title: Multilineage long-term engraftment potential of drug-resistant hematopoietic progenitors.
abstract: Peripheral blood progenitor cells (PBPCs) are increasingly used instead of bone marrow for autologous or allogeneic transplantation. In this study PBPCs mobilized in cancer patients by chemotherapy and granulocyte-colony stimulating factor were collected by apheresis and first enriched by immunoaffinity removal of lineage positive cells. When these cells were exposed to both cyclophosphamide and taxol or cultured for 7 days in the presence of 5-fluorouracil, stem cell factor, and interleukin-3, 88% to 93% of the enriched PBPCs were killed and short-term clonogenic capacity in methylcellulose assays was lost, but week-5 cobblestone area-forming cell (CAFC) enrichment was higher than 10-fold in comparison to enriched PBPCs and higher than 700-fold in comparison to unmanipulated apheresis cells. After drug exposure, most of the progenitors displayed a CD34+, CD38-, multidrug-resistance (MDR+), Rhodamine 123 low, Hoechst 33342 low phenotype, and as few as 180 of these drug-resistant cells were able to generate a stable multilineage human hematopoiesis in sublethally irradiated immunodeficient mice. In these animals, the level of human hematopoietic engraftment was significantly increased by cotransplantation of irradiated cells from the human L87/4 stromal cell line. These observations are consistent with the functional isolation of a population of very early hematopoietic progenitors and might help to design new protocols for the removal of neoplastic cells from autografts.
authors.affiliation: Division of Medical Oncology, IRCCS Maugeri Foundation, Pavia Medical Center, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Bertolini
authors.forename: M
authors.initials: M
authors.lastname: Battaglia
authors.forename: A
authors.initials: A
authors.lastname: Lanza
authors.forename: N
authors.initials: N
authors.lastname: Gibelli
authors.forename: B
authors.initials: B
authors.lastname: Palermo
authors.forename: L
authors.initials: L
authors.lastname: Pavesi
authors.forename: M
authors.initials: M
authors.lastname: Caprotti
authors.forename: G
authors.initials: G
authors.lastname: Robustelli della Cuna
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001781:Blood Component Removal; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D004351:Drug Resistance; D005472:Fluorouracil / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017239:Paclitaxel / Q000494:pharmacology; D010641:Phenotype; D011956:Receptors, Cell Surface; D019089:Stem Cell Factor / Q000494:pharmacology; D019172:Transplantation Conditioning; D014960:X Chromosome
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D007377:Interleukin-3; D008562:Membrane Glycoproteins; C097871:PLXNA3 protein, human; D011956:Receptors, Cell Surface; D019089:Stem Cell Factor; C048341:mafosfamide; D003520:Cyclophosphamide; D017239:Paclitaxel; D005472:Fluorouracil