2005
DOI: 10.1007/s00280-005-0007-6 View full text |Buy / Rent full text
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Abstract: The effect of 7-alkyl substitutions on growth inhibition in seven Camptothecin (CPT) ring systems with various groups at the ten position was evaluated in three human breast cancer cell lines that model (1) hormone-sensitive (MCF-7/wt), (2) hormone insensitive (MDA-MB-231), or (3) alkylator-resistant (MCF-7/4-hc) forms of disease. To assess the impact of persistence of cleavage complexes on antiproliferative activity, a post-exposure recovery period in drug-free medium was incorporated into the growth inhibiti… Show more

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“…Camptothecin (CPT) and its derivatives selectively target mammalian DNA topoisomerase (Top) I (Hsiang et al, 1985;Nitiss and Wang, 1988;Bjornsti et al, 1989;Pommier et al, 2003;Marchand et al, 2006) and are effective anticancer drugs (Wall and Wani, 1995;Garcia-Carbonero and Supko, 2002;Pizzolato and Saltz, 2003;Capranico et al, 2004;Adams et al, 2006). By trapping the DNA-Top1 intermediate, these drugs form a ternary complex that, upon encountering a replication fork, becomes a lethal lesion, leading to druginduced cytotoxicity .…”
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“…Camptothecin (CPT) and its derivatives selectively target mammalian DNA topoisomerase (Top) I (Hsiang et al, 1985;Nitiss and Wang, 1988;Bjornsti et al, 1989;Pommier et al, 2003;Marchand et al, 2006) and are effective anticancer drugs (Wall and Wani, 1995;Garcia-Carbonero and Supko, 2002;Pizzolato and Saltz, 2003;Capranico et al, 2004;Adams et al, 2006). By trapping the DNA-Top1 intermediate, these drugs form a ternary complex that, upon encountering a replication fork, becomes a lethal lesion, leading to druginduced cytotoxicity .…”
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“…Greater lipophilicity also enhances entry into cells, thereby increasing the effective intracellular concentration, and entropically favours complex formation (the hydrophobic effect) and thus, potentially, affinity of drug for intracellular receptors/targets. Numerous studies indicate a selectivity of lipophilic compounds for impacting rapidly proliferating cancer cells over normal cells [37,38] and others show, amongst related series of compounds, a clear correlation between anti-proliferative activity/cytotoxicity and degree of lipophilicity [39][40][41]. When this relationship was examined for the newly synthesized analogues of MDMA, a strong correlation was indeed observed with anti-lymphoma potency closely tracking calculated lipophilicity, at least for those compounds with aromatic α-substituents.…”
Section: Discussionmentioning
“…Our interest in BACPT initially stemmed from the analog’s enhanced activity in breast cancer cell lines when cultured at acidic pH [4, 5], and thus it’s potential to exploit the tumor pH gradient. Uptake and efflux data in MCF-7 cells [5] support the concept that BACPT behaves as a weak acid.…”
Section: Discussionmentioning
“…Like other camptothecins, BACPT acts by inhibiting nuclear topoiso-merase I (top1) to create cytotoxic DNA double strand breaks. Molecular modeling studies based on the X-ray crystal structure for topotecan in the ternary top1/DNA complex revealed that binding of BACPT is further stabilized by a direct hydrogen bond between the 10-amino moiety and an oxygen atom of the side chain of Glu-346 [4]. The butyl substituent at the 7 position orients the drug such that it imitates a DNA base pair.…”
Section: Introductionmentioning