亮丙瑞林对顺铂所致大鼠卵巢毒性保护的实验研究

目的:探讨亮丙瑞林(GnRH-a)对大鼠顺铂所致卵巢功能损伤的保护作用。方法:选择SPF级别12周龄SD雌鼠96只,随机分为4组,每组24只。A组为正常对照组,腹腔注射生理盐水2ml/d。B组为顺铂组,C组为亮丙瑞林(GnRHa)+顺铂组,D组为单用亮丙瑞林组。于间情期C、D组皮下注射亮丙瑞林0.25mg/只(单次给药)。B、C组腹腔注射顺铂2mg/(kg.d),连续用药10天。用药结束后及结束后30天分别每组处死8只;每组剩余的雌鼠按2:1与雄鼠交配,产仔后处死。称体重、卵巢及子宫重量,统计卵泡数量和各级卵泡直径,观察卵巢和子宫病理学变化。测雌二醇(E2)、卵泡刺激素(FSH)。观察孕鼠产仔数量及外观。结果:用药结束后B、C组大鼠精神及饮食状况差,体重及子宫重量下降(P<0.05),以B组最为明显(P<0.05)。用药结束后30天4组大鼠体重增加,B组体重恢复得最慢(P<0.05)。用药结束后B、D组子宫黏膜层变薄,纤维成分多,子宫腺体少。C组子宫黏膜层变薄,但腺上皮细胞比B组清晰,有顶浆分泌现象。C、D组原始卵泡较多,生长卵泡、成熟卵泡数减少,各级卵泡的粒细胞层明显减少(P<0.05)。B组成熟卵泡减少明显(P<0.05)。用药结束后30天,B、C、D组子宫内膜厚度及腺体量均有所改善。B组成熟卵泡数减少(P<0.05)。C组和D组成熟卵泡数增多(P<0.05)。用药结束后B、C、D组FSH升高,E2下降(P<0.05),B组与C、D组相比,FSH升高,E2下降更明显(P<0.05)。用药结束后30天,C、D组FSH降低,E2升高(P<0.05)。4组鼠仔未见畸形,B组产仔数减少。结论:顺铂对大鼠卵巢有毒性作用。亮丙瑞林可使原始卵泡数增多,卵泡处于静止期,降低顺铂对卵巢的毒性作用。     

抗苗勒氏管激素作为预测化疗后卵巢储备功能状态的实验性研究

目的:探讨化疗时抗苗勒氏管激素(anti-Müllerian hormone,AMH)作为预测大鼠卵巢储备功能状态的可行性。方法:雌性SD大鼠24只,随机分为3组:对照组(NS)、顺铂化疗低剂量组(4.5 mg/kg,CL)和高剂量组(6.0 mg/kg,CH),每组8只。免疫组织化学染色检测AMH在卵巢的表达,光学显微镜下计数AMH阳性卵泡百分比,ELISA检测血清AMH、FSH水平。结果:各组大鼠卵巢组织均可见AMH表达,主要位于初级卵泡、窦前卵泡及小窦状卵泡的颗粒细胞,给予顺铂12 d后,AMH的表达强度减弱、范围缩小。CL组和CH组的AMH阳性卵泡百分比均较NS组明显降低(P<0.05)。卵巢AMH强阳性的卵泡百分比随顺铂剂量的增高而降低(P<0.05),CH组最低,而AMH阴性或弱阳性卵泡百分比升高;血清AMH水平变化与免疫染色结果相平行,即顺铂CL组及CH组的AMH水平较对照组明显降低,且呈剂量依赖性(P<0.01)。血清FSH水平顺铂化疗后虽有增高趋势,但各组间未见明显差异。结论:临床常用化疗药顺铂可损伤正常卵巢组织,使颗粒细胞表达AMH减少,致使卵巢储备功能下降,血清AMH水平能够较好地反映这一变化,作为预测化疗后卵巢储备功能状态的指标具有较高的可信性。     

