Cell Cycle Kinetics of Human Lung Cancer

Straus, Marc J.; Moran, Ruth E.

doi:10.1055/s-2007-1012195

Cited by 3 publications

(2 citation statements)

References 17 publications

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“…Clearly, a number of relevant differences exist between other tumor types and non-small lung cancer cells ( − ). Furthermore, important and as yet undescribed pharmacokinetic differences may exist between TOP-53 and etoposide.…”

Section: Discussionmentioning

confidence: 99%

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DNA Topoisomerase II as the Target for the Anticancer Drug TOP-53: Mechanistic Basis for Drug Action

et al. 2000

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TOP-53 is a promising anticancer agent that displays high activity against non-small cell lung cancer in animal tumor models [Utsugi, T., et al. (1996) Cancer Res. 56, 2809-2814]. Compared to its parent compound, etoposide, TOP-53 is considerably more toxic to non-small cell lung cancer cells, is more active at generating chromosomal breaks, and displays improved cellular uptake and pharmacokinetics in animal lung tissues. Despite the preclinical success of TOP-53, several questions remain regarding its cytotoxic mechanism. Therefore, this study characterized the basis for drug action. Results indicate that topoisomerase II is the primary cytotoxic target for TOP-53. Furthermore, the drug kills cells by acting as a topoisomerase II poison. TOP-53 exhibits a DNA cleavage site specificity that is identical to that of etoposide. Like its parent compound, the drug increases the number of enzyme-mediated DNA breaks by interfering with the DNA religation activity of the enzyme. TOP-53 is considerably more efficient than etoposide at enhancing topoisomerase II-mediated DNA cleavage and exhibits high activity against human topoisomerase IIalpha and IIbeta in vitro and in cultured cells. Therefore, at least in part, the enhanced cytotoxic activity of TOP-53 can be attributed to an enhanced activity against topoisomerase II. Finally, TOP-53 displays nearly wild-type activity against a mutant yeast type II enzyme that is highly resistant to etoposide. This finding suggests that TOP-53 can retain activity against systems that have developed resistance to etoposide, and indicates that substituents on the etoposide C-ring are important for topoisomerase II-drug interactions.

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Section: Discussionmentioning

confidence: 99%

“…Several specific attributes of non-small cell lung cancer cells may explain this difference. When compared to small cell lung cancer cells, non-small cell lung cancers display a 2−3-fold longer doubling time, a lower labeling index, and a decreased nuclear concentration and activity of topoisomerase II ( , ).…”

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confidence: 99%