Membrane transport of alkylating agents

Goldenberg, Gerald J.; Begleiter, Asher

doi:10.1016/0163-7258(80)90048-0

Cited by 45 publications

(23 citation statements)

References 83 publications

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“…We have shown that nitrogen mustard is selectively toxic to exponential-phase LLTC cultures (Figure 4c), as previously reported for EMT6 cells (Twentyman & Bleehen, 1975;Kwok & Twentyman, 1985). In contrast chlorambucil, which probably enters cells passively (Goldenberg & Begleiter, 1980) is equally active against exponential and plateau-phase LLTC (Figure 4d). …”

Section: Discussionsupporting

confidence: 60%

“…Byfield and Calabro-Jones (1981) suggested that alkylating agents show selectivity for cycling cells if they are transported into cells by carrier-dependent mechanisms with diminished activity in non-cycling cells. Nitrogen mustard appears to be an example since it is taken up by cells via the choline transport system (Goldenberg et al, 1971;Goldenberg & Sinha, 1973), the activity of which may decline in non-cycling cells (Goldenberg & Begleiter, 1980). Similarly, cell proliferation-dependent uptake and cytotoxicity of melphalan have been described (Blosmanis et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

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Cytokinetic factors in drug resistance of Lewis lung carcinoma: comparison of cells freshly isolated from tumours with cells from exponential and plateau-phase cultures

Wilson²,

Bc³

1987

Br J Cancer

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Cytokinetic factors in drug resistance of Lewis lung carcinoma: comparison of cells freshly isolated from tumours with cells from exponential and plateau-phase cultures

Wilson²,

Bc³

1987

Br J Cancer

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“…The effects of temperatures on melphalan transport described here are very similar to the previously described effects of heat on adriamycin transport (Bates & Mackillop, 1986;Nagaoka et al, 1986). This is unexpected since adriamycin probably enters cells by passive diffusion (Siegfried et al, 1985) whereas melphalan is taken up by at least two separate amino acid transport systems (Goldenberg & Begleiter, 1980;Goldenberg et al, 1979). We have predicted that melphalan uptake would decrease with increasing temperature as we moved away from the usual operating temperature of the transport system but increases in the rate of facilitated diffusion (LeCavalier & Mackillop, 1985) and active transport (Bates & Mackillop, 1985) 39°C to 44°C.…”

Section: Discussionmentioning

confidence: 99%

“…Melphalan is taken up by two separate amino acid transport systems (Goldenberg & Begleiter, 1980;Goldenberg et al, 1979). Previous studies have reported no significant difference in the rate of drug influx (2 min) between the drug-sensitive and drug-resistant CHO cell lines used in this study, despite a higher Vmax in the drug-sensitive cells (Begleiter et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

The effect of hyperthermia in combination with melphalan on drug-sensitive and drug-resistant CHO cells in vitro

