Cell line-dependent differences in uptake and retention of the hypoxia-selective nuclear imaging agent Cu-ATSM Journal Article
| Authors: | Burgman, P.; O'Donoghue, J. A.; Lewis, J. S.; Welch, M. J.; Humm, J. L.; Ling, C. C. |
| Article Title: | Cell line-dependent differences in uptake and retention of the hypoxia-selective nuclear imaging agent Cu-ATSM |
| Abstract: | Background: Cu-diacetyl-bis(N4-methylthiosemicarbazone) [Cu-ATSM] is a potential marker for tumor hypoxia that has been under evaluation for clinical use. In this study, we examined the mechanisms underlying the uptake of 64Cu in cells incubated with 64Cu-ATSM. Methods: The in vitro uptake of 64Cu was determined as a function of oxygenation conditions and incubation time with 64Cu-ATSM using four and two tumor cell lines of human origin and rodent origin, respectively. Additionally, the rate of 64Cu efflux and Cu-ATSM metabolism was determined. Results: 64Cu accumulation is rapid during the first 0.5-1 h of incubation. It is highest in anoxic cells but is also significant in normoxic cells. After this initial period, the level of intracellular 64Cu varies depending on the cell line and the oxygenation conditions and, in some circumstances, may decrease. During the first 0.5-1 h, the ratio of 64Cu levels between anoxic and normoxic cells is ∼2:10 and that between hypoxic (0.5% O2) and normoxic cells is ∼1:2.5, depending on the cell line. These ratios generally decrease at longer times. The 64Cu-ATSM compound was found to be metabolized during incubation in a manner dependent on oxygenation conditions. Within 2 h under anoxic conditions, 64Cu-ATSM could no longer be detected, although 60-90% of the amount of 64Cu added as 64Cu-ATSM was present in the medium. Non-ATSM 64Cu was taken up by the cells, albeit at a much slower rate. Efflux rates of 64Cu were found to be cell line dependent and appeared to be inversely correlated with the final 64Cu uptake levels under anoxic conditions. Conclusion: The uptake and retention of 64Cu and their relation to oxygenation conditions were found to be cell line dependent. Given the complexities in the oxygen dependence and cell line-dependent kinetics of uptake and retention of Cu following exposure to Cu-ATSM, the clinical utility of this compound may be disease site specific. © 2005 Elsevier Inc. All rights reserved. |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; positron emission tomography; neoplasms; animal cell; animals; oxygen; culture medium; cell line; tumor cells, cultured; hypoxia; correlation analysis; statistical significance; drug accumulation; drug retention; drug uptake; tissue distribution; cell hypoxia; rats; rodent; drug metabolism; pet; time series analysis; organometallic compounds; oxygenation; copper; anoxia; thiosemicarbazones; copper radioisotopes; incubation time; copper derivative; cu-atsm; semicarbazone derivative; nuclear imaging; diacetylbis(n 4 methylthiosemicarbazone) cu 64 |
| Journal Title: | Nuclear Medicine and Biology |
| Volume: | 32 |
| Issue: | 6 |
| ISSN: | 0969-8051 |
| Publisher: | Elsevier Science Inc. |
| Date Published: | 2005-08-01 |
| Start Page: | 623 |
| End Page: | 630 |
| Language: | English |
| DOI: | 10.1016/j.nucmedbio.2005.05.003 |
| PUBMED: | 16026709 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 46" - "Export Date: 24 October 2012" - "CODEN: NMBIE" - "Source: Scopus" |
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331Ling
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