Carboplatin and paclitaxel interact antagonistically in a megakaryoblast cell line--a potential mechanism for paclitaxel-mediated sparing of carboplatin-induced thrombocytopenia.
OBJECTIVE
Clinical observation has shown that paclitaxel ameliorates the antiplatelet toxicity of carboplatin when the two drugs are combined, although antitumour activity and white cell toxicity are at least additive. We hypothesized that this is due to an interaction between the two drugs at the level of the platelet precursor.


METHODS
We measured inhibition of growth of the megakaryoblast cell line MEG-01 following exposure to paclitaxel and carboplatin singly or combined. Drug interaction was assessed by median effect analysis.


RESULTS
An antagonistic interaction was observed, and this was most marked at drug concentrations giving a low level of growth inhibition (P < 0.002, sign test). The interaction was not sequence-dependent. There was no significant difference in whole-cell accumulation of platinum or the amount of platinum adducts on DNA following combined treatment in comparison with carboplatin alone.


CONCLUSIONS
These results provide the first evidence of an antagonistic interaction between paclitaxel and carboplatin in a platelet precursor and provide an explanation for the platelet-sparing effect of the combination of these chemotherapeutic agents. While the mechanisms underlying the interaction described in this report are yet to be fully elucidated, this study provides evidence that the antagonism between paclitaxel and carboplatin in MEG-01 cells is not due to reduced platination of DNA.
Guminski
A D
AD
Department of Medical Oncology, Westmead Hospital, Faculty of Medicine, University of Sydney at Westmead Hospital, NSW, Australia. alexg@westgate.wh.usyd.edu.au
Harnett
P R
PR
deFazio
A
A
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D016190:Carboplatin / Q000009:adverse effects / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018736:DNA Adducts / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004347:Drug Interactions; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000188:drug therapy; D017239:Paclitaxel / Q000494:pharmacology*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000517:prevention & control*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D018736:DNA Adducts; D004273:DNA, Neoplasm; D016190:Carboplatin; D017239:Paclitaxel