Sequestration and deactivation of anthracycline by adipocytes in the leukemia microenvironment

肥胖会增加多种癌症的发病率和死亡率。儿童和成人 确诊时肥胖的高危急性淋巴细胞性白血病(ALL)风险增加50% 与他们瘦弱的同龄人相比，复发的可能性更大。使用小鼠和组织培养模型，我们证明了 肥胖直接影响ALL的进展和治疗结果。我们发现脂肪细胞可以保护 来自多种化疗药物的所有细胞，包括蒽环素柔红霉素(DNR)。我们发现了 脂肪细胞将DNR分解为不活跃的形式，从而耗尽局部水平并保护附近的所有细胞 从这次化疗中脱身。 在目前的赠款中，我们将使用细胞培养、小鼠的组合来进一步阐明这种机制。 实验和临床研究。我们将首先研究脂肪细胞中的哪些酶对它们的 能够分解像DNR这样的蒽环类药物，并探索阻止这些酶的策略。我们将使用 小鼠模型确定体内脂肪细胞如何改变全身柔红霉素的利用度，以及在骨骼中的可利用度 骨髓和其他所有微环境。我们还将探索临床变量，如年龄和性别 改变这些效果。最后，我们将在瘦和肥胖儿童中进行有限抽样PK研究，以估计 DNR和DNR-ol在所有治疗期间的血浆和细胞内暴露。这些研究将增加我们的 了解白血病微环境如何导致治疗失败，特别是在 肥胖状态。这一发现可能导致改善儿童和儿童的蒽环类药物剂量和监测策略 成年人。这些结果，以及我们之前关于脂肪细胞如何影响长春新碱和L-天冬酰胺酶的研究 PK和PD，将为儿童诱导化疗的个性化剂量研究奠定基础 和所有人在一起。

Obesity increases both the incidence and mortality of numerous types of cancer. Children and adults who are obese at the time of diagnosis of high-risk acute lymphoblastic leukemia (ALL) have a 50% increased risk of relapse compared to their lean counterparts. Using mouse and tissue culture models, we showed that obesity directly impacts the progression and treatment outcome of ALL. We discovered that adipocytes protect ALL cells from a number of chemotherapies, including the anthracycline daunorubicin (DNR). We have found that fat cells break down DNR to an inactive form, which depletes local levels and protects nearby ALL cells from this chemotherapy. In the present grant, we will further elucidate this mechanism, using a combination of cell culture, mouse experiments, and clinical studies. We will first investigate which enzymes in adipocytes contribute to their ability to breakdown anthracyclines like DNR, and explore strategies to block these enzymes. We will use mouse models to determine how adipocytes in vivo alter systemic DNR availability, as well as that in the bone marrow and other ALL microenvironments. We will also explore how clinical variables such as age and gender alter these effects. Finally, we will perform a limited sampling PK study in lean and obese children, to estimate DNR and DNR-ol plasma and intracellular exposure during ALL therapy. These studies will increase our understanding of how the leukemia microenvironment can contribute to treatment failure, particularly in the obese state. Findings could lead to improved strategies for anthracycline dosing and monitoring in children and adults. These results, along with our previous studies on how adipocytes affect vincristine and L-asparaginase PK and PD, will lay the groundwork for a personalized dosing study of Induction chemotherapies in children with ALL.