Effects of in vitro purging with 4-hydroperoxycyclophosphamide on the hematopoietic and microenvironmental elements of human bone marrow Journal Article

  

Authors:	Siena, S.; Castro-Melaspina, H.; Gulati, S. C.; Lu, L.; Colvin, M. O.; Clarkson, B. D.; O'Reilly, R. J.; Moore, M. A. S.
Article Title:	Effects of in vitro purging with 4-hydroperoxycyclophosphamide on the hematopoietic and microenvironmental elements of human bone marrow
Abstract:	We describe the effects of 4-hydroperoxycyclophosphamide (4-HC) on the hematopoietic and stromal elements of human bone marrow. Marrow cells were exposed to 4-HC and then assayed for mixed (CFU-Mix), erythroid (BFU-E), granulomonocytic (CFU-GM), and marrow fibroblast (CFU-F) colony-forming cells and studied in the long-term marrow culture (LTMC) system. The inhibition of colony formation by 4-HC was dose and cell-concentration dependent. The cell most sensitive to 4-HC was CFU-Mix (ID50 31 μmol/L) followed by BFU-E (ID50 41 μmol/L), CFU-GM (ID50 89 μmol/L), and CFU-GM production was noted. Marrows treated with 300 μmol/L 4-HC were completely depleted of CFU-GM but were able to generate these progenitors in LTMC. Marrow stromal progenitors giving rise to stromal layers in LTMC, although less sensitive to 4-HC cytotoxicity, were damaged by 4-HC also in a dose-related manner. Marrows treated with 4-HC up to 300 μmol/L gave rise to stromal layers composed of fibroblasts, endothelial cells, adipocytes, and macrophages. Cocultivation experiments with freshly isolated autologous hematopoietic cells showed that stromal layers derived from 4-HC-treated marrows were capable of sustaining the long-term production of CFU-GM as well as controls. In conclusion: (1) Hematopoietic progenitor cells, CFU-Mix, BFU-E, and CFU-GM, are highly sensitive to 4-HC, whereas marrow stromal progenitor cells are relatively resistant. (2) Marrows treated with 300 μmol/L 4-HC that are depleted of CFU-Mix, BFU-E, and CFU-GM can generate CFU-GM in LTMC, suggesting that most primitive hematopoietic stem cells (not represented by CFU-Mix) are spared by 4-HC up to this dose. (3) Consequently, the above colony assays are not suitable tools for predicting pluripotent stem cell survival after 4-HC treatment in vitro.
Keywords:	human cell; drug efficacy; bone marrow; in vitro study; stem cell; hematopoiesis; drug therapy; therapy; normal human; 4 hydroperoxycyclophosphamide; human; priority journal; blood and hemopoietic system
Journal Title:	Blood
Volume:	65
Issue:	3
ISSN:	0006-4971
Publisher:	American Society of Hematology
Date Published:	1985-03-01
Start Page:	655
End Page:	662
Language:	English
DOI:	10.1182/blood.v65.3.655.655
PUBMED:	3971044
PROVIDER:	scopus
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-0021992902&doi=10.1182%2fblood.v65.3.655.655&partnerID=40&md5=371e84ea10b1e7f8ad90041142a70cfd
Notes:	PDF misspelled the author: Hugo Castro-Malaspina's last name -- Source: Scopus

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