In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2543-2543
Abstract:
Murine xenograft models are one of the primary tools used for screening of new therapeutic compounds and regimens. However, one major limitation of utilizing murine xenograft studies to assess therapeutic efficacy is that significant inter-species differences in drug sensitivity can exist between mice and humans. It is possible that the levels of a therapeutic compound reached in a mouse xenograft model may not be achievable in humans due to differential toxicity profiles. There is a growing need for in vivo models that can simulate efficacy of promising therapeutic regimens but at the same time can evaluate the potential for off-target human toxicity. Since bone-marrow toxicity can be a major life-threatening side effect of treatment, models to screen for the impact of treatment on human hematopoiesis would improve our ability to select compounds with decreased off-target toxicities. In this study, a xenograft model containing humanized bone marrow is utilized as an in vivo assay to monitor hematotoxicity. As a proof-of-concept, the impact of a combination therapy consisting of O6-benzylguanine and temozolomide (O6-BG/TMZ) on human hematopoiesis in vivo was investigated since this regimen is currently being evaluated in clinical trials and the main dose-limiting toxicity in these patients is myelosuppression. A dose-intensive O6-BG/TMZ-dosing regimen that requires stem-cell rescue was developed that significantly inhibits the growth of human-glioblastoma xenografts in NOD/SCID/γchainnull mice. To monitor human hematotoxicity profiles, NOD/SCID/gammanull mice were next transplanted with human CD34+ cells and reconstitution confirmed one month post-transplantation by peripheral blood analysis. The dose-intensive regimen was then administered to NOD/SCID/gammanull mice reconstituted with human hematopoietic cells and the impact of treatment on human hematopoiesis evaluated. Flow cytometric analyses indicated that the human bone-marrow cells were significantly more sensitive to treatment than the murine bone-marrow cells in vivo, and that the regimen was highly toxic to human-derived hematopoietic cells of all lineages (CD34+ progenitor, CD45+CD19+ lymphoid, and CD33+ myeloid). This proof-of-concept study indicates that use of NOD/SCID/γchainnull mice with humanized bone marrow can be used as an in vivo toxicity measure of human hematopoiesis. This model holds promise as a new approach for monitoring the impact of anti-cancer therapies on human hematopoiesis and could lead to subsequent refinement of therapies prior to clinical evaluation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2543. doi:10.1158/1538-7445.AM2011-2543
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-2543
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Bookmarklink