Antitumor activity of edotecarin in breast carcinoma models.
OBJECTIVE
Edotecarin (J-107088, formerly ED-749) is a potent indolocarbazole topoisomerase-I inhibitor that has the potential to treat solid tumors. The current studies evaluated the potency and antitumor activity of edotecarin, as a single agent and in combination with capecitabine or docetaxel.


METHODS
Antiproliferative activity was tested in vitro in a panel of 13 mammary cell lines and antitumor efficacy was tested in vivo in various breast cancer models.


RESULTS
Edotecarin inhibited cellular proliferation in breast carcinoma cell lines: 50% inhibitory concentrations ranged from 8 nmol/L in SKBR-3 cells to approximately 30 micromol/L in BT20 cells. Single dose and weekly intravenous treatments with edotecarin 30 and 150 mg/kg produced significant antitumor activity in the SKBR-3 human breast carcinoma xenograft model, with no major toxicities, compared with vehicle solvent treatment. Daily administration of edotecarin 15 mg/kg for 10 days was not well tolerated, whereas the total dose of 150 mg/kg was safe when administered in a single injection. Edotecarin 3 and 30 mg/kg given after docetaxel in the nude mouse SKBR-3 xenograft model produced tumor growth delays that were greater than those observed with either agent alone and with no toxicity as evaluated on the basis of body weight reduction (<20%). Furthermore, edotecarin 3 mg/kg in combination with capecitabine produced more than additive effects and the combination was well tolerated. However, edotecarin at a dose of 30 mg/kg in combination with capecitabine was lethal. Edotecarin also exhibited potent antitumor activity against xenografted human MX-1 cells, MMTV-v-Ha-ras oncogene-driven mouse breast tumors, and chemically induced rat mammary tumors.


CONCLUSIONS
The data suggest that edotecarin may be useful as a single agent or a component of combination chemotherapy regimens for treating human breast cancer.
Ciomei
Marina
M
Cell Biology/Oncology, Nerviano Medical Sciences, Viale Pasteur, 10, 20014 Nerviano (MI), Italy. marina.ciomei@nervianoms.com
Croci
Valter
V
Stellari
Fabio
F
Amboldi
Nadia
N
Giavarini
Rosa
R
Pesenti
Enrico
E
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002227:Carbazoles / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051381:Rats; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000627:therapeutic use; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D002227:Carbazoles; D007211:Indoles; D043823:Taxoids; D059004:Topoisomerase I Inhibitors; D000077143:Docetaxel; C121395:edotecarin