Resveratrol prevents cisplatin-induced lipid peroxidation in the non-gravid uterus of Sprague-Dawley rats

Background

Several studies have demonstrated Cisplatin-induced toxicity on the ovary. However, there is a dearth of literature on the effect of Cisplatin on the non-gravid uterus.

Safety of nelfinavir use during pregnancy. An experimental approach in rats

This experimental study aimed to evaluate the safety of nelfinavir when administered in normal up to high doses during the entire period of rat pregnancy. The renal and liver compartments of both mothers and fetuses were studied. For this purpose, three groups of pregnant rats were treated with nelfinavir (E1 = 40 mg/kg; E2 = 120 mg/kg; E3 = 360 mg/kg; no. = 10 in every group) from "zero" up to the 20th day of gestation. These doses were divided into two daily administrations by gavage. Controls (no. = 10) received distilled water in the same schedule. At term-pregnancy, the rats were deeply anesthesized and blood samples were collected for alanine and aspartate aminotransferases, creatinine and urea determinations. Fragments of maternal and fetal livers and kidneys were taken and processed for histopathological study. In all groups blood transaminases were within the normal limits, as were the levels of creatinine and urea, thus indicating that the treatment with nelfinavir during the entire gestation was essentially devoid of liver or kidney effects which could result in altered metabolic parameters. Morphological (light microscopy) studies revealed that no significant effects of the drug could be detected regarding either maternal or fetal organs of the E1 and E2 groups. However, the maternal hepatocytes in the E3 group showed heterochromatic nuclei. In addition, there was some fatty infiltration, congested sinusoids and portal dilatation. It is concluded that only doses of nelfinavir used during the entire gestation in doses well above the usual human doses could be considered to be potentially hepatotoxic for the pregnant rat.     

MG132对卵巢上皮性癌裸鼠移植瘤生长的影响及联合顺铂作用效应的研究

目的:探讨蛋白酶体抑制剂MG132应用于卵巢上皮性癌裸鼠移植瘤的新型治疗及联合顺铂协同抗肿瘤的潜在价值和可行性。方法:建立人卵巢癌裸鼠皮下移植瘤模型,20只裸鼠随机平均分为4组,每日腹腔内注射给药1次,共7日。对照组(0.2 ml的0.9%氯化钠液),MG132组(2 mg/kg),顺铂组(1 mg/kg),联合组[MG132(2 mg/kg)+顺铂(1 mg/kg)]。移植瘤模型建立4周后比较各组移植瘤质量抑制率,IHC、FIA、Western blot、RT-PCR检测各组肿瘤促凋亡基因(Caspase3)、自噬基因(Beclin1)的表达情况。结果:1顺铂组、MG132组、联合组对移植瘤的瘤质量抑制率分别为15.38%、53.85%、88.46%,顺铂联合MG132理论相加的瘤质量抑制率为60.95%;2IHC、FIA、Western blot检测:与对照组相比,顺铂组、MG132组、联合组Beclin1、Caspase3阳性表达均明显增强,其中联合组阳性表达更强。3RT-PCR检测:顺铂组、MG132组、联合组的Beclin1、Caspase3 mRNA表达均明显高于对照组(P0.05);且联合组又高于顺铂组、MG132组(P0.05)。结论:MG132对卵巢上皮性癌裸鼠移植瘤生长具有抑制作用,且与顺铂联合治疗卵巢癌具有协同抗肿瘤效应,有望成为治疗顺铂耐药型难治性卵巢癌的一种有效抗肿瘤药物。     

