Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer

Abstract

Summary Agents capable of reversing P-glycoprotein-associated multidrug resistance have usually failed to enhance chemotherapy activity in patients with solid tumours. Based on its toxicity profile and experimental potency, dexverapamil, the R-enantiomer of verapamil, is considered to be promising for clinical use as a chemosensitizer. The purpose of this early phase 11 trial was to evaluate the effects of dexverapamil on epirubicin toxicity, activity and pharmacokinetics in patients with metastatic breast cancer. A two-stage design was applied. Patients first received epirubicin alone at 120 mg m-2 i.v. over 15 min, repeated every 21 days. Patients with refractory disease continued to receive epirubicin at the same dose and schedule but supplemented with oral dexverapamil 300 mg every 6 h x 13 doses. The Gehan design was applied to the dexverapamil/epirubicin cohort of patients. Thirty-nine patients were entered on study, 25 proceeded to receive epirubicin plus dexverapamil. Dexverapamil did not increase epirubicin toxicity. The dose intensity of epirubicin was similar when used alone or with dexverapamil. In nine intrapatient comparisons, the area under the plasma concentration-time curve (AUC) of epirubicin was significantly reduced by dexverapamil (mean 2968 vs 1901 gg ml-1 h-1, P= 0.02). The mean trough plasma levels of dexverapamil and its major metabolite nor-dexverapamil were 1.2 and 1.5 gM respectively. The addition of dexverapamil to epirubicin induced partial responses in 4 of 23 patients evaluable for tumour response (17%, Cl 5-39%, s.e.,p 0.079). The remissions lasted 3, 8, 11 and 11 + months. These data suggest that the concept of enhancing chemotherapy activity by adding chemosensitizers may function not only in haematological malignancies but also in selected solid tumours. An increase in the AUC and toxicity of cytotoxic agents does not seem to be a prerequisite for chemosensitizers to enhance anti-tumour activity.

Estrogen‐mediated post transcriptional down‐regulation of P‐glycoprotein in MDR1‐transduced human breast cancer cells

“…Clinical trials of P‐gp inhibitors have now been conducted against various malignancies, including advanced breast cancers. ( 31–34 ) Tidefelt et al . examined the effects of the cyclosporinee derivative, PSC 833, on the concentration of daunorubicin in leukemic blast cells in vivo during treatment.…”

Calcium channel blockers, ACE inhibitors, and the risk of cancer in hypertensive patients: a report from the Department of Health Hypertension Care Computing Project (DHCCP)

“…On the other hand, some evidence suggests that CCBs might inhibit carcinogenesis, and in several studies CCBs, as inhibitors of P-glycoprotein, were successfully used as chemosensitizers in the treatment of various cancer types (advanced/metastatic breast cancer, non-small lung cancer, skin cancers, lymphomas). [29][30][31][32][33][34][35][36][37][38][39] In the group receiving methyldopa plus a diuretic the adjusted RR was increased (1.47; 95% CI 1.05 to 2.06). This is consistent with our previous finding of a normal cancer mortality with atenolol treatment where the RR of methyldopa compared with atenolol was 1.5 in men (95% CI 1.0 to 2.2).…”

BCRP Transports Dipyridamole and is Inhibited by Calcium Channel Blockers

“…In addition to their use in these diseases, calcium channel blockers such as verapamil and dihydropyridines are effective inhibitors of P-gp and multidrug resistance protein 1 (MRP1) (26Y34). Some of these compounds have been tested to determine if they can reverse multidrug resistance in cancer patients (35,36). Calcium channel blockers remain one of the most extensively characterized classes of modulating agents for ABC transporters.…”