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DD Ross, CC Joneckis and CA Schiffer
The effects of verapamil on the intracellular pharmacokinetics of
daunorubicin (DNR) in blast cells from the bone marrows of patients with
acute nonlymphocytic leukemia (ANLL) were studied to determine whether
verapamil was capable of enhancing intracellular accumulation and retention
of DNR in ANLL, as has been observed in murine P388 cells resistant to DNR.
Seventeen marrows from ANLL patients were studied, 13 of which were from
patients who were considered to be clinically refractory to DNR. We took
care to include such patients in this study since, in the P388 model,
verapamil enhancement of DNR uptake is observed only in cells resistant to
DNR. Intracellular accumulation of DNR was studied by exposing blast cells
to DNR (1 microgram/mL) +/- verapamil (6.6 mumol/L) for up to 4 hours.
Following a 2-hour exposure of cells to DNR +/- verapamil, intracellular
retention of DNR was studied by incubating the cells in DNR-free medium for
3 hours. Intracellular DNR/10(6) cells was quantified by fluorometry. In 12
of 15 patient marrows, verapamil failed to enhance intracellular
accumulation of DNR. Three patient marrows had a very small increment in
DNR uptake in response to verapamil (approximately 14% greater than DNR
alone) that was significant (P less than .05) by paired t test.
Intracellular retention of DNR (t 1/2) and the area under the intracellular
DNR v time curve (AUC) were studied in 17 patients marrow specimens. No
significant alterations in these parameters were observed in response to
verapamil. These data indicate either that verapamil did not substantially
enhance DNR uptake or retention in blast cells obtained from ANLL patients
who are clinically resistant to DNR, or that the frequency of DNR-resistant
cells (ie, verapamil-responsive cells) among the blast cells obtained from
these patients was too low to influence the population mean of
intracellular DNR as measured in these studies.
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| Copyright © 1986 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||