Investigation of the platelet sparing mechanism of paclitaxel and carboplatin chemotherapy

Paclitaxel (P) and carboplatin (C) chemotherapy is reported to be a platelet-sparing drug combination. We investigated possible mechanisms for this by studying P & Cʹs effects on: 1] normal human, and P- and C- treated patient-derived erythroid (BFU-E), myeloid (CFU-GM), and megakaryocyte (CFU-Meg) progenitor cell growth; 2] P-glycoprotein (P-gp) protein and glutathione S-transferase (GST) mRNA expression; 3] P & C patient serum levels of TPO, SCF, IL-6, IL-11, IL-1b, IL-8 and TNFa; and 4] marrow stromal cell production of TPO and SCF after P & C exposure. We found that CFU-Meg were more resistant to P alone, or in combination with C, than CFU-GM and BFU-E. We also found that CFU-Meg express P-gp protein and GST mRNA. That the former might play a role in drug resistance is suggested by the finding that verapamil treatment significantly increased P & Cʹs toxicity to CFU-Meg (colony formation decreased not, vert, similar70%, p < .001). Compared to normals, serum TPO levels in P- and C- treated patients were significantly elevated 5 hours post infusion, and remained elevated at day 7 (287 ± 63% increase, p < .001). The source of this TPO might be marrow stroma, since normal stromal cell production of TPO increased 110 ± 58% after exposure to P & C, a result consistent with reports that TPO mRNA is inducible in stromal cells. We conclude that P-gp–mediated efflux of P, and perhaps GST-mediated detoxification of C, 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 observed in patients treated with P & C.