Phase I Trial of 6-Hour Infusion of Glufosfamide, a New Alkylating Agent With Potentially Enhanced Selectivity for Tumors That Overexpress Transmembrane Glucose Transporters: A Study of the European Organization for Research and Treatment of Cancer Early Clinical Studies Group

Briasoulis, Evangelos; Judson, Ian; Pavlidis, Nicholas; Beale, Philip; Wanders, J.; Groot, Y.; Veerman, Gijbert; Schuessler, M.; Niebch, G.; Siamopoulos, Konstantinos; Tzamakou, Eleftheria; Rammou, Dimitra; Wolf, Lisa; Walker, R.; Hanauske, Axel R.

doi:10.1200/jco.2000.18.20.3535

Cited by 54 publications

(38 citation statements)

References 17 publications

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“…Similar outcomes were reported also for the glycoconjugate of the nitrogen mustard alkylating agents ifosfamide and glufosfamide (Fig. 3), for which enhancement in anticancer activity upon conjugation was assessed in tumor cells overexpressing GLUTs [46]. Remarkably, in both cases, no evidence of GLUT inhibition was observed.…”

Section: Drug Glycoconjugation As Anticancer Approachsupporting

confidence: 82%

Metal-based glycoconjugates and their potential in targeted anticancer chemotherapy

Pettenuzzo¹,

Pigot²,

Ronconi³

2016

Metallodrugs

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Glucose is a key source of energy and an essential nutrient for cell growth. Rapidly dividing cancer cells are well-known to require more nutrients and energy than normal ones to sustain their higher proliferation rates, and glucose is no exception. Therefore, the biomolecules involved in the promotion/regulation of the glycolytic flux may be regarded as potential targets for tackling tumor progression. Among all, glucose transporters (GLUTs), devoted to the recognition and cellular internalization of glucose, are largely overexpressed in tumors, thus indicating glycolysis as the major anaerobic glucose metabolism. Accordingly, such increased demand of glucose by fast-proliferating cancer cells makes it very attractive to selectively target tumor sites. In particular, tailored glucose-like substrates can be conjugated to chemotherapeutics (including metal-containing anticancer agents) so as to attain the site-specific delivery of drugs into the affected tissues. Progress in the development of metal-based glycoconjugates are here summarized and discussed.

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Section: Drug Glycoconjugation As Anticancer Approachsupporting

confidence: 82%

Metal-based glycoconjugates and their potential in targeted anticancer chemotherapy

Pettenuzzo¹,

Pigot²,

Ronconi³

2016

Metallodrugs

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“…This approach depends on the expression of SGLT genes in tumor cells and would take advantage of the ability of cotransporters to accumulate toxic substrates in cells. For example, a nitrogen mustard glucoside (glucosfamide), a putative substrate for SGLT3 [75], has been evaluated in a phase-1 clinical trial [5]. Finally, there is excitement in some quarters about using NIS for the diagnosis and treatment of cancers [60].…”

Section: Pharmacological and Pharmaceutical Aspectsmentioning

confidence: 98%

The sodium/glucose cotransport family SLC5

Turk

Wright²

2004

Pfl�gers Archiv European Journal of Physiology

181

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The sodium/glucose cotransporter family (SLCA5) has 220 or more members in animal and bacterial cells. There are 11 human genes expressed in tissues ranging from epithelia to the central nervous system. The functions of nine have been revealed by studies using heterologous expression systems: six are tightly coupled plasma membrane Na(+)/substrate cotransporters for solutes such as glucose, myo-inositol and iodide; one is a Na(+)/Cl(-)/choline cotransporter; one is an anion transporter; and another is a glucose-activated ion channel. The exon organization of eight genes is similar in that each comprises 14-15 exons. The choline transporter (CHT) is encoded in eight exons and the Na(+)-dependent myo-inositol transporter (SMIT) in one exon. Mutations in three genes produce genetic diseases (glucose-galactose malabsorption, renal glycosuria and hypothyroidism). Members of this family are multifunctional membrane proteins in that they also behave as uniporters, urea and water channels, and urea and water cotransporters. Consequently it is a challenge to determine the role(s) of these genes in human physiology and pathology.

