4'Epidoxorubicin Plus Verapamil in Anthracycline - Refractory Cancer Patients

Abstract

Four patients refractory to doxorubicin (DX) and 9 patients refractory to 4'epidoxorubicin (4'EpiDX) were treated with verapamil (VRP) (120 mg every 6 h for 3 days) plus 4'EpiDX (80 mg/m2 i.v. bolus, together with the 6th VRP administration). Three patients had partial remissions lasting 3, 3.5 and 7 months, respectively. Toxicity grading did not exceed usual levels. The study demonstrates that VRP, when added at conventional doses to 4'EpiDX, can induce objective responses in some patients refractory to anthracyclines.

Multidrug Resistance Reversal Agents

“…64 In contrast to hematological malignancies, refractory solid tumors were never shown to respond to verapamil when this reverter was added to classical chemotherapy, likely because the doses administered were too low as a consequence of the fear of cardiac toxicity. [65][66][67] The encouraging results obtained in no-small-cell lung cancer and pediatric cancers were not confirmed. 68,69 An interesting randomized study performed in anthracycline-resistant metastatic breast cancer patients treated by vindesine with or without verapamil revealed a significant increase of survival of patients receiving verapamil.…”

“…In acute myeloid leukemia, after several phase I or I/II studies, 93,[95][96][97][98] two phase III studies were under- [59][60][61][62][63][64][65][66][67][68]70,134 coronary vasodilator too toxic by itself nifedipine 135 coronary vasodilator not active enough trifluoperazine [136][137][138] antipsychotic not active enough cyclosporine A [76][77][78][79]81,82,[84][85][86][87][88]139,140 immunosuppressive too toxic by itself quinidine 106 antiarrhythmic too toxic by itself quinine 107,109,141 antimalarial not active enough tamoxifen 69,[142][143][144] antiestrogen not active enough progesterone 145 progestative not active enough dipyridamole 146,147 coronary vasodilator not active enough amiodarone 148 coronary vasodilator not active enough bepridil…”

“…In myeloma and non-Hodgkin's lymphomas, verapamil was clearly shown to be active in situations of resistance to standard protocols with anthracyclines and/or Vinca alkaloids. − However, patient survival was not increased in a phase III study combining verapamil and cytotoxic drugs in the treatment of multiple myeloma . In contrast to hematological malignancies, refractory solid tumors were never shown to respond to verapamil when this reverter was added to classical chemotherapy, likely because the doses administered were too low as a consequence of the fear of cardiac toxicity. − The encouraging results obtained in no-small-cell lung cancer and pediatric cancers were not confirmed. , An interesting randomized study performed in anthracycline-resistant metastatic breast cancer patients treated by vindesine with or without verapamil revealed a significant increase of survival of patients receiving verapamil …”

Multidrug resistance in oncology: diagnostic and therapeutic approaches

“…In solid tumours, the efficacy of verapamil has not been demonstrated. Several phase II trials were negative [52–54], probably because the doses administered were insufficient to recruit responders to combination therapy. Indeed, the plasma level of verapamil in such studies barely reached 1 μmol L −1 , which is much lower than the concentrations used for MDR reversal in vitro .…”