Combined preconditioning and in vivo chemoselection with 6-thioguanine alone achieves highly efficient reconstitution of normal hematopoiesis with HPRT-deficient bone marrow.
Exp Hematol
; 40(1): 3-13.e3, 2012 Jan.
Article
en En
| MEDLINE
| ID: mdl-22001673
Purine analogs such as 6-thioguanine (6TG) cause myelotoxicity upon conversion into nucleotides by hypoxanthine-guanine phosphoribosyltransferase (HPRT). Here we have developed a novel and highly efficient strategy employing 6TG as a single agent for both conditioning and in vivo chemoselection of HPRT-deficient hematopoietic stem cells. The dose-response and time course of 6TG myelotoxicity were first compared in HPRT wild-type mice and HPRT-deficient transgenic mice. Dosage and schedule parameters were optimized to employ 6TG for myelosuppressive conditioning, immediately followed by in vivo chemoselection of HPRT-deficient transgenic donor bone marrow (BM) transplanted into syngeneic HPRT wild-type recipients. At appropriate doses, 6TG induced selective myelotoxicity without any adverse effects on extrahematopoietic tissues in HPRT wild-type mice, while hematopoietic stem cells deficient in HPRT activity were highly resistant to its cytotoxic effects. Combined 6TG conditioning and post-transplantation chemoselection consistently achieved â¼95% engraftment of HPRT-deficient donor BM, with low overall toxicity. Long-term reconstitution of immunophenotypically normal BM was achieved in both primary and secondary recipients. Our results provide proof-of-concept that single-agent 6TG can be used for both myelosuppressive conditioning without requiring irradiation and for in vivo chemoselection of HPRT-deficient donor cells. Our results show that by applying the myelosuppressive effects of 6TG both before (as conditioning) and after transplantation (as chemoselection), highly efficient engraftment of HPRT-deficient hematopoietic stem cells can be achieved.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Tioguanina
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Médula Ósea
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Trasplante de Médula Ósea
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Acondicionamiento Pretrasplante
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Hematopoyesis
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Hipoxantina Fosforribosiltransferasa
Límite:
Animals
Idioma:
En
Revista:
Exp Hematol
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos