In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 95, No. 6 ( 1998-03-17), p. 2914-2919
Abstract:
For β- d -glucosylisophosphoramide mustard (β- d -Glc-IPM), a new alkylating drug in which isophosphoramide mustard is stabilized, a higher selectivity and lower myelotoxicity was observed than for the currently used cytostatic ifosfamide. Because β- d -Glc-IPM is hydrophilic and does not diffuse passively through the lipid bilayer, we investigated whether a transporter may be involved in the cellular uptake. A variety of cloned Na + -sugar cotransporters were expressed in Xenopus oocytes, and uptake measurements were performed. By tracer uptake and electrical measurements it was found that β- d -Glc-IPM was transported by the low-affinity Na + - d -glucose cotransporter SAAT1, which had been cloned from pig and is also expressed in humans. At membrane potentials between −50 and −150 mV, a 10-fold higher substrate affinity ( K m ≈ 0.25 mM) and a 10-fold lower V max value were estimated for β- d -Glc-IPM transport than for the transport of d -glucose or methyl-α- d -glucopyranoside (AMG). Transport of β- d -Glc-IPM and glucose by SAAT1 is apparently performed by the same mechanism because similar sodium dependence, dependence on membrane potential, electrogenicity, and phlorizin inhibition were determined for β- d -Glc-IPM, d -glucose, and AMG. Transcription of human SAAT1 was demonstrated in various human carcinomas and tumor cell lines. In one of these, the human carcinoma cell line T84, phlorizin inhibitable uptake of β- d -Glc-IPM was demonstrated with substrate saturation and an apparent K m of 0.4 mM. The data suggest that the Na + - d -glucose cotransporter SAAT1 transports β- d -Glc-IPM into human tumor cells and may accumulate the drug in the cells. They provide an example for drug targeting by employing a plasma membrane transporter.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.95.6.2914
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
1998
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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