Edotecarin: a novel topoisomerase I inhibitor.
Edotecarin (PHA-782615; formerly J-107088) is a derivative of NB-506, an indolocarbazole antitumor agent. It is a novel inhibitor of topoisomerase I that induces single-strand DNA cleavage more effectively than NB-506 or camptothecin (CPT) and at different DNA sequences. The DNA-topoisomerase I complexes induced by edotecarin are more stable than those occurring after exposure to CPT or NB-506. The antitumor activity of edotecarin is less cell cycle dependent than other topoisomerase I inhibitors. Being an indolocarbazole, it is structurally related to staurosporine but does not possess protein kinase inhibitory properties. In addition, edotecarin does not form active metabolites and is not a substrate for in vitro P450-mediated metabolism. The antitumor activity of edotecarin has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in breast, cervix, pharynx, lung, prostate, colon, gastric, and hepatic cancer models. Edotecarin is effective on cells that have acquired resistance related to P-glycoprotein. In vitro synergy has been demonstrated when edotecarin was tested in combination with cisplatin, 5-fluorouracil, etoposide, paclitaxel, doxorubicin, vincristine, CPT, and gemcitabine. Three phase I and 5 phase II studies have been carried out to date. Combination studies of edotecarin with other chemotherapeutic agents are in current clinical trials. The primary dose-limiting toxicities were grade 3/4 neutropenia and febrile neutropenia. Dose-limiting diarrhea was observed only with a twice-weekly administration schedule. Recent progress in preclinical and clinical studies of edotecarin is reviewed.
Saif
M Wasif
MW
Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294-3300, USA. wasif.saif@ccc.uab.edu
Diasio
Robert B
RB
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002227:Carbazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D002986:Clinical Trials as Topic; D003967:Diarrhea / Q000139:chemically induced; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy; D059004:Topoisomerase I Inhibitors
D002227:Carbazoles; D007211:Indoles; D059004:Topoisomerase I Inhibitors; C121395:edotecarin