Kropp Jenna, Roti Roti Elon C, Ringelstetter Ashley, Khatib Hasan, Abbott David H, Salih Sana M
Department of Animal Sciences, University of Wisconsin, Madison, Wisconsin, United States of America.
Department of Obstetrics and Gynecology, University of Wisconsin, Madison, Wisconsin, United States of America.
PLoS One. 2015 Nov 6;10(11):e0142588. doi: 10.1371/journal.pone.0142588. eCollection 2015.
Advances in cancer treatment utilizing multiple chemotherapies have dramatically increased cancer survivorship. Female cancer survivors treated with doxorubicin (DXR) chemotherapy often suffer from an acute impairment of ovarian function, which can persist as long-term, permanent ovarian insufficiency. Dexrazoxane (Dexra) pretreatment reduces DXR-induced insult in the heart, and protects in vitro cultured murine and non-human primate ovaries, demonstrating a drug-based shield to prevent DXR insult. The present study tested the ability of Dexra pretreatment to mitigate acute DXR chemotherapy ovarian toxicity in mice through the first 24 hours post-treatment, and improve subsequent long-term fertility throughout the reproductive lifespan. Adolescent CD-1 mice were treated with Dexra 1 hour prior to DXR treatment in a 1:1 mg or 10:1 mg Dexra:DXR ratio. During the acute injury period (2-24 hours post-injection), Dexra pretreatment at a 1:1 mg ratio decreased the extent of double strand DNA breaks, diminished γH2FAX activation, and reduced subsequent follicular cellular demise caused by DXR. In fertility and fecundity studies, dams pretreated with either Dexra:DXR dose ratio exhibited litter sizes larger than DXR-treated dams, and mice treated with a 1:1 mg Dexra:DXR ratio delivered pups with birth weights greater than DXR-treated females. While DXR significantly increased the "infertility index" (quantifying the percentage of dams failing to achieve pregnancy) through 6 gestations following treatment, Dexra pretreatment significantly reduced the infertility index following DXR treatment, improving fecundity. Low dose Dexra not only protected the ovaries, but also bestowed a considerable survival advantage following exposure to DXR chemotherapy. Mouse survivorship increased from 25% post-DXR treatment to over 80% with Dexra pretreatment. These data demonstrate that Dexra provides acute ovarian protection from DXR toxicity, improving reproductive health in a mouse model, suggesting this clinically available drug may provide ovarian protection for cancer patients.
利用多种化疗方法进行癌症治疗的进展显著提高了癌症患者的生存率。接受多柔比星（DXR）化疗的女性癌症幸存者常常遭受卵巢功能的急性损害，这种损害可能会持续成为长期的永久性卵巢功能不全。右丙亚胺（Dexra）预处理可减轻DXR对心脏的损伤，并保护体外培养的小鼠和非人类灵长类动物卵巢，证明了一种基于药物的屏障可预防DXR损伤。本研究测试了Dexra预处理减轻小鼠在DXR化疗后最初24小时内急性卵巢毒性的能力，并改善其在整个生殖寿命期内的后续长期生育能力。青春期CD-1小鼠在DXR治疗前1小时接受Dexra治疗，Dexra与DXR的比例为1:1毫克或10:1毫克。在急性损伤期（注射后2 - 24小时），1:1毫克比例的Dexra预处理降低了双链DNA断裂的程度，减少了γH2FAX激活，并减少了DXR导致的后续卵泡细胞死亡。在生育力和繁殖力研究中，用任一Dexra与DXR剂量比例预处理的母鼠产仔数均大于接受DXR治疗的母鼠，且以1:1毫克Dexra与DXR比例治疗的小鼠所产幼崽的出生体重高于接受DXR治疗的雌性小鼠。虽然DXR在治疗后的6次妊娠中显著增加了“不孕指数”（量化未怀孕母鼠的百分比），但Dexra预处理显著降低了DXR治疗后的不孕指数，提高了繁殖力。低剂量Dexra不仅保护了卵巢，还在接受DXR化疗后赋予了相当大的生存优势。小鼠生存率从DXR治疗后的25%提高到Dexra预处理后的80%以上。这些数据表明，Dexra可提供急性卵巢保护，使其免受DXR毒性影响，改善小鼠模型中的生殖健康，表明这种临床可用药物可能为癌症患者提供卵巢保护。