饱和氢盐水对化疗致卵巢损伤的保护作用

目的:研究饱和氢盐水对环磷酰胺(CTX)所致大鼠卵巢损伤的影响。方法:将54只雌性SD大鼠随机分为3组:A组为正常对照组,B组为CTX组,C组为CTX+饱和氢盐水组。腹腔注射CTX复制化疗所致卵巢损伤模型,首日负荷量为50 mg/kg,后以每日8 mg/kg的维持量持续14 d。饱和氢盐水处理为首次给予CTX开始每日早晚8点2次腹腔注射饱和氢盐水10 ml/kg,持续14 d。于停药后第1日(即15 d)、第16日(即30 d)和第31日(即45 d)分批处死大鼠,留取卵巢固定,HE染色观察卵巢病理;外周血离心取血清,检测卵泡刺激素(FSH)、雌二醇(E2)、超氧化物岐化酶(SOD)、过氧化氢酶(CAT)、丙二醛(MDA)的变化情况。结果:血清FSH和E2的检测结果显示:B组动物血清FSH表达高于A组,E2低于A组,差异有统计学意义(P<0.05);而C组动物血清FSH显著低于B组、E2高于B组(P<0.05)。病理切片显示:B组动物卵巢内卵泡丢失、闭锁,卵巢间质严重损害,可见血管壁增厚,呈玻璃样变,局部可见纤维化;C组可见卵巢皮质、髓质结构清晰,各级卵泡丰富。血清SOD、CAT和MDA的检测结果显示:与A组相比,B组动物血清SOD、CAT水平降低,MDA升高(P<0.05);而与B组相比,C组动物血清SOD和CAT含量增加,MDA降低(P<0.05)。结论:饱和氢盐水可有效防止化疗药物诱发的卵巢损伤,可能与调节体内氧化与抗氧化平衡有关。     

壬基酚孕期经口染毒对F1代昆明小鼠卵巢发育的影响

目的:观察壬基酚孕期暴露对F1代昆明小鼠卵巢发育的影响。方法:交配后7d起,对孕鼠分别每日灌胃壬基酚(NP)(分别为1.2mg/kg、12mg/kg、120mg/kg),对照组灌胃花生油,直至交配后17d,每组7只。子代小鼠出生14d时取卵巢组织病理学检查,计数各级卵泡。观察子代雌鼠观察阴道开口时间和规律动情周期出现时间。子代雌鼠成年3月龄后,于动情前期处死,放免法测定血清E2、FSH浓度,酶联免疫吸附法测定血清抑制素B浓度,取卵巢组织行病理学检查,计数各级卵泡。结果:NP低剂量组阴道开口出现时间提前(P<0.05);低、中剂量组规律动情周期出现时间提前并可见动情周期延长(P<0.05);高剂量组性成熟期始基卵泡数减少(P<0.05),血清抑制素B水平降低(P<0.05);各用药组动情前期血清E2水平降低(P<0.05),FSH水平无明显变化。用药组体质量较对照组明显升高(P<0.05)。结论:壬基酚胎仔宫内暴露,在较低剂量时可影响小鼠的动情起始及动情周期,在较高剂量时可降低卵巢储备,并可影响成年后小鼠雌激素水平。     

人脐血单个核细胞移植对卵巢早衰大鼠卵巢功能的影响

目的本研究旨在探讨人脐血单个核细胞(HCMNCs)在大鼠卵巢早衰模型中的修复作用,以期为临床细胞治疗卵巢早衰提供一种理论和实验依据。方法(1)建立卵巢早衰模型;(2)确定POF造模成功;(3)利用Ficoll密度梯度离心法制备HCMNCs细胞悬液;(4)将大鼠随机分为三组:A组大鼠不予任何处置,B组大鼠双侧卵巢各注入10■细胞悬液,C组将等量的L-DMEM培养基注入大鼠的双侧卵巢;(5)利用ELISA方法检测血清E2、FSH、LH水平,卵巢组织切片进行HE染色,观察卵巢未闭锁卵泡数量及卵巢形态学情况。结果HCMNCs细胞悬液移植后50 d:(1)B组大鼠动情周期紊乱率较C组有明显的减少,阴道脱落细胞涂片开始有上皮细胞、角化细胞、白细胞等多样细胞交替的变化;(2)B组血清E2水平较C组升高,两者差异有高度统计学意义(P0.001);LH、FSH水平较C组LH、FSH水平降低,两者差异有高度统计学意义(P0.001);(3)卵巢病理切片形态学观察B组未闭锁卵泡数目较C组明显增多,差异有高度统计学意义(P0.001)。结论人脐血单个核细胞参与修复受损卵巢的功能,可缓解低雌激素的状态,对卵巢早衰的治疗起到积极的作用。     

