CRM197 enhances antitumor effect of paclitaxel in ovarian cancer

CRM197, an inhibitor of heparin-binding EGF-like factor (HB-EGF), is synergistic with paclitaxel against ovarian cancer, according to a report in the March 15th issue of the International Journal of Cancer.HB-EGF appears to play a critical role in ovarian cancer cell growth and tumor progression, the authors explain. CRM197 binds to HB-EGF and blocks its mitogenic activity by preventing it from binding to EGFR. Dr. Shingo Miyamoto from Fukuoka University, Japan, and colleagues investigated the antitumor effects of paclitaxel and CRM197 in ovarian cancer cell culture and in nude mice injected subcutaneously with ovarian cancer cells. Paclitaxel induced transient ERK activation and sustained activation of JNK and p38 MAPK, effects that were reduced by overexpression of HB-EGF, the authors report. CRM197 effectively suppressed the paclitaxel-induced anti-apoptotic signals mediated by ERK and Akt, and enhanced the pro-apoptotic signals JNK and p38 MAPK. In nude mice with ovarian cancer xenografts, the researchers note, paclitaxel and CRM197 synergistically inhibited tumor formation, completely blocking tumor formation at doses of 10 mg/kg paclitaxel and 5 mg/kg CRM197. "In this study," the authors conclude, "the enhancement of HB-EGF expression abrogates the antitumor effect of paclitaxel by altering the balance of anti-apoptotic and pro-apoptotic signals induced by paclitaxel. The treatment of CRM197 in conjunction with paclitaxel results in a marked synergistic antitumor effect in ovarian cancer cells in vivo, suggesting a novel combination therapy for ovarian cancer patients including those showing chemo-resistance." "Phase 1 study of the use of CRM197 has already started for patients with advanced ovarian cancer in Fukuoka University under the approval of the ethical committee," the investigators add.