Investigating the platelet-sparing mechanism of paclitaxel/carboplatin combination chemotherapy.
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-1beta, IL-8, and tumor necrosis factor-alpha 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.
Pertusini
E
E
Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Ratajczak
J
J
Majka
M
M
Vaughn
D
D
Ratajczak
M Z
MZ
Gewirtz
A M
AM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001792:Blood Platelets / Q000187:drug effects*; D016190:Carboplatin / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D002455:Cell Division; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000097:blood; D005434:Flow Cytometry; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006133:Growth Substances / Q000096:biosynthesis; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000187:drug effects; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D012333:RNA, Messenger / Q000096:biosynthesis; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013926:Thrombopoietin / Q000096:biosynthesis; D014700:Verapamil / Q000494:pharmacology / Q000633:toxicity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016207:Cytokines; D006133:Growth Substances; D012333:RNA, Messenger; D013926:Thrombopoietin; D016190:Carboplatin; D014700:Verapamil; D005982:Glutathione Transferase; D017239:Paclitaxel