miR-21调控PTEN及PDCD4基因治疗化疗性卵巢早衰

目的:探讨miR-21在化疗性卵巢早衰大鼠模型中的治疗潜能及其可能机制。方法:体外构建miR-21慢病毒载体(LV-miR-21)。将大鼠随机分为空白对照组、模型组、空载组及miR-21组,通过腹腔注射环磷酰胺(CTX)建立化疗所致卵巢早衰大鼠模型。建模后往miR-21组大鼠双侧卵巢注射LV-miR-21,注射后第1、15、30、45、60天分批处死大鼠。阴道脱落细胞涂片检测大鼠动情周期;化学发光法与免疫放射法测定性激素水平;进行卵巢称重、计数各级卵泡数;TUNEL法测定卵巢组织颗粒细胞凋亡率;qRT-PCR、Western blot法检测miR-21靶基因PTEN、PDCD的mRNA及蛋白水平。结果:体外成功构建miR-21慢病毒载体。实验结束时,miR-21组有64%(16/25)大鼠恢复规律动情周期。注射后第15、30、45、60天,miR-21组的E_2水平、卵巢颗粒细胞凋亡率均高于模型组和空载组(P=0.000),FSH水平以及PTEN、PDCD4的mRNA、蛋白表达较相应时间点的模型组和空载组显著下降(P=0.000)。注射后第30、45、60天,miR-21组的卵巢重量显著高于模型组和空载组,但仍低于空白对照组;注射后第45、60天,miR-21组各级卵泡数均多于模型组和空载组(P=0.000);结论:miR-21在化疗诱导卵巢早衰大鼠模型中具有治疗潜能,其具体作用机制可能与下调靶基因PTEN、PDCD4有关。     

过表达miR-21的骨髓间充质干细胞在化疗性卵巢早衰大鼠模型中的治疗潜能及机制

目的:探讨过表达miR-21的BMMSCs对化疗性卵巢早衰的治疗作用及可能机制。方法:采用分子生物学方法构建miR-21慢病毒表达载体(LV-miR-21)。使用LV-miR-21转染体外分离培养的大鼠BMMSCs,获得过表达miR-21的BMMSCs(miR-21-BMMSCs)。建立化疗性卵巢早衰大鼠模型,双侧卵巢注射miR-21-BMMSCs,分别于注射后第15天、30天、45天、60天分批处死大鼠。采用阴道涂片测定动情周期,卵巢称重,HE染色进行卵泡计数,化学发光法测定性激素水平,TUNEL法测定卵巢颗粒细胞凋亡率,qRT-PCR、Western blot法检测miR-21及PTEN、PDCD4的mRNA及蛋白水平。结果:双侧卵巢注射miR-21-BMMSCs后,化疗诱导的POF大鼠动情周期恢复率、卵巢重量、各级卵泡数和E2水平增加,而FSH水平及卵巢颗粒细胞凋亡率下降。此外,miR-21表达水平的上升伴随PTEN、PDCD4 mRNA及蛋白水平的下降。结论:过表达miR-21的BMMSCs能更有效地治疗化疗性卵巢早衰,可能与其调控靶基因PTEN、PDCD4密切相关。     

骨髓间充质干细胞移植修复化疗所致卵巢损伤的实验研究

目的:探讨大鼠骨髓间充质干细胞(MSCs)移植对化疗所致卵巢损伤的影响。方法:采用腹腔注射环磷酰胺(CTX)建立化疗所致大鼠卵巢损伤模型,并随机分为模型组、实验对照组及移植组。同龄正常大鼠作为空白对照组。移植组在建模结束后每侧卵巢注射绿色荧光标记约1×106个MSCs。于移植后1、15、30、45天及60天,留取各组血标本,并于后4个时间点分批处死大鼠,留取卵巢标本。荧光显微镜下观察绿色荧光及其分布情况。阴道脱落细胞涂片观察大鼠动情周期的变化;以化学发光法检测雌二醇(E2)浓度,放射免疫法检测卵泡刺激素(FSH)浓度;计数各级卵泡数。结果:移植MSCs后15天,移植组卵巢组织内可见到明亮的绿色荧光,持续至移植后2月。绿色荧光分布在卵巢间质组织。移植组30%(6/20)的大鼠在移植后15~30天内恢复正常的动情周期,在移植后30~60天内又有4只大鼠恢复正常的动情周期。移植后15、30、45天和60天时,移植组E2浓度高于实验对照组相应时间点E2浓度,而FSH浓度则低于实验对照组相应时间点FSH浓度,差异有显著性。移植45、60天时,移植组各级卵泡数目均高于模型组和实验对照组,低于空白对照组。结论:骨髓间充质干细胞可以在环磷酰胺损伤的大鼠卵巢组织中存活、迁移,但其分化为卵泡组分的可能性小。骨髓间充质干细胞移植可修复环磷酰胺损伤的卵巢组织,部分改善卵巢内分泌功能。     

