Primary lymphocytes as predictors for species differences in cytotoxic drug sensitivity

Hassan, Saadia Bashir; Haglund, Caroline; Åleskog, Anna; Larsson, Rolf; Lindhagen, Elin

doi:10.1016/j.tiv.2007.03.009

Cited by 15 publications

(13 citation statements)

References 24 publications

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“…The semi-physiological model of myelosuppression [1] has earlier been applied on both rat neutrophils [46] and patient neutrophils [6,10] following administration of topotecan. In line with the larger sensitivity of topotecan in patients compared with rats [30], the Slope estimate was lower in rats (39 L/mg) than in patients (133-143 L/mg) in these previous reports.…”

Section: Discussionsupporting

confidence: 81%

“…The success is likely because the prediction was based on a model built on knowledge of the underlying physiological system and that this system is similar in rats and man. Based on the fact that some maturation and proliferation occurs for circulating lymphocytes, in contrast to neutrophils, it was recently shown that species differences in sensitivity of anticancer drugs for primary lymphocytes are similar to what have been found in the CFU-GM assay [30]. This less labor intensive lymphocyte assay may therefore be a good alternative to the CFU-GM assay to evaluate species differences in sensitivity and when scaling Slope rat to Slope sensitivity values.…”

Section: Discussionmentioning

confidence: 87%

“…Thereby it was assumed that rats and mice have more similar bone marrow sensitivity to the anticancer drugs than they have with patients, which has indeed been shown to be the case for primary lymphocytes [30].…”

Section: Scalingmentioning

confidence: 99%

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Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

2009

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 87%

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Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

2009

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“…It has been reported that IC 50 of bortezomib is 0.047 µM (equivalent to 18.1 ng/ml) in normal canine peripheral blood mononuclear cells [7]. Since it has been much higher than those in canine neoplastic lymphoid cell lines resulted in the present study (Table 1), neoplastic lymphoid cells especially with constitutive NF-κB activation can be more sensitive to bortezomib than normal blood cells.…”

Section: Discussionmentioning

confidence: 50%

Analyses on Activation of NF-κB and Effect of Bortezomib in Canine Neoplastic Lymphoid Cell Lines

Kojima

Fujino

Goto‐Koshino

et al. 2013

The Journal of Veterinary Medical Science

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ABSTRACT. Lymphoid malignancies, such as leukemia, and many types of lymphoma are common and severe disorders in dogs. Since shortening remission duration caused by resistance to chemotherapy often becomes clinically critical problems, development of novel and effective therapy should be required. The present study investigated the status of NF-κB and effect of its inhibitor, bortezomib, in six canine neoplastic lymphoid cell lines. NF-κB p65 and p50 were detected in the nuclear fraction of GL-1, CLBL-1 and CL-1, suggesting that NF-κB was constitutively activated in the cells. NF-κB p65 was detected in the cytoplasmic fraction of UL-1 and Ema. After incubation with bortezomib, NF-κB p50 and p65 became undetectable in the nuclear fraction of GL-1, CLBL-1 and CL-1, and CLBL-1, respectively, and p65 was clearly degraded in the cytoplasmic fraction of CLBL-1 and CL-1. Bortezomib inhibited the proliferation of all cell lines except Nody-1 in a concentration-dependent manner. The results indicated that constitutive activation of NF-κB could contribute to the proliferation of canine neoplastic lymphoid cells, and bortezomib would have suppressive effects on the NF-κB activation and the proliferation of neoplastic lymphoid cells in dogs.

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“…[20] This issue cannot be evaluated in preclinical HCT models because human lymphocytes are more sensitive to the cytotoxicity of fludarabine than those from mice, rats, or dogs. [38] Using pooled lymphocytes from four individuals, Wilkins et al observed ex vivo that the CD4 + /CD8 + ratio has an inverse relationship with the amount of apoptosis of lymphocytes and CD4 + cells, but not CD8 + cells, with or without radiation. [20] In our study, the average CD4 + /CD8 + ratio rose from 1.65 before fludarabine administration to 3.08 afterwards (Table 3).…”

Section: Discussionmentioning

confidence: 99%

Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients

Mager

Bemer

Sandmaier

et al. 2015

Cancer Chemother Pharmacol

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Purpose Fludarabine monophosphate (fludarabine) is an integral component of many reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Fludarabine’s metabolite, 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), undergoes cellular uptake and activation to form the active cytotoxic metabolite fludarabine triphosphate (F-ara-ATP), which inhibits cellular DNA synthesis in CD4+ and CD8+ cells. In this study, we evaluated whether fludarabine-based pharmacologic biomarkers were associated with clinical outcomes in HCT recipients. Methods Participants with hematologic diseases were conditioned with fludarabine and low-dose total body irradiation (TBI) followed by allogeneic HCT and post-grafting immunosuppression. After fludarabine administration, we evaluated pharmacological biomarkers for fludarabine – F-ara-A area under the curve (AUC) and the ratio of circulating CD4+ and CD8+ cells (CD4+/CD8+ ratio) after fludarabine administration – in 102 patients; F-ara-ATP accumulation rate in enriched CD4+ and CD8+ cells was evaluated in 34 and 36 patients, respectively. Results Interpatient variability in the pharmacological biomarkers was high, ranging from 3.7-fold (F-ara-A AUC) to 39-fold (F-ara-ATP in CD8+ cells). Circulating CD8+ cells were more sensitive to fludarabine administration. A population pharmacokinetic-based sampling schedule successfully allowed for estimation of F-ara-A AUC in this outpatient population. There was poor correlation between the F-ara-AUC and the F-ara-ATP accumulation rate in CD4+ (R2=0.01) and CD8+ cells (R2=0.00). No associations were seen between the four biomarkers and clinical outcomes (day +28 donor T-cell chimerism, acute graft-versus-host disease (GVHD), neutrophil nadirs, cytomegalovirus reactivation, chronic GVHD, relapse, non-relapse mortality, or overall mortality). Conclusions Considerable interpatient variability exists in pharmacokinetic and fludarabine-based biomarkers, but these biomarkers are not associated with clinical outcomes in fludarabine/TBI-conditioned patients.

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Primary lymphocytes as predictors for species differences in cytotoxic drug sensitivity

Cited by 15 publications

References 24 publications

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

Scaling the time-course of myelosuppression from rats to patients with a semi-physiological model

Analyses on Activation of NF-κB and Effect of Bortezomib in Canine Neoplastic Lymphoid Cell Lines

Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients

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