Oxygen dependence of the cytotoxicity of the enediyne anti-tumour antibiotic esperamicin A1.
The enediyne anti-tumour antibiotics are extremely potent cytotoxins, apparently because of their conversion to diradical species which induce DNA double strand breaks with high efficiency. The potency of enediynes suggests their possible utility as effector units for prodrugs which can be activated selectively in tumours, such as bioreductive drugs (BD) or radiation-activated cytotoxins (RAC). However, the similarity of the radical-induced DNA breakage reactions of the enediynes to those caused by ionising radiation suggested that resistance of hypoxic cells might be a potential problem. Experiments with AA8 cells in culture demonstrated that the enediyne antibiotics neocarzinostatin and esperamicin A, (ESP) are much less toxic under hypoxic than aerobic conditions. Sensitivity to ESP (concentration for 90% cell kill 10 pM) decreased 15-fold under hypoxia, and was partially restored by simultaneous exposure to misonidazole. ESP induced chromosome breakage (micronucleus formation) with an efficiency similar to gamma radiation at equivalent cell kill, suggesting a clastogenic mechanism of cytotoxicity. In contrast, little micronucleus formation was evident after exposure to ESP under hypoxia, even at concentrations giving equivalent cell killing. These findings suggest that resistance of hypoxic cells may limit the utility of enediynes as cytotoxic effectors for BD or RAC prodrug development, and that further investigation of enediynes as anti-tumour agents should include strategies capable of eliminating hypoxic cells.
Batchelder
R M
RM
Department of Pathology, University of Auckland School of Medicine, New Zealand.
Wilson
W R
WR
Hay
M P
MP
Denny
W A
WA
D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D053281:Enediynes; D006801:Humans; D051379:Mice; D010100:Oxygen / Q000494:pharmacology*; D009353:Zinostatin / Q000494:pharmacology
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D009353:Zinostatin; C047543:esperamicin A1; D010100:Oxygen