Journal of Clinical Oncology, Vol 5, 641-647, Copyright © 1987 by American Society of Clinical Oncology
Verapamil and adriamycin in the treatment of drug-resistant ovarian cancer patients
RF Ozols, RE Cunnion, RW Klecker Jr, TC Hamilton, Y Ostchega, JE Parrillo and RC Young
Eight patients with refractory ovarian cancer were treated on a pilot
protocol of verapamil plus Adriamycin (Adria Laboratories, Columbus, OH).
This trial was based on our previous laboratory studies which demonstrated
that Adriamycin resistance in human ovarian cancer cell lines could be
partially reversed by exposure of the cells to high concentrations of
verapamil (3,000 ng/mL). Patients were treated in an intensive care unit
with continuous cardiovascular monitoring. The dose of verapamil was
escalated in each patient until hypotension or heart block developed, and
this dose was maintained for 72 hours. Adriamycin (50 mg/m2) was infused
over 24 hours during the second day of the verapamil infusion and verapamil
alone was administered on the third day in an effort to block efflux from
drug-resistant cells. This intensive approach led to a median plasma
verapamil level of 1,273 ng/mL (range, 720 to 2,767). However, the high
infusion rates of verapamil (9 micrograms/kg/min) required to achieve these
plasma levels produced an unacceptable degree of cardiac toxicity. Two
patients developed transient atropine-responsive complete heart block and
four patients developed transient congestive heart failure with increases
in pulmonary capillary wedge pressure. There was no evidence that the
noncardiac toxicities of Adriamycin were enhanced by verapamil. There were
no objective responses to therapy. Future studies should use less
cardiotoxic calcium channel blockers that can be safely administered to
produce the plasma levels required for in vitro sensitization of drug
resistant cells.
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