MolPharm xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Karolak, L.
Right arrow Articles by Hannun, Y. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Karolak, L.
Right arrow Articles by Hannun, Y. A.

High-dose chemotherapy-induced platelet defect: inhibition of platelet signal transduction pathways

L Karolak, A Chandra, W Khan, B Marks, WP Petros, WP Peters, CS Greenberg and YA Hannun

Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.

Patients receiving high-dose chemotherapy and autologous bone marrow transplantation acquire a platelet secretion defect. The role of chemotherapeutic agents and their metabolites in mediating this platelet defect was investigated. 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU), but not cyclophosphamide or cis-platinum, was found to inhibit platelet aggregation in vitro in response to activation by either ADP, thrombin, or collagen. Inhibition by BCNU was dose dependent and required preincubation of platelets with BCNU. After a 60-min preincubation, 30 microM BCNU produced 50% inhibition of platelets in platelet-rich plasma. The cyclophosphamide metabolites acrolein and 4- hydroperoxycyclophosphamide also inhibited platelet aggregation in a dose-dependent manner, with a requirement for preincubation. Platelet inhibition occurred at clinically relevant concentrations of BCNU and metabolites of cyclophosphamide. The effects of acrolein were totally prevented by coincubation with the sulfhydryl-protecting agents N- acetylcysteine and 2-mercaptoethanesulfonic acid, whereas the effects of BCNU were incompletely prevented. The mechanism of platelet inhibition was investigated next by examining protein phosphorylation in response to platelet agonists. Acrolein inhibited thrombin- and phorbol ester-induced phosphorylation of a 40-kDa polypeptide and other substrates, indicating a cellular defect in protein kinase C signaling. BCNU did not interfere with protein phosphorylation, indicating preservation of initial signaling pathways. Thus, chemotherapeutic agents and their metabolites inhibit platelet function by inhibiting distinct components of the intracellular activation pathways.

Volume 43, Issue 1, pp. 37-44, 01/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


Home page
 Infect. Immun.Home page
A. B. Herrero, M. C. Lopez, S. Garcia, A. Schmidt, F. Spaltmann, J. Ruiz-Herrera, and A. Dominguez
Control of Filament Formation in Candida albicans by Polyamine Levels
Infect. Immun., September 1, 1999; 67(9): 4870 - 4878.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1993 by the American Society for Pharmacology and Experimental Therapeutics