两种玻璃化法冻存小鼠卵巢的研究

目的:探讨2种玻璃化法对小鼠卵巢组织、器官形态和功能保存作用的影响。方法:以改良的DMEM-F12为玻璃化液,分别采用常规玻璃化法(A组)和超速玻璃化法(B组)冻存小鼠卵巢组织及器官,解冻后通过组织学观察、卵巢组织异体、卵巢器官自体肾被膜下移植,观察动情周期恢复率、恢复时间、卵泡发育状况,并分别以新鲜卵巢组织异体移植、卵巢器官自体移植(C组)为对照,评价2种玻璃化法的冻存效果。结果:①A组、B组、C组卵巢组织异体移植小鼠动情周期出现率为100%,出现动情周期分别10.5±5.4d、8.0±2.2d、6.3±1.0d。A组与C组比,差异显著(P<0.05);B组与C组无差异,A组与B组间也无差异(P均>0.05)。②A组、B组、C组卵巢器官自体移植小鼠动情周期出现率为100%,出现动情周期分别为9.4±0.9d、6.9±1.1d、6.1±1.1d,A组与B、C组相比有统计学差异(P<0.05),而B组与C组间无差异(P>0.05)。移植存活的卵巢组织、器官内均可见不同发育阶段的卵泡,形态正常。结论:2种玻璃化法可有效地冻存卵巢组织及器官,但超速玻璃化法效果较优。     

GDF-9转染的脂肪间充质干细胞治疗化疗性卵巢早衰大鼠

目的:研究上调生长分化因子-9(GDF-9)表达的大鼠脂肪间充质干细胞(ASC)输注治疗化疗性卵巢早衰(POF)大鼠的效果。方法:酶解贴壁法从大鼠脂肪中培养ASC,脂质体法转染p EGFP-N3-GDF-9质粒入ASC,并验证GDF-9表达。腹腔注射顺铂建立大鼠POF模型,1周后通过尾静脉分别回输ASC和ASC-GDF-9细胞,观察大鼠体重、卵巢重量、血清中雌二醇(E_2)、卵泡刺激素(FSH)和促黄体激素(LH)值,并分析卵泡形成情况。结果:ASC细胞生长旺盛能向成骨和脂肪细胞分化,转染后可顺利表达GDF-9蛋白,转染效率为(43±9.68)%。顺铂腹腔注射可降低大鼠体重伴随卵巢体积缩小,各级卵泡减少,E_2降低,FSH和LH明显升高。输注ASC-GDF-9细胞4次后,可显著增加各级卵泡数目和基质细胞密度,降低LH和FSH激素水平。结论:转染GDF-9的ASC经尾静脉输注后,可更好地改善卵巢功能,恢复各级卵泡的发育,改善激素紊乱状态。     

The effect of carvacrol on the proinflammatory cytokines,histology, and fertility outcome of cisplatin-related ovarian change in a rat model

