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Proc Natl Acad Sci U S A
1998 Mar 17;956:2914-9. doi: 10.1073/pnas.95.6.2914.
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Transport of the new chemotherapeutic agent beta-D-glucosylisophosphoramide mustard (D-19575) into tumor cells is mediated by the Na+-D-glucose cotransporter SAAT1.
Veyhl M
,
Wagner K
,
Volk C
,
Gorboulev V
,
Baumgarten K
,
Weber WM
,
Schaper M
,
Bertram B
,
Wiessler M
,
Koepsell H
.
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For beta-D-glucosylisophosphoramide mustard (beta-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 beta-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 beta-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 (Km approximately 0.25 mM) and a 10-fold lower Vmax value were estimated for beta-D-Glc-IPM transport than for the transport of D-glucose or methyl-alpha-D-glucopyranoside (AMG). Transport of beta-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 beta-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 beta-D-Glc-IPM was demonstrated with substrate saturation and an apparent Km of 0.4 mM. The data suggest that the Na+-D-glucose cotransporter SAAT1 transports beta-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.
ARNOLD,
[On the relation between the chemical composition and the cancerotoxic effect in a series of phosphamide esters of bis-(beta-chloroethyl)-a mine].
1961, Pubmed
ARNOLD,
[On the relation between the chemical composition and the cancerotoxic effect in a series of phosphamide esters of bis-(beta-chloroethyl)-a mine].
1961,
Pubmed
Brock,
Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture.
1989,
Pubmed
BROCK,
[Pharmacological characterization of cyclic nitrogen mustard phosphamide esters as cancer therapeutic agents].
1958,
Pubmed
Busch,
Electrogenic properties and substrate specificity of the polyspecific rat cation transporter rOCT1.
1996,
Pubmed
,
Xenbase
Busch,
Monoamine neurotransmitter transport mediated by the polyspecific cation transporter rOCT1.
1996,
Pubmed
,
Xenbase
Chomczynski,
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
1987,
Pubmed
Fuhrman,
Prognostic significance of morphologic parameters in renal cell carcinoma.
1982,
Pubmed
Gopalan,
Exolytic hydrolysis of toxic plant glucosides by guinea pig liver cytosolic beta-glucosidase.
1992,
Pubmed
Hediger,
Expression cloning and cDNA sequencing of the Na+/glucose co-transporter.
,
Pubmed
,
Xenbase
Hediger,
Homology of the human intestinal Na+/glucose and Escherichia coli Na+/proline cotransporters.
1989,
Pubmed
Hediger,
Molecular physiology of sodium-glucose cotransporters.
1994,
Pubmed
Hirayama,
Transport of cycasin by the intestinal Na+/glucose cotransporter.
1994,
Pubmed
,
Xenbase
Kanai,
The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose.
1994,
Pubmed
,
Xenbase
Kong,
Cloning and expression of a mammalian Na+/amino acid cotransporter with sequence similarity to Na+/glucose cotransporters.
1993,
Pubmed
Kwon,
Cloning of the cDNa for a Na+/myo-inositol cotransporter, a hypertonicity stress protein.
1992,
Pubmed
,
Xenbase
Lambotte,
The human gene of a protein that modifies Na(+)-D-glucose co-transport.
1996,
Pubmed
,
Xenbase
Lind,
Pharmacokinetics of alkylating agents.
1993,
Pubmed
Lostao,
Phenylglucosides and the Na+/glucose cotransporter (SGLT1): analysis of interactions.
1994,
Pubmed
,
Xenbase
Mackenzie,
SAAT1 is a low affinity Na+/glucose cotransporter and not an amino acid transporter. A reinterpretation.
1994,
Pubmed
,
Xenbase
Mackenzie,
Biophysical characteristics of the pig kidney Na+/glucose cotransporter SGLT2 reveal a common mechanism for SGLT1 and SGLT2.
1996,
Pubmed
,
Xenbase
Pohl,
D-19575--a sugar-linked isophosphoramide mustard derivative exploiting transmembrane glucose transport.
1995,
Pubmed
Poppe,
Expression of the Na+-D-glucose cotransporter SGLT1 in neurons.
1997,
Pubmed
Schwabe,
[Enzymatically cleavable specific transport forms of cancerostatics. 3. 4-/N.N-bis-(2-chlorethyl)-amino/-derivatives of phenyl-O-beta-D-cellobiosids and pyrocatechol-bis-/O-beta-D-cellobiosids].
1976,
Pubmed
Schwartsmann,
Anticancer drug screening and discovery in the 1990s: a European perspective.
1992,
Pubmed
Stüben,
Pharmacokinetics and whole-body distribution of the new chemotherapeutic agent beta-D-glucosylisophosphoramide mustard and its effects on the incorporation of [methyl-3H]-thymidine in various tissues of the rat.
1996,
Pubmed
Veyhl,
Cloning of a membrane-associated protein which modifies activity and properties of the Na(+)-D-glucose cotransporter.
1993,
Pubmed
,
Xenbase
Wells,
Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter.
1992,
Pubmed
,
Xenbase
