Document Detail

Polyamine aza-cyclic compounds demonstrate anti-proliferative activity in vitro but fail to control tumour growth in vivo.
MedLine Citation:
PMID:  20845462     Owner:  NLM     Status:  MEDLINE    
Cationic polyamines such as the poly(propylenimine) dendrimers (DAB16) are anti-tumour agents (Dufes et al., 2005, Cancer Res 65:8079-8084). Their mechanism of action is poorly understood, but the lack of in vivo toxicity suggests cancer specificity. To explore this polyamine pharmacophore we cross-linked the aza-cyclic compound, hexacyclen, with 1,4-dibromobutane or 1,8-dibromooctane to yield the polyamines [poly(butylhexacyclen)--CL4] or [poly(octylhexacyclen)--CL8] respectively, both free of primary amines. We characterised the compounds and their respective nanoparticles and examined their interaction with the putative targets of the cationic polyamines: the cell membrane and DNA. Like DAB 16, CL4 and CL8 bind plasmid DNA and all three compounds interrupted the cell cycle of A431 epidermoid carcinoma cells in the S-phase. Additionally all three compounds disrupted erythrocyte membranes, with CL8 and DAB 16 being more active, in this respect, than CL4. CL4 (IC(50) =775.1 µg mL(-1)) and CL8 (IC(50) =8.4 µg mL(-1)), in a similar manner to DAB 16, were anti-proliferative against A431 cells; although unlike DAB 16, CL4 and CL8 were not tumouricidal against A431 xenografts in mice, indicating that primary amines may play an important role in the in vivo activity of DAB 16.
Pui Ee Wong; Laurence Tetley; Christine Dufès; Kar Wai Chooi; Katherine Bolton; Andreas G Schätzlein; Ijeoma F Uchegbu
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  99     ISSN:  1520-6017     ISO Abbreviation:  J Pharm Sci     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-09-16     Completed Date:  2011-01-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985195R     Medline TA:  J Pharm Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4642-57     Citation Subset:  IM    
Copyright Information:
© 2010 Wiley-Liss, Inc. and the American Pharmacists Association
Division of Infection & Immunity, University of Glasgow, Glasgow, UK.
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MeSH Terms
Antineoplastic Agents / chemistry,  pharmacology*,  therapeutic use
Apoptosis / drug effects
Aza Compounds / chemistry,  pharmacology*,  therapeutic use
Carcinoma, Squamous Cell / drug therapy*
Cell Cycle / drug effects
Cell Line
DNA / metabolism
Mice, Nude
Polyamines / chemistry,  pharmacology*,  therapeutic use
Reg. No./Substance:
0/Antineoplastic Agents; 0/Aza Compounds; 0/Polyamines; 9007-49-2/DNA

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