Verapamil with mitoxantrone for advanced ovarian cancer: A negative phase II trial

Abstract

Fourteen patients with advanced epithelial ovarian cancer were treated with oral verapamil 240 to 480 mg daily for 3 days and intravenous mitoxantrone 12 to 14 mg/m2 on the second days of verapamil administration. Courses were repeated at 21 day intervals to a maximum of 4 courses. Most patients had cancers refractory to prior cisplatin or carboplatin, or had cancers which recurred quickly after such treatments. This poor prognostic profile of patients probably accounted for the lack of objective responses to verapamil plus mitoxantrone. Despite maximally tolerated daily oral verapamil doses (480 mg daily) our inability to achieve in vivo levels of verapamil that in vitro have an optimum cytotoxic potentiating effect mitigate against further clinical exploration of verapamil as a sole enhancing agent.

Squamous cell cancers contain a side population of stem-like cells that are made chemosensitive by ABC transporter blockade

“…Thus, it is increasingly important that cancer treatments target and eradicate putative cancer stem cells to halt clinical tumour recurrence. Intriguingly, early combinatorial therapy experiments demonstrated an effective synergistic therapeutic effect using verapamil plus mitoxantrone administration in the treatment of ovarian cancer (Tsuruo et al, 1985;Hendrick et al, 1991). Whether or not this in vivo chemosensitisation occurred via similar mechanisms to those described in our current study is not known, although clearly these findings highlight the need for more research into this potentially combined therapy.…”

P-glycoprotein antagonists confer synergistic sensitivity to short-chain ceramide in human multidrug-resistant cancer cells

“…From these and other studies [23–25], it becomes clear that P-gp expression occurs with high frequency in ovarian cancer and plays a major role in prognosis and treatment response. In spite of this, the employ of P-gp antagonists to increase anticancer drug retention in ovarian cancer patients has not met with clinical success [16, 26, 27]. …”

Overcoming drug resistance in ovarian carcinoma

“…Other investigators treated 14 women with advanced ovarian carcinoma with mitoxantrone and verapamil. In this study, all but one patient had prior systemic therapy (including one patient with previous doxorubicin therapy) and in 12 patients, t h e s e d r u g s h a d b e e n d i s c o n t i n u e d l e s s t h a n 4 months before initiation of verapamil and mitoxantrone [46]. There were no objective responses, but only one patient had been previously treated with an antineoplastic agent known to cause P-gp drug resistance.…”