Investigating the platelet-sparing mechanism of paclitaxel/carboplatin combination chemotherapy

Author:

Pertusini Esther1,Ratajczak Janina1,Majka Marcin1,Vaughn David1,Ratajczak Mariusz Z.1,Gewirtz Alan M.1

Affiliation:

1. From the Departments of Internal Medicine, Pathology, and Laboratory Medicine, and the Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA.

Abstract

AbstractPaclitaxel and carboplatin chemotherapy is reported to be a platelet-sparing drug combination. This study investigated potential mechanisms for this observation by studying the effects of paclitaxel and carboplatin on (1) normal donor and chemotherapy patient-derived erythroid (burst-forming units-erythroid [BFU-E]), myeloid (colony-forming units-granulocyte/macrophage [CFU-GM]), and megakaryocyte (CFU-Meg) progenitor cell growth; (2) P-glycoprotein (P-gp) protein and glutathione S-transferase (GST) messenger RNA (mRNA) expression; (3) serum thrombopoietin (Tpo), stem cell factor (SCF), interleukin-6 (IL-6), IL-11, IL-1β, IL-8, and tumor necrosis factor-α levels in patients treated with paclitaxel and carboplatin; and (4) stromal cell production of Tpo and SCF after paclitaxel and carboplatin exposure. CFU-Meg were more resistant to paclitaxel alone, or in combination with carboplatin, than CFU-GM and BFU-E. Although all progenitors expressed P-gp protein and GST mRNA, verapamil treatment significantly, and selectively, increased the toxicity of paclitaxel and carboplatin to CFU-Meg, suggesting an important role for P-gp in megakaryocyte drug resistance. Compared to normal controls, serum Tpo levels in patients receiving paclitaxel and carboplatin were significantly elevated 5 hours after infusion and remained elevated at day 7 (287% ± 63% increase,P < .001). Marrow stroma was shown to be the likely source of this Tpo. It is concluded here that P-gp–mediated efflux of paclitaxel, and perhaps GST-mediated detoxification of carboplatin, results in relative sparing of CFU-Meg, which may then respond to locally high levels of stromal cell–derived Tpo. The confluence of these events might lead to the platelet-sparing phenomenon observed in patients treated with paclitaxel and carboplatin chemotherapy.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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