Bates

Wj²

1990

Br J Cancer

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Summary The effect of temperature on the cytotoxicity of melphalan in a pleiotropic drug-resistant mutant CHO cell line (CHR C5) and in its drug-sensitive parent (Aux BI) was studied in vitro using a clonogenic assay. The cytotoxicity of melphalan was significantly enhanced at elevated but non-lethal temperatures (39-41 'C) and hyperthermia potentiated the effect of melphalan in the lethal temperature range (43-44 'C) in both cell lines. The effect of temperature on membrane permeability to melphalan was studied to determine whether the increase in cytotoxicity was associated with increased intracellular drug levels. The uptake of '4C-labelled melphalan during 5 min increased with increasing temperature. Drug efflux, however, also increased at elevated temperatures. Intracellular drug levels at equilibrium were increased at elevated temperatures but the magnitude of this effect was small in comparison with the much larger increases in cytotoxicity.The failure of chemotherapy to eradicate tumours which initially respond to treatment may be due to the selection of drug-resistant clones of tumour cells (Goldie & Coldman, 1979). It has been shown that the acquisition of resistance to one cytotoxic drug may confer cross resistance to several other chemotherapeutic agents and that this pleiotropic drug resistance is frequently associated with increased expression of a 170,000 dalton glycoprotein (p-glycoprotein) (Center, 1983;Louie et al., 1986;Riordan & Ling, 1979). There is good evidence that p-glycoprotein is part of a cellular export system which increases drug efflux by an energy dependent mechanism (Center, 1983;Dano, 1973;Gerlach et al., 1986;Inaba et al., 1979;Skovsgaard, 1978), although reduction in intracellular drug levels alone is insufficient to account for the level of resistance observed in some systems (Bates et al., 1985a). It has previously been shown that influx of several chemotherapeutic agents is increased at elevated temperatures (Bates & Mackillop, 1986;Hahn, 1979;Nagaoka et al., 1986) and we have therefore explored the possibility that hyperthermia might be capable of overcoming the type of pleiotropic drug resistance which is associated with increased drug efflux.The combination of hyperthermia with certain chemotherapeutic agents has exhibited potentiation of effect in experimental systems (Barlogie et al., 1980; Bates et al., 1987b;Bates & Mackillop, 1986;Hahn, 1979;Herman et al., 1982;Nagaoka et al., 1986). Regional hyperthermia, therefore, has the potential to increase the cytotoxic effects of a systemically administered agent within a defined target region and may thus be of clinical value. Thermo-chemotherapy has not been extensively tested in human tumours but for some time melphalan has been used with hyperthermia in the treatment of human melanoma by a limb perfusion (Rege et al., 1983;Stehlin, 1980;Storm et al., 1982). Studies of the interaction between hyperthermia and melphalan at the cellular level have, until now, been limited (Bates et al., 1987b). We have therefore studied the...

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“…This transport system may be an effective strategy as a CNS delivery vector for drugs that have positively charged quaternary ammonium grouping within their structure, such as the quaternized ellipticines that are cytotoxic against isolated human brain tumor cells (Vistica et al, 1994). It has already been demonstrated that lymphoblast choline transporters are effective in delivering nitrogen mustard alkylating agents intracellularly (Goldenberg and Begleiter, 1980). These latter studies suggest that choline transporters can be used opportunistically to deliver drugs across cell membranes.…”

mentioning

confidence: 93%

Active Transport of High-Affinity Choline and Nicotine Analogs into the Central Nervous System by the Blood-Brain Barrier Choline Transporter

Allen¹,

Lockman²,

Roder³

et al. 2002

J Pharmacol Exp Ther

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Cigarette smoking is strongly implicated in the development of cardiovascular disorders. Recently identified nicotinium analogs may have therapeutic benefit as smoking cessation therapies but may have restricted entry into the central nervous system by the blood-brain barrier (BBB) due to their physicochemical properties. Using the in situ perfusion technique, lobeline, choline, and nicotinium analogs were evaluated for binding to the BBB choline transporter. Calculated apparent K i values for the choline transporter were 1., 393 M lobeline, and Ն1000 M Nmethylnicotinium iodide. Nicotine and N-methylpyridinium iodide, however, do not apparently interact with the BBB choline transporter. Given NONI's apparent K i value determined in this study and its ability to inhibit nicotine-evoked dopamine release from superfused rat brain slices, potential brain entry of NONI via the BBB choline transporter was evaluated. [3 H]NONI exhibited a BBB transfer coefficient value of ϳ1.6 ϫ 10 Ϫ3 ml/s/g and a K m of ϳ250 M. Unlabeled choline addition to the perfusion fluid reduced [ 3 H]NONI brain uptake. We hypothesize the N-n-octyl group on the pyridinium nitrogen of NONI facilitates brain entry via the BBB choline transporter. Thus, NONI may have utility as a smoking cessation agent, given its ability to inhibit nAChRs mediating nicotine-evoked dopamine release centrally, and to be distributed to brain via the BBB choline transporter.

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Membrane transport of alkylating agents

Cited by 45 publications

References 83 publications

Cytokinetic factors in drug resistance of Lewis lung carcinoma: comparison of cells freshly isolated from tumours with cells from exponential and plateau-phase cultures

Cytokinetic factors in drug resistance of Lewis lung carcinoma: comparison of cells freshly isolated from tumours with cells from exponential and plateau-phase cultures

The effect of hyperthermia in combination with melphalan on drug-sensitive and drug-resistant CHO cells in vitro

Active Transport of High-Affinity Choline and Nicotine Analogs into the Central Nervous System by the Blood-Brain Barrier Choline Transporter

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