Slowing proliferation in head and neck tumors: in vitro growth inhibitory effects of the polyamine analog BE-4-4-4-4 in human squamous cell carcinomas.
OBJECTIVE
These preclinical studies were carried out to examine the potential of the antiproliferative polyamine analog 1,19-bis-(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4) to serve as a therapy adjuvant to radiation for patients with rapidly dividing tumors of the head and neck (H&N).


METHODS
Cytostatic and cytotoxic effects of this polyamine analog were investigated in three squamous cell carcinoma (SCC) cell lines derived from human H&N tumors.


RESULTS
Growth inhibition was achieved in all cell lines within 3-4 days of continuous 10 microM drug exposure, and inhibition of cell cycle proliferation kinetics was confirmed via flow cytometry. Cytotoxicity was pronounced (3-4 log cell kill) in the SCC-38 and SCC-4Y cell lines with continuous 10 microM analog exposure over 5 days, and was minimal in the SCC-13Y cell line. No demonstrable effect of BE-4-4-4-4 on single dose radiation survival was identified in any SCC cell line. Ornithine decarboxylase (ODC) activity was rapidly inhibited (1-2 h) following 10 microM BE-4-4-4-4 exposure in all SCC cell lines (approximately 90%), whereas identical exposure to 10 microM difluoromethylornithine (DFMO) induced animal ODC inhibition (approximately 10%). Dose-dependent depletion of endogenous polyamines (putrescine, spermidine, spermine) was achieved in all SCC cell lines following 1 microM and 10 microM BE-4-4-4-4 exposures. Difluoromethylornithine was significantly less potent than BE-4-4-4-4 in its capacity to deplete endogenous polyamines, with no measureable depletion of spermine pools even with 5 mM x 48 h DFMO exposures.


CONCLUSIONS
These data evaluate cytostatic and cytotoxic properties of the polyamine analog BE-4-4-4-4 in human SCCs, and suggest a role for investigation of such agents as an adjuvant to radiation in the therapeutic approach to rapidly dividing human tumors such as those that occur in the H&N.
Harari
P M
PM
Department of Human Oncology, University of Wisconsin School of Medicine, Madison, USA.
Pickart
M A
MA
Contreras
L
L
Petereit
D G
DG
Basu
H S
HS
Marton
L J
LJ
D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000201:enzymology / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000737:chemistry / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000032:analysis; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D006131:Growth Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; C082768:BE 4-4-4-4; D013096:Spermine