顺铂诱导化疗损伤性卵巢早衰大鼠模型的探讨

目的:探讨顺铂诱导大鼠化疗损伤性卵巢功能早衰大鼠模型的可行性。方法:成熟雌性SD大鼠腹腔注射低、高剂量顺铂4.5 mg/kg(A组)、6.0 mg/kg(B组)和生理盐水(C组),每周1次,共2次,建立大鼠化疗损伤性卵巢早衰模型。检测血清FSH水平及光学显微镜下计数卵巢最大切面原始卵泡、初级卵泡、闭锁卵泡,阴道涂片观察动情周期变化。结果:A、B组大鼠动情周期均明显长于C组(P<0.05),并呈现剂量相关性改变。B组动情周期天数明显长于注射前(P<0.01);血清FSH水平A组与C组相比无统计学意义(P>0.05),B组明显高于A组和C组(P<0.05)。各顺铂组血清FSH水平注射后均较注射前明显升高(P<0.05)。腹腔注射顺铂后,A组、B组大鼠卵巢最大切面原始卵泡数和初级卵泡数均明显降低(P>0.05),而闭锁卵泡数均明显增加(P<0.05),并呈现剂量相关性改变。结论:顺铂可诱导化疗损伤性卵巢早衰。此化疗损伤性卵巢早衰大鼠模型血FSH明显升高,卵巢组织学衰退性改变与人类化疗损伤性卵巢早衰病变过程相似。     

Phase II trial of liposomal doxorubicin at 40 mg/m(2) every 4 weeks in endometrial carcinoma: a Gynecologic Oncology Group Study

OBJECTIVE: In patients with disseminated endometrial carcinoma, liposomal doxorubicin has possible advantages over doxorubicin which has proven single agent activity but well known cardiac toxicity. Before replacing doxorubicin in clinical trials, the Gynecologic Oncology Group (GOG) decided to conduct a phase II clinical trial of liposomal doxorubicin (Ortho Biotech Products L. P., Raritan, NJ) in first-line therapy of patients with disseminated endometrial carcinoma. METHODS: Patients with initial histologic confirmation of endometrial carcinoma presenting with disseminated or recurrent cancer who had not previously received cytotoxic drugs were considered for participation in this clinical trial. Eligible patients had measurable disease, GOG performance status 0-2, and adequate bone marrow, renal, and hepatic function according to standard criteria. Liposomal doxorubicin 40 mg/m(2) was given by intravenous injection on an every 4-week cycle until toxicity or progression. Patients who remained free from tumor progression or intolerable toxicity received at least one to a maximum of 20 cycles of liposomal doxorubicin. RESULTS: Fifty-six patients were registered, of whom three were determined ineligible (prior malignancy = 2, inadequate pathology material = 1). One patient never received therapy, leaving 52 evaluable patients. Two patients (3.8%) achieved a complete response, four (7.7%) exhibited a partial response, and 31 (59.7%) had stable disease. The most common adverse events were constitutional (32/52), anemia (28/52), pain (27/52), dermatologic (25/52), and cardiovascular (12/52). CONCLUSIONS: In this trial, liposomal doxorubicin had a response rate of 11.5% in first-line treatment of disseminated endometrial carcinoma when given at 40 mg/m(2) every 4 weeks. In view of the associated skin toxicity at this dose, liposomal doxorubicin does not appear to be a suitable replacement for the more active doxorubicin for therapy of endometrial carcinoma.     

Histomorphometric effects of Kigelia africana (Bignoniaceae) fruit extract on the testis following short-term treatment with cisplatin in male Sprague–Dawley rats

ObjectiveTo investigate the short-term effects of Kigelia africana fruit extract (KAFE) on cisplatin-induced testicular histo-morphometric changes in Sprague–Dawley (SD) rats.DesignThis is an experimental animal study.Materials and methodsFifty-seven male SD rats were acclamatized and grouped into 10 of five rats per group. Each rat was administered either KAFE in 100 and 500mg/kg doses orally or cisplatin 10mg/kg i.p. or normal saline to controls. Experiment was terminated after 28days by i.p. injection of ketamin 50mg/kg. Testicular tissue was processed for histological and morphometric analyses while catalase enzyme activity, lipid peroxidation and glutathione levels were assayed accordingly. Sperm count/motility was also assessed.ResultsCisplatin treatment caused over 37.5% mortality of SD rats. Qualitative histological assessment showed no deleterious changes following treatment with KAFE alone or as a pre-treatment with cisplatin. KAFE post-treatment resulted in focal vacuolar changes in the seminiferous tubules (ST) of the SD rats. Cisplatin-treatment negatively affected the histoarchitecture of the seminiferous tubules with massive loss of spermatogenic cells. There was also a significant reduction in testicular weight/volume, ST diameter and cross-sectional areas (P<0.001) but KAFE positively improved these parameters. KAFE alone and as prophylaxis significantly increased body weight, serum testosterone and follicle-stimulating hormone (P<0.001). It showed a significant elevation in catalase activity, decline in malondialdehyde and up-regulated glutathione levels (P<0.001). These parameters were negatively affected by cisplatin treatment.ConclusionThe cytoprotection against cisplatin-induced testicular damage by KAFE is likely via an antioxidant modulatory pathway. Also, it is possible that KAFE possesses an androgen-stimulating property.     