ObjectiveIn women, agents used in chemotherapy treatment have side effects such as accelerating follicular depletion and early menopause. Thus, cytotoxic treatments may cause various effects ranging from partial damage to the ovary to premature ovarian failure (POI) and infertility.This study aimed to investigate the protective effect of carvacrol on cisplatin (CIS)-induced reproductive toxicity in female rats.Materials and methodsThe animals were divided to four groups; a healthy group (HG), administered only cisplatin 2.5 mg/kg (CIS); cisplatin 2.5 mg/kg + carvacrol mg/kg (CC-50), and cisplatin 2.5 mg/kg + carvacrol 100 mg/kg (CC-100). In this study, the CC-50 and CC-100 groups were injected with carvacrol at 50 and 100 mg/kg intraperitoneally (IP). The CIS and HG groupswere administered normal saline as a solvent in the same way. One hour afterwardthe CC-50 and CC-100 groups were injected with cisplatin at 2.5 mg/kg IP. This procedure was continued once a day for 14 days. At the end of this period, six rats from each group were euthanized with high-dose anaesthesia. Biochemical (oxidant-antioxidant and proinflammatory cytokines) and histopathological examinations were performed on the right ovarian tissue removed from the dead rats. The remaining (n = 6 in each group) animals were kept in the laboratory with mature male rats for two months for breeding. Rats that didn't give birth within two months were considered infertile. A one-way ANOVA test was used for the biochemical analysis, the a Kruskal Wallis test was used for the histopathological analysis.ResultsIt has been observed that cisplatine causes oxidative stress and inflammatory damage in the ovarian tissue of animals and ultimately causes infertility due to this oxidative stress. While carvacrol significantly suppressed cisplatin-related oxidative stress in ovarian tissue at the 50 and 100 mg/kg doses, it could suppress proinflammatory cytokine increase only at thecytokine increase only at the 100 mg/kg dose. In addition, carvacrol significantly reduced the development of cisplatin-related infertility (from 0 to 83.3%) at a dose of 100 mg/kg.ConclusionThese findings suggest that carvacrol at high doses can reduce the harmful effects of cisplatin on the ovary and improve ovarian reserve in rats.     

Effect of chemotherapy on primordial follicular reserve of rat: an animal model of premature ovarian failure and infertility

AIM: To determine the effect of paclitaxel and cisplatin in the reduction of primordial follicular reserve in rat. MATERIAL AND METHODS: Thirty young female rats were divided randomly into three groups of 10 rats each. Paclitaxel 7.5 mg/kg and cisplatin 5 mg/kg were administered intraperitoneally in a single dose sterile technique to paclitaxel (n=10), and cisplatin (n=10) groups, and sterile saline solution was given to a control group (n=10). To assess the effects of chemotherapeutic agents on the primordial follicles, the rats were oophorectomised 7 days after the administration of chemotherapeutic agents. Haematoxylin and eosin staining was used to determine the number of primordial follicles. Primordial follicles were identified by the presence of an oocyte encapsulated partially or completely by a single layer of flattened follicular cells without a theca layer at the ovarian cortex. RESULTS: The number of primordial follicles in the control group was 23.1 +/- 16.1 follicles. The number of primordial follicles were decreased significantly in both paclitaxel and cisplatin groups compared to control group (10.3 +/- 13.0 and 13.9 +/- 15.2 follicles, respectively) (P=0.001 and P=0.01, respectively). The difference in the number of primordial follicles between the paclitaxel and cisplatin groups was insignificant (P=0.465). CONCLUSION: The administration of high dose paclitaxel and cisplatin to young rats causes the depletion of primordial follicles. However, no significant difference was observed between the two agents.     

Could erythropoietin reduce the ovarian damage of cisplatin in female rats?

The aim of this study is to investigate whether erythropoietin (EPO) can reduce the ovarian damage of cisplatin or not. Thirty, female, Wistar-Albino rats were used in the study. Control group (N?=?10): Intraperitoneal saline infusion, Cisplatin group (N?=?10): Intraperitoneal 7?mg/kg cisplatin, Cisplatin?+?EPO group (N?=?10): Intraperitoneal 7?mg/kg cisplatin and subcutaneous 200?IU/kg/day EPO. Serum AMH concentrations were measured by enzyme-linked immunosorbent assay kit of AMH. Follicular counts were evaluated according to mean diameter of the follicles. Ovarian damage; including follicular cell degeneration, vascular congestion, hemorrhage, and inflammation was scored histologically using a graduated scale. Posttreatment AMH levels of cisplatin group were significantly lower than control and cisplatin?+?EPO groups. In cisplatin group, there was a significant decrement in posttreatment AMH level compared to pretreatment AMH level. The total damage score of cisplatin group was significantly higher than scores of control and cisplatin?+?EPO groups. The mean primordial follicle counts of control and cisplatin?+?EPO groups were significantly higher than that of cisplatin group (p?=?.007 and p?=?.003). The results of this study revealed that EPO administration to cisplatin chemotherapy could ameliorate the ovarian damage. Erythropoietin administration to chemotherapeutic agents might suggest to protect ovarian failure and infertility.     

小剂量顺铂增强放疗诱导HeLa细胞凋亡的实验研究

目的 :实验研究小剂量顺铂增强放疗诱导HeLa细胞凋亡的作用。方法 :将细胞分为单纯放疗组、单纯化疗组、放疗加化疗组和空白对照组 4组 ,采用TUNEL法分别检测各组细胞的凋亡率。结果 :单纯放疗、化疗都可诱导HeLa细胞凋亡 ,顺铂 (化疗 )可以明显增强放疗诱导的细胞凋亡。结论 :小剂量顺铂可明显增加放疗诱导的HeLa细胞凋亡 ,为临床应用小剂量顺铂使放疗增效提供了理论依据     

PRL-3抑制剂对子宫内膜异位症大鼠异位病灶的作用

目的:建立子宫内膜异位症动物模型,探索PRL-3抑制剂对SD大鼠异位病灶的影响。方法:选取36只雌性SD大鼠,将自体子宫内膜移植至腹壁造模,免疫组化实验鉴定病灶内膜的上皮及间质组织。内异症大鼠腹腔注射PRL-3抑制剂,按给药浓度分组:对照组(0mg/kg)、低剂量组(0.1mg/kg)、中剂量组(1mg/kg)和高剂量组(10mg/kg),比较处理前后各组病灶情况。结果:SD大鼠自体子宫内膜移植建模存活率为86.1%,存活大鼠的造模成功率为92.5%。SD大鼠各组处理后对比处理前,对照组病灶明显增大(P0.05),低剂量组和中剂量组病灶大小无明显变化,高剂量组病灶显著缩小(P0.05)。高剂量组的病灶显著小于对照组(P0.05)。结论:SD大鼠内异症模型可用于内异症的体内实验研究,是一种操作性强、重复性好且成本低的内异症模型。一定剂量的PRL-3抑制剂可抑制SD大鼠自体异位内膜病灶的生长;PRL-3抑制剂对内异症的靶向治疗有一定的潜在价值。     

中药“红藤方”对子宫内膜异位症模型大鼠异位内膜的形态学影响

目的:探讨清热活血中药红藤方治疗子宫内膜异位症模型大鼠异位内膜的作用。方法:采 用手术方法建立子宫内膜异位症模型大鼠。将模型大鼠83只,随机分为6组:空白对照组,去势 组,达那唑组80 mg／kg,红藤方高剂量组110 g生药／kg,中剂量组77．5 g／kg和低剂量组55g/kg。 灌胃给药3周后,剖腹测量异位子宫内膜体积,并取材作组织切片,以半自动图象分析仪对异位 内膜形态进行定量分析。结果:用药后,低剂量组与对照组异位内膜体积抑制率比较无显著性差 异(P>0．05)外,其它各组均显著低于对照组(P<0．05)。其中,高剂量组与达那唑组相比也显著 降低(P<0．05)。同时,除低剂量外,其余各组异位内膜上皮高度均显著低于对照组(P<0．01)。 结论:中药红藤方能抑制异位子宫内膜的生长。     

Novel, dose intensive, single-agent cisplatin in the first-line management of advanced stage ovarian cancer

Cisplatin-based combination chemotherapy is the current standard chemotherapy for the management of advanced stage, epithelial ovarian cancer. However, correlation has been demonstrated previously between dose intensity and response for cisplatin, but not for the other cytotoxic drugs commonly used. We treated 46 consecutive, newly diagnosed patients following standard debulking laparotomy with cisplatin 60 mg m⁻² every 2 weeks for a total of 8 cycles. Survival and toxicity were compared with those of a similar cohort of 24 consecutive, newly diagnosed patients treated with cisplatin 75 mg m⁻² plus cyclophosphamide 600 mg m⁻² every 4 weeks for 6 cycles, at the same institution immediately prior to the current cohort. The single-agent cisplatin cohort received a mean relative cisplatin-equivalent dose intensity of 1.43 compared with a received mean relative cisplatin-equivalent dose intensity of 0.88 in the combination chemotherapy cohort, a 62.5% increase in the cisplatin dose intensity. At 2 years, 69% of the patients receiving single-agent cisplatin were alive, compared with 38% of the group receiving the combination chemotherapy ( P = 0.014). Alopecia ( P < 0.00001) and myelosuppression ( P < 0.0000001) were markedly less in the patient group receiving single-agent cisplatin. There was no significant difference in the incidence of neurotoxicity ( P = 0.28) or nephrotoxicity ( P = 0.38) between the two patient groups. In summary, relatively dose intensive, single-agent cisplatin given in a biweekly schedule for the first-line management of advanced stage, ovarian cancer produced a survival advantage compared with the previous combination cyclophosphamide/platinum combination chemotherapy. This novel therapy takes one-third less time to complete and causes fewer side effects than the current standard of combination cyclophosphamide and cisplatin.     

Toxicities in rats with free versus liposomal encapsulated cisplatin

Wistar rats (five in each group) were given either 1 mg/kg of free cisplatin, 1 or 2 mg/kg of liposomal encapsulated cisplatin, or saline solution intraperitoneally biweekly for 15 injections. Rats in the free drug group showed significantly less weight gain; two rats died during the study. At necropsy, the free cisplatin--treated rats showed gross and microscopic evidence of peritoneal fibrosis that was not detected in any of the remaining groups. The free cisplatin--treated rats showed serum and histologic evidence of renal damage; all five rats had moderate or severe acute tubular necrosis. No renal abnormalities were detected in rats that received 1 mg/kg, and only focal or mild changes were found in rats that received 2 mg/kg of the liposomal preparation. Neurotoxicity, as determined by nerve conduction and inclined plane studies, developed in rats treated with free and liposomal cisplatin. These results are encouraging and warrant further investigation.     

Effect of prechemotherapy filgrastim on the bone marrow toxicity of topotecan

PURPOSE: To investigate the efficacy and safety of single-dose filgrastim administered 24 hours prior to chemotherapy in the prevention of topotecan-related myeloid suppression. METHODS: No medication was given to 21 rats in group 1; 1.5 mg/m2/day topotecan was administered intraperitoneally for five days every three weeks to 21 rats in group II; a single dose of 5 microg/kg filgrastim was injected intraperitoneally 24 hours before the intraperitoneal administration of the same dose of topotecan to 21 rats in group III. After completion of six cycles of chemotherapy. the rats were decapitated and blood samples were immediately collected into citrated tubes for complete blood counts. RESULTS: White blood cell and lymphocyte counts in the control and the filgrastim + topotecan groups were similar (p > 0.05) and significantly higher than the counts in the topotecan group (p < 0.05). There was no difference in means of neutrophil, monocyte, eosinophil, basophil and erythrocyte counts among the groups (p > 0.05). CONCLUSION: Filgrastim administration prior to chemotherapy seems to be beneficial and further investigations are needed.     

Antitumor effects of high-dose cisplatin in hypertonic saline against human ovarian tumors heterotransplanted in nude mice

To overcome the dose limiting toxicity of cisplatin we administered high-dose (12 mg/kg) cisplatin together with hypertonic (3%) saline to tumor-bearing nude mice three times at four day intervals. The heterotransplanted human ovarian tumors consisted of a mucinous cystadenocarcinoma (designated as OVA-1), a poorly differentiated adenocarcinoma (OVA-2), an endometrioid adenocarcinoma (OVA-3) and three yolk sac tumors (YST-1,-2,-3). The mean volumes of the tumors in animals treated with a standard dose 6 mg/kg of cisplatin in 0.9% NaCl or 12 mg/kg of cisplatin in 3% NaCl were, as a percentage of the mean tumor volume in untreated animals: 51 and 26 for OVA-1, 28 and 15 for OVA-2, 11 and 7 for OVA-3, 7 and 14 for YST-1, 3 and 12 for YST-2, and 11 and 10 for YST-3, respectively. The most interesting result was that a high dose (12 mg/kg) of cisplatin succeeded in producing a strong antitumor effect on mucinous cystadenocarcinoma (OVA-1), which was resistant to standard dose cisplatin (6 mg/kg). A comparison of the body weight of tumor-bearing nude mice before and on Day 30 of treatment did not show any appreciable treatment-related changes.