Increased myelotoxicity of idarubicin: is there a pharmacological basis? Results of a pharmacokinetic and an in vitro cytotoxicity study.
BACKGROUND
Clinical trials evaluating idarubicin (IDA) in acute myeloid leukemia, multiple myeloma and non-Hodgkin's lymphoma (NHL) have provided some evidence for an increased myelotoxicity of IDA compared to other anthracyclines. IDA is known to be less sensitive towards multidrug resistance mediated by P-glycoprotein (P-gp). This phenotype is a major impediment to successful antineoplastic treatment, but P-gp is also expressed on hematopoietic stem cells (HSC).


METHODS
We investigated the pharmacokinetics of IDA and etoposide (ETO) in seven previously untreated patients with aggressive NHL. The patients received a CHOP-derived protocol (CIVEP) in which doxorubicin (DOX) was substituted by IDA 11-16 mg/m(2) and ETO 3 x 100 mg/m(2) was added. Furthermore, we evaluated in vitro the impact of P-gp expression on the cytotoxicity of DOX and IDA in cells from three parental chemosensitive leukemia and lymphoma cell lines (HL60, U937, CCRF) and their resistant sublines, as well as in CD34-positive HSC.


RESULTS
The peak plasma levels (C(max)), terminal elimination half-life (t(1/2)) and area under the concentration curve (AUC) both for IDA and for ETO did not differ from published data. In cell line models the numbers of viable cells in a P-gp-expressing resistant CCRF-VCR100 subline were significantly more reduced by IDA ( P<0.001), but there was no difference in the cytotoxicities of IDA and DOX in chemosensitive CCRF cells and in the (non-P-gp-expressing) resistant U937 and HL60 sublines. Cytotoxicity against HSC was more pronounced after incubation with IDA than after treatment with DOX ( P=0.014), even when a tenfold higher concentration of DOX than of IDA was used. The addition of cyclosporin A increased the cytotoxic effect of DOX but not that of IDA in HSC.


CONCLUSIONS
The pharmacokinetics of IDA and its main metabolite idarubicinol in CHOP-derived protocols were not different from data obtained with other combinations or monotherapy. The increased myelotoxicity of IDA may be a consequence of P-gp expression in CD34-positive HSC.
Kroschinsky
Frank
F
1st Medical Department, Carl Gustav Carus University Hospital, Fetscherstrasse 74, 01307, Dresden, Germany. kroschinsky@mk1.med.tu-dresden.de
Schleyer
Eberhard
E
Renner
Ulf
U
Schimming
Claudia
C
Schimmelpfennig
Christoph
C
Bornhäuser
Martin
M
Illmer
Thomas
T
Trümper
Lorenz
L
Ehninger
Gerhard
G
Schaich
Markus
M
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology; D008228:Lymphoma, Non-Hodgkin / Q000097:blood / Q000188:drug therapy*; D008875:Middle Aged; D014407:Tumor Cells, Cultured
D005047:Etoposide; D015255:Idarubicin