Antitumor activity of edotecarin in breast carcinoma models.

Abstract

PURPOSE:

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.

• Authors: Marina Ciomei, Valter Croci, Fabio Stellari, Nadia Amboldi, Rosa Giavarini, Enrico Pesenti
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 60 Issue 2 Pg. 229-35 (Jul 2007) ISSN: 0344-5704 [Print] Germany
• PMID: 17089166 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Carbazoles
• Indoles
• Taxoids
• Topoisomerase I Inhibitors
• Docetaxel
• edotecarin

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols
• Breast Neoplasms (drug therapy, pathology)
• Carbazoles (therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Docetaxel
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Female
• Humans
• Indoles (therapeutic use)
• Inhibitory Concentration 50
• Mammary Neoplasms, Experimental (chemically induced, drug therapy, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Rats
• Rats, Sprague-Dawley
• Taxoids (therapeutic use)
• Topoisomerase I Inhibitors