Influence of pentoxifylline, A-802710, propentofylline and A-802715 (Hoechst) on the expression of cell cycle blocks and S-phase content after irradiation damage.
The toxicity of the five methylxanthine derivatives, caffeine, pentoxifylline, A802710, propentofylline and A802715, was determined against the two human melanoma lines, Be11 and MeWo, and against the two human squamous cell carcinoma lines, 4197 and 4451, by vital dye staining assay. Pentoxifylline and A802710 emerge as the least toxic showing TD(50) (toxic dose of 50%) levels of 3.0-4.0 mM. Propentofylline and caffeine take an intermediate position. A802715 has a TD(50) of 0.9-1.1 mM and is the most toxic. Subtoxic concentrations (<TD50)added after irradiation at maximum expression of the G2/M block show that pentoxifylline and A802710 effectively abrogate the G2/M block, whereas A802715 and propentofylline prolong the G2/M block or remain ineffective depending on the p53 status of the cell line. In p53 wt cells BrdU incorporations show that the irradiation-induced suppression of S-phase entry is marginally enhanced by pentoxifylline but strongly enhanced by propentofylline and A802715. This effect was not seen in p53 mutant cells. Since propentofylline and A802715 prolong the G2/M block and effectively suppress BrdU incorporation these two drugs emerge as antagonists to pentoxifylline, caffeine and A802710. Common structural features of propentofylline and A802715 are a propyl substituent at the N7 position in contrast to pentoxifylline, caffeine and A802710 where the N7 substituent is a methyl group. The results document the effectiveness of four methylxanthines in influencing cell regulation and damage response in human tumor cells.
Bohm
L
L
Department of Radiation Oncology, Faculty of Medicine, University of Stellenbosch, P.O. Box 19063, 7505, Tygerberg, South Africa. elb@gerga.sun.ac.za
Theron
T
T
Binder
A
A
D002110:Caffeine / Q000494:pharmacology / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects* / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects; D005840:Gentian Violet; D006131:Growth Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007202:Indicators and Reagents; D008938:Mitosis / Q000187:drug effects; D015394:Molecular Structure; D015739:Nocodazole; D010431:Pentoxifylline / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D016196:S Phase; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014970:Xanthines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007202:Indicators and Reagents; D011838:Radiation-Sensitizing Agents; D014970:Xanthines; C078398:A 802715; D002110:Caffeine; C032114:propentofylline; D005840:Gentian Violet; C025189:lisofylline; D010431:Pentoxifylline; D015739:Nocodazole