akiyama S. Adenosine triphosphate-depen-dent transport of leukotriene C4 by membrane vesicles prepared from cisplatin-resistant human epidermoid carcinoma tumor cells. J Natl Cancer Inst 1994 86 1781-1784. 

Fleck C, Hilger R, Jurkutat S, et al. 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. Urol Res 2002 30 256-262. 

Transplatin reacts 360 times faster than cisplatin with glutathione [27], a reaction likely to remove platinum from the cell, through ATP-dependent efflux [28]. It has been shown that a thioether ligand on a platinum triamine complex can be slowly replaced by a guanine-N(7), suggesting a possible platinum transporter role for such thioether compounds towards DNA [6], (This topic is discussed in the contribution by J. Reedijk and J. M. Teuben.)... 

In vitro circumvention of acquired cisplatin resistance due to decreased transport, increased glutathione and enhanced DNA repair ... 

Fig. 3 Venn-diagram for selected compounds interacting with the key MDR-related ABC transporters. MDR-substrate anticancer agents. Abbreviations VCR vincristine, VP-16 etoposide, STER steroids, TAM tamoxiphen, TKI-INHIB tyrosin kinase inhibitors e.g. STI-571, DOX doxorubicine or adriamycin, DNR daunorubicin, EPIR epirubicin, MX mitoxantrone, TOPOT topotecan, iridotecan, BISANT bisanthrone, COLCH colchicin, ACT-D actinomycin D, MYTOM mytomycin, TX methotrexate, CPHAM cyclophosphamide, CHLB chlorambucil, CARM carmustine, LCV leucovorin, HUR hydroxy urea, CISPL cisplatin, TAXOL paclitaxel. (Reproduced from [4])...

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