Chemotherapy-induced toxicity is highly heritable in Drosophila melanogaster.
Chemotherapy-induced toxicity is highly heritable in Drosophila melanogaster.
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DOI：
10.1097/fpc.0b013e3283514395
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发表时间：
2012-04
影响因子：
2.6
通讯作者：
Long AD
中科院分区：
文献类型：
--
作者：
Kislukhin G;Murphy ML;Jafari M;Long AD
鉴定果蝇中负责化疗毒性的基因可能允许鉴定类似地介导人类毒性的人类直系同源物。为了开发果蝇作为解剖化学毒性的模型，我们首先需要开发标准化的高通量毒性测定，并证明通过这种测定测量的毒性的个体间差异是高度遗传的。我们开发了一种方法，用于口服给药的常用化疗药物的果蝇。给药后雌性生殖力显示出对不同水平化疗药物的剂量依赖性反应。我们将每种药物的剂量固定在导致生育力降低50%的水平上，并使用父系半同胞遗传力设计来计算可归因于通过女性生育力降低测定的化疗毒性的遗传力。检测的化疗药物为卡铂、阿糖胞苷、盐酸吉西他滨、甲氨蝶呤、丝裂霉素C和盐酸拓扑替康。我们发现，目前广泛使用的六种化疗药物降低了D。在剂量依赖性和高度遗传的方式。发现以下遗传力估计值：卡铂-0.72、阿糖胞苷-0.52、盐酸吉西他滨-0.72、甲氨蝶呤-0.99、丝裂霉素C-0.64和盐酸托泊替康-0.63。在本研究中观察到的高遗传性估计值，无论检查的药物的特定类别如何，表明人类毒性也可能具有相当大的遗传成分。
Identifying the genes responsible for chemotherapy toxicity in Drosophila melanogaster may allow for the identification of human orthologs that similarly mediate toxicity in humans. In order to develop Drosophila melanogaster as a model of dissecting chemotoxicity, we first need to develop standardized high throughput toxicity assays and prove that inter-individual variation in toxicity as measured by such assays is highly heritable. We developed a method for the oral delivery of commonly used chemotherapy drugs to Drosophila. Post-treatment female fecundity displayed a dose dependent response to varying levels of the chemotherapy drug delivered. We fixed the dose for each drug at a level that resulted in a 50% reduction in fecundity and used a paternal half-sibling heritability design to calculate the heritability attributable to chemotherapy toxicity assayed via a decrease in female fecundity. Chemotherapy agents tested were carboplatin, floxuridine, gemcitabine hydrochloride, methotrexate, mitomycin C, and topotecan hydrochloride. We found that six currently widely prescribed chemotherapeutic agents lowered fecundity in D. melanogaster in both a dose dependent and highly heritable manner. The following heritability estimates were found: carboplatin – 0.72, floxuridine – 0.52, gemcitabine hydrochloride – 0.72, methotrexate – 0.99, mitomycin C – 0.64, and topotecan hydrochloride – 0.63. The high heritability estimates observed in this study, irrespective of the particular class of drug examined, suggest that human toxicity may also have a sizable genetic component.