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“…Recently, Briasoulis et al 29) reported the results of a phase I trial of glufosfamide (β-D-glucosylisophosphoramide mustard; D-19575), a new alkylating agent that targets the glucose transport system, in tumor cells. In vitro data suggested that a low-affinity Na + /glucose cotransporter transports glufosfamide into tumor cells, and that the drug accumulates in the cells.…”

Section: Discussionmentioning

confidence: 99%

SGLT Gene Expression in Primary Lung Cancers and Their Metastatic Lesions

Ishikawa

Oguri

Isobe

et al. 2001

Japanese Journal of Cancer Research

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Cancer cells show increased glucose uptake and utilization in comparison with their normal counterparts. Glucose transporters play an important role in glucose uptake. We previously reported the differential gene expression of the GLUT family in primary and metastatic lesions of lung cancer. To investigate the role of Na + /glucose cotransporter (SGLT) genes in cancers, we examined the levels of expression of SGLT1 and SGLT2 genes in primary lung cancers and their metastatic lesions. Ninety-six autopsy samples (35 primary lung cancers, 35 corresponding normal lung tissues, 10 metastatic liver lesions, and 16 metastatic lymph nodes) from 35 patients were analyzed for SGLT1 and SGLT2 expression by reverse transcription (RT)-polymerase chain reaction (PCR). There were no significant differences in the level of expression of either gene between the primary lung cancers and normal lung tissues. The level of SGLT1 expression in the metastatic lesions and primary lung cancers did not differ significantly. The level of SGLT2 expression was, however, significantly higher in the metastatic lesions of both the liver and lymph node than in the primary lung cancers. These results suggest that SGLT2 plays a role in glucose uptake in the metastatic lesions of lung cancer. Key words: SGLT1 -SGLT2 -Lung cancerGlucose is a basic source of energy in mammalian cells. Cancer cells show increased glucose uptake and utilization relative to their normal counterparts.1-3) Two classes of glucose transporters have been described in mammalian cells. 4,5) One class is the facilitative glucose transporter (GLUT) family, which mediates the energy-independent transport of glucose. There are five functional isoforms of GLUT (GLUT1-GLUT5). The five transporters have different functions and distribution in human tissues. The second class is the Na + /glucose cotransporter (SGLT) family, which utilizes the electrochemical sodium gradient to transport glucose against the cell's internal concentration gradient. 4,5) Two isoforms (SGLT1 and SGLT2) have been cloned in mammalian cells.6, 7) SGLT1 is strongly expressed in the small intestine, and is expressed at lower levels in the kidneys, liver, and lungs. 8) In contrast to SGLT1, the kidneys express a high level of SGLT2, and the small intestine does not. 9)Previous studies have demonstrated the overexpression of GLUT1 in various human cancers relative to normal tissues.10) In addition, increased GLUT3 expression has been found in several cancers.11) Overexpression of GLUT5 was found in breast cancers.12) On the other hand, the expression of SGLT genes in cancers has not been studied, and the role of SGLT genes is still unclear in cancers.Recently, we studied the expression of genes belonging to the GLUT family in lung cancers and their metastatic lesions.13) Our results showed the differential expression of GLUT genes in primary lung cancers and their metastatic lesions. To investigate the role of the SGLT family in cancers, we examined the expression levels of SGLT1 and SGLT2 in primary lung cancer...

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Phase I Trial of 6-Hour Infusion of Glufosfamide, a New Alkylating Agent With Potentially Enhanced Selectivity for Tumors That Overexpress Transmembrane Glucose Transporters: A Study of the European Organization for Research and Treatment of Cancer Early Clinical Studies Group

Cited by 54 publications

References 17 publications

Metal-based glycoconjugates and their potential in targeted anticancer chemotherapy

Metal-based glycoconjugates and their potential in targeted anticancer chemotherapy

The sodium/glucose cotransport family SLC5

SGLT Gene Expression in Primary Lung Cancers and Their Metastatic Lesions

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