Modulation of multidrug resistance by dexverapamil in EPOCH-refractory lymphomas.
We conducted a controlled trial of dexverapamil, an inhibitor of Pgp, in 45 Hodgkin's (HD) and 154 Non-Hodgkin's (NHL) lymphomas refractory to EPOCH chemotherapy. A total of 154 patients initially received EPOCH alone and (4.2%) with stable disease over two cycles or progressive disease "crossed over" to receive dexverapamil with EPOCH. Dexverapamil was escalated 8 dose levels, from 240 to 1200 mg/m2 per day. When possible, serial biopsies were obtained to measure MDR-1 expression by quantitative polymerase chain reaction. Median age was 44 years, 67% had stage IV disease, and median (range) prior regimens were 2 (1-12) in NHL and 1 (1-4) in HD. The maximum tolerated dose of dexverapamil was 900 mg/m2/day, and median plasma average concentrations of dexverapamil and nor-dexverapamil were 1.2 and 1.4 microM, respectively. There were 3 complete and 2 partial responses (12%) and 5 minor responses in NHL, and 2 of 10 HD patients achieved partial responses. MDR-1 was measured in 44 biopsies from 19 patients. Pre-therapy, MDR-1 was low (median 2.5 U) but increased (median 12.2 U) at cross-over. Among 6 patients with MDR-1 > 15, 3 responded to dexverapamil whereas only 1/8 patients with MDR-1 < 15 responded. EPOCH and dexverapamil were well tolerated. This study suggests that MDR-1 plays a role in clinical drug resistance of lymphomas, but also suggests that non-MDR-1 mechanisms are present in such patients. Earlier intervention with dexverapamil may be more effective and warrants further study.
Wilson
W H
WH
Medicine Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Bates
S E
SE
Fojo
A
A
Chabner
B A
BA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000037:antagonists & inhibitors*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D018592:Cross-Over Studies; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D014700:Verapamil / Q000008:administration & dosage*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D014700:Verapamil