Effect of ultrafilterable platinum concentration on cisplatin and carboplatin cytotoxicity in human tumor and bone marrow cells in vitro.
The importance of the ultrafilterable platinum (fPt) fraction of cisplatin (CDDP) and carboplatin (CBDCA) for cytotoxicity and myelotoxicity was studied in vitro. By incubating CDDP or CBDCA with fetal calf serum (FCS) various fractions of fPt were prepared and determined by atomic absorption spectroscopy. A relation of % fPt fraction and incubation time (h) of 87e-0.1123t (r = -0.99) and 101e-0.0087t (r = -0.99) were determined for CDDP and CBDCA, respectively. Cytotoxicity in the human small cell lung carcinoma cell line GLC4 and fPt fraction were closely related for CDDP (r = 0.99) and for CBDCA r = 0.97). However, at a similar fPt fraction the concentrations inhibiting cell survival by 50% (IC50) of CBDCA exceeded that of CDDP by a factor of 10-18 with 4 h exposure and a factor of 5 with continuous exposure. Tested in the range of peak concentrations in plasma of patients and at a clinically relevant fPt fraction of 10%, CDDP was not toxic for human bone marrow cells in the CFU-GM assay, whereas it was toxic at fPt fractions of 50% and 90%. However, CBDCA was myelotoxic at a (clinically relevant) fPt fraction of 50%, and also at 75% and 90%. The use of different fPt fractions, produced by the incubation method described in this study, permits the study of platinum drugs in vitro while approximating in vivo conditions might be used to evaluate myelotoxicity of new platinum drugs prospectively. For CDDP and CBDCA the fraction fPt determines cytotoxicity on tumor cells, and their different fPt fraction in patients account at least partly for their difference in myelotoxicity.
Guchelaar
H J
HJ
Department of Pharmacy, University Hospital Groningen, The Netherlands.
de Vries
E G
EG
Meijer
C
C
Esselink
M T
MT
Vellenga
E
E
Uges
D R
DR
Mulder
N H
NH
D001853:Bone Marrow / Q000187:drug effects*; D016190:Carboplatin / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D003470:Culture Media; D006801:Humans; D010984:Platinum / Q000494:pharmacology*; D011485:Protein Binding; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014462:Ultrafiltration
D003470:Culture Media; D010984:Platinum; D016190:Carboplatin; D002945:Cisplatin