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.

Abstract

PURPOSE:

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 AND MATERIALS:

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.

• Authors: P M Harari, M A Pickart, L Contreras, D G Petereit, H S Basu, L J Marton
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 32 Issue 3 Pg. 687-94 (Jun 15 1995) ISSN: 0360-3016 [Print] United States
• PMID: 7790255 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Growth Inhibitors
• Ornithine Decarboxylase Inhibitors
• Polyamines
• BE 4-4-4-4
• Spermine

Topics

• Carcinoma, Squamous Cell (chemistry, enzymology, pathology)
• Cell Cycle (drug effects)
• Cell Division (drug effects, radiation effects)
• Drug Screening Assays, Antitumor
• Flow Cytometry
• Growth Inhibitors (pharmacology)
• Head and Neck Neoplasms (chemistry, enzymology, pathology)
• Humans
• Ornithine Decarboxylase Inhibitors
• Polyamines (analysis)
• Spermine (analogs & derivatives, pharmacology)
• Tumor Cells, Cultured