Department of Ecology and Evolution, University of California, Irvine, California, USA.
Pharmacogenet Genomics. 2012 Apr;22(4):285-9. doi: 10.1097/FPC.0b013e3283514395.
Identification of the genes responsible for chemotherapy toxicity in Drosophila melanogaster may allow for the identification of human orthologs that similarly mediate toxicity in humans. To develop D. melanogaster as a model of dissecting chemotoxicity, we first need to develop standardized high-throughput toxicity assays and prove that the interindividual 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 by a decrease in female fecundity. The 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 a 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.
鉴定导致黑腹果蝇化疗毒性的基因，可能有助于鉴定在人类中同样介导毒性的人类同源基因。为了将黑腹果蝇发展为剖析化学毒性的模型，我们首先需要开发标准化的高通量毒性测定法，并证明此类测定法所测量的个体间毒性差异具有高度遗传性。
我们开发了一种向果蝇口服给予常用化疗药物的方法。经处理的雌性果蝇的生育力对所给予的化疗药物剂量呈剂量依赖性反应。我们将每种药物的剂量固定在导致生育力降低 50%的水平，并采用父系半同胞遗传设计，根据雌性生育力下降来计算归因于化疗毒性的遗传力。所测试的化疗药物为卡铂、氟尿嘧啶、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均以剂量依赖性和高度遗传性的方式降低了黑腹果蝇的生育力。发现的遗传力估计值如下：卡铂，0.72；氟尿嘧啶，0.52；盐酸吉西他滨，0.72；甲氨蝶呤，0.99；丝裂霉素 C，0.64；盐酸拓扑替康，0.63。
本研究观察到的高遗传力估计值，无论所检查的特定药物类别如何，均表明人类毒性也可能具有相当大的遗传成分。
