Development, pharmacology, role of DT-diaphorase and prospects of the indoloquinone EO9.
1. The indoloquinone EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2- (1H-indole-4,7-dione)-propenol; E85/053; NSC 382,459) is a synthetic bioreductive alkylating agent that is structurally related to mitomycin C (MMC). 2. EO9 does, however, show a different mechanism of action and a broader antitumour profile than MMC. It is also a more potent cytotoxic agent in vitro than MMC, probably because of its impressive efficient activation by reductive enzymes, particularly DT-Diaphorase. This enzyme is elevated in several tumours compared to normal tissues. 3. The preferential cytotoxicity of EO9 under hypoxic conditions makes it an interesting compound to combine with radiation. 4. In preclinical and the Phase I clinical studies, no myelosuppression was observed but reversible proteinuria was dose-limiting. Phase II clinical studies were started in the summer of 1994.
Smitskamp-Wilms
E
E
Dept. of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Hendriks
H R
HR
Peters
G J
GJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001388:Aziridines / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D045563:Indolequinones; D007211:Indoles / Q000494:pharmacology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D010084:Oxidation-Reduction
D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D007211:Indoles; D016660:NAD(P)H Dehydrogenase (Quinone); C060817:apaziquone