4-Amino-1,8-naphthalimide: a novel inhibitor of poly(ADP-ribose) polymerase and radiation sensitizer.
OBJECTIVE
Poly(ADP-ribose) polymerase (PARP; EC 2.4.2.30) is a chromatin-bound enzyme which is known to regulate chromatin structure by poly(ADP-ribosyl)ation of nuclear proteins, to facilitate DNA base excision repair, and to contribute to cellular recovery following DNA damage. Because inhibitors of PARP are able to potentiate the cell-killing effects of some DNA-damaging agents and to inhibit the repair of induced DNA strand breaks, such compounds may enhance the anti-tumour efficacy of radiotherapy or cytotoxic drug treatment. The PARP-inhibitory effects and radiosensitization of a new compound, 4-amino-1,8-naphthalimide (ANI), were examined.


METHODS
The inhibition of radiation-induced poly(ADP-ribosyl)ation (50 Gy; 60Co gamma-radiation) was evaluated by immunofluorescence assay using MoAb 10H directed against poly(ADP-ribose). Cell survival was assessed by colony forming assay (CFA) to determine the cytotoxicity of radiosensitization potential in exponentially growing hamster lung fibroblasts (V79), rat prostate carcinoma (R3327-AT1) and human prostate carcinoma (DU145) cells.


RESULTS
At concentrations above 30 nmol x dm(-3) ANI, radiation-induced poly(ADP-ribose) was not detectable by immunofluorescence in V79, AT1 and DU145 cells. At the highest concentration tested for chronic exposure (20 micromol x dm(-3)), ANI was not cytotoxic and significantly potentiates the cytotoxicity of gamma-irradiation. The level of radiation enhancement was directly proportional to drug concentration. Survival curves for the three cell lines using 20 micromol x dm(-3) ANI revealed sensitizer enhancement ratios of 1.3 for V79, 1.5 for AT1 and 1.3 for DU145.


CONCLUSIONS
In living cells, ANI is about 1000-fold more potent at inhibiting PARP activity compared with 3-aminobenzamide (3-ABA). CFA studies demonstrated that ANI is a radiation sensitizer at non-toxic and lower concentrations (20 micromol x dm(-3)) than 3-ABA (10 mmol x dm(-3)).
Schlicker
A
A
Department of Radiation Oncology, German Cancer Research Centre (DKFZ), Heidelberg.
Peschke
P
P
Bürkle
A
A
Hahn
E W
EW
Kim
J H
JH
D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D053644:Naphthalimides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D015363:Quinolones / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats