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Blood, 1 February 2001, Vol. 97, No. 3, pp. 638-644
HEMATOPOIESIS
Investigating the platelet-sparing mechanism of
paclitaxel/carboplatin combination chemotherapy
Esther Pertusini,
Janina Ratajczak,
Marcin Majka,
David Vaughn,
Mariusz Z. Ratajczak, and
Alan M. Gewirtz
From the Departments of Internal Medicine, Pathology,
and Laboratory Medicine, and the Cancer Center, University of
Pennsylvania School of Medicine, Philadelphia, PA.
Paclitaxel 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-1 , IL-8, and tumor necrosis
factor- 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.
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