In vitro antagonistic cytotoxic interactions between platinum drugs and taxanes on bone marrow progenitor cell CFU-GM.
We have designed and used an in vitro bone marrow cell culturing system for investigating pharmacodynamic interactions between platinum anti-cancer drugs and taxanes. With this system, in which the bone marrow progenitor cell CFU-GM is proliferating and differentiating into granulocytes and monocytes, we could show a strong antagonistic cytotoxicity of the combination carboplatin and Taxotere, in three different schedules, and of the combination cisplatin and Taxol, in two out of the three schedules tested. Modulation of intracellular platinum drug accumulation in granulocytes and monocytes does not seem to be a plausible explanation for the observed antagonism. In vitro co-incubation of granulocytes/monocytes with the combination carboplatin and Taxotere did not reveal an effect of Taxotere on intracellular platinum accumulation. Although Taxol reduced intracellular cisplatin levels by 12%, this effect was not significantly different from the co-incubation of cisplatin with Cremophor EL, the solvent for paclitaxel in Taxol. The toxicity data obtained in this study seem to be in accordance with recent clinical trials where combination therapies with platinum drugs and taxanes resulted in marked reductions in myelosuppression in patients. Therefore, these types of assays could be useful as to the assessment of bone marrow toxicities of clinically important drug combinations.
de Graaff
M
M
Department of Experimental Therapy and Medical Oncology, The Netherlands Cancer Institute, Amsterdam.
Maliepaard
M
M
Pluim
D
D
Floot
B J
BJ
Slaper-Cortenbach
I C
IC
Schellens
J H
JH
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage*; D002478:Cells, Cultured / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage*; D000077143:Docetaxel; D004336:Drug Antagonism; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D011136:Polysorbates / Q000008:administration & dosage; D043823:Taxoids
D011136:Polysorbates; D043823:Taxoids; D000077143:Docetaxel; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin