Polyamine aza-cyclic compounds demonstrate anti-proliferative activity in vitro but fail to control tumour growth in vivo

P.E. Wong, L. Tetley, C. Dufès, K.W. Chooi, K. Bolton, A.G. Schätzlein, I.F. Uchegbu

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 (IC50 = 775.1 µg mL−1) and CL8 (IC50 = 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
Original languageEnglish
Pages (from-to)4642-4657
Number of pages16
JournalJournal of Pharmaceutical Sciences
Volume99
Issue number11
Early online date13 May 2010
DOIs
Publication statusPublished - Nov 2010

Fingerprint

Aza Compounds
Polyamines
Growth
Inhibitory Concentration 50
Amines
Neoplasms
Dendrimers
DNA
Erythrocyte Membrane
S Phase
Heterografts
Nanoparticles
Squamous Cell Carcinoma
Cell Cycle
Plasmids
Cell Membrane
In Vitro Techniques

Keywords

  • polyamines
  • aza-cyclic compounds
  • cytotoxicity
  • cancer
  • poly
  • (propylenimine)
  • dendrimers
  • DAB 16
  • DNA binding

Cite this

Wong, P. E., Tetley, L., Dufès, C., Chooi, K. W., Bolton, K., Schätzlein, A. G., & Uchegbu, I. F. (2010). Polyamine aza-cyclic compounds demonstrate anti-proliferative activity in vitro but fail to control tumour growth in vivo. Journal of Pharmaceutical Sciences, 99(11), 4642-4657. https://doi.org/10.1002/jps.22165
Wong, P.E. ; Tetley, L. ; Dufès, C. ; Chooi, K.W. ; Bolton, K. ; Schätzlein, A.G. ; Uchegbu, I.F. / Polyamine aza-cyclic compounds demonstrate anti-proliferative activity in vitro but fail to control tumour growth in vivo. In: Journal of Pharmaceutical Sciences. 2010 ; Vol. 99, No. 11. pp. 4642-4657.
@article{cdc5d8e2c9334cd1814762170b975c7a,
title = "Polyamine aza-cyclic compounds demonstrate anti-proliferative activity in vitro but fail to control tumour growth in vivo",
abstract = "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 (IC50 = 775.1 µg mL−1) and CL8 (IC50 = 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",
keywords = "polyamines, aza-cyclic compounds, cytotoxicity, cancer, poly, (propylenimine), dendrimers, DAB 16, DNA binding",
author = "P.E. Wong and L. Tetley and C. Duf{\`e}s and K.W. Chooi and K. Bolton and A.G. Sch{\"a}tzlein and I.F. Uchegbu",
year = "2010",
month = "11",
doi = "10.1002/jps.22165",
language = "English",
volume = "99",
pages = "4642--4657",
journal = "Journal of Pharmaceutical Sciences",
issn = "0022-3549",
number = "11",

}

Wong, PE, Tetley, L, Dufès, C, Chooi, KW, Bolton, K, Schätzlein, AG & Uchegbu, IF 2010, 'Polyamine aza-cyclic compounds demonstrate anti-proliferative activity in vitro but fail to control tumour growth in vivo', Journal of Pharmaceutical Sciences, vol. 99, no. 11, pp. 4642-4657. https://doi.org/10.1002/jps.22165

Polyamine aza-cyclic compounds demonstrate anti-proliferative activity in vitro but fail to control tumour growth in vivo. / Wong, P.E.; Tetley, L.; Dufès, C.; Chooi, K.W.; Bolton, K.; Schätzlein, A.G.; Uchegbu, I.F.

In: Journal of Pharmaceutical Sciences, Vol. 99, No. 11, 11.2010, p. 4642-4657.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Polyamine aza-cyclic compounds demonstrate anti-proliferative activity in vitro but fail to control tumour growth in vivo

AU - Wong, P.E.

AU - Tetley, L.

AU - Dufès, C.

AU - Chooi, K.W.

AU - Bolton, K.

AU - Schätzlein, A.G.

AU - Uchegbu, I.F.

PY - 2010/11

Y1 - 2010/11

N2 - 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 (IC50 = 775.1 µg mL−1) and CL8 (IC50 = 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

AB - 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 (IC50 = 775.1 µg mL−1) and CL8 (IC50 = 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

KW - polyamines

KW - aza-cyclic compounds

KW - cytotoxicity

KW - cancer

KW - poly

KW - (propylenimine)

KW - dendrimers

KW - DAB 16

KW - DNA binding

UR - http://www.scopus.com/inward/record.url?scp=78149328783&partnerID=8YFLogxK

U2 - 10.1002/jps.22165

DO - 10.1002/jps.22165

M3 - Article

VL - 99

SP - 4642

EP - 4657

JO - Journal of Pharmaceutical Sciences

JF - Journal of Pharmaceutical Sciences

SN - 0022-3549

IS - 11

ER -