环境内分泌干扰物2-溴丙烷对大鼠睾丸毒性的研究

目的 :研究 2 -溴丙烷对大鼠睾丸的毒性。方法 :雄性成年 SD大鼠 40只 ,分为 1 80 0mg/ kg、6 0 0 mg/ kg、2 0 0 mg/ kg和对照组。腹腔注射 2 -溴丙烷 ,每日 1次 ,连续 5d。结果 :高剂量组大鼠体重下降 ,睾丸湿重和重量系数与对照组相比显著降低 ,而附属性腺的重量无显著改变。随着染毒剂量的增加 ,曲细精管损伤率升高 ( P<0 .0 5) ,精原细胞占曲细精管中生精细胞的比率显著降低 ,高剂量组大鼠的曲细精管面积减小。结论 :睾丸是 2 -溴丙烷生殖毒性的靶器官 ,2 -溴丙烷最早损伤精原细胞且毒作用最严重。     

醋酸甲羟孕酮增强顺铂对人卵巢癌耐药细胞抗癌作用的研究

目的:观察醋酸甲羟孕酮(MPA)对人卵巢癌CoC1/cDDP细胞移植瘤的生长抑制作用及对DDP的耐药逆转作用,并分析其作用机制。方法:建立人卵巢癌裸鼠皮下移植瘤模型,随机分为4组,每组5只。(1)对照组:腹腔注射等体积生理盐水;(2)DDP治疗组:每只每次腹腔注射DDP 3mg/kg。(3)MPA治疗组:每只每次灌胃30mg/kg;(4)联合治疗组:每只每次灌胃MPA 30mg/kg,1h后每只每次腹腔注射DDP 3mg/kg,每隔2天给药1次,共4次,于治疗第1、5、10、15、20天分别测瘤体积,20天后处死裸鼠,完整剥出瘤组织,称瘤重,计算抑瘤率;通过流式细胞仪检测亚G1期细胞及AnnexinV+/PI-细胞鉴定细胞凋亡,分析移植瘤细胞周期;用半定量RT-PCR法检测移植细胞组织Survivin-ΔEx3、caspase-3、P21WAF1/CIP1及GST-π4基因mRNA表达。结果:(1)MPA组、MPA+DDP组治疗第10天起皮下移植瘤体积明显小于DDP组和对照组,且进行性缩小(P<0.01);抑瘤率分别为51.63%、62.21%,均明显大于DDP组的6.84%(P<0.01),并且两组间有显著差异(P<0.01);(2)流式细胞仪分析显示,移植瘤出现亚G1期峰及AnnexinV+/PI-细胞均证实MPA能诱导CoC1/cDDP细胞凋亡,并显著高于对照组及DDP组,并出现G1期阻滞;与DDP合用除出现G1期阻滞外又出现G2/M期阻滞,S期明显减少,亚G1期细胞及AnnexinV+/PI-细胞进一步上升;(3)半定量RT-PCR检测显示,MPA组Survivin-ΔEx3、GST-πmRNA下调,而P21WAF1/CIP1、caspase-3 mRNA上调,与DDP合用后,对Survivin-ΔEx3、P21WAF1/CIP1及GST-πmRNA的表达无协调作用,而对caspase-3 mRNA有协同上调作用。结论:MPA通过阻滞G0/G1期明显抑制了CoC1/cDDP移植瘤生长,并有很强的致凋亡作用,同时下调GST-πmRNA,从而逆转对顺铂耐药。     

醋炔诺酮肟的抗着床作用及其毒性研究

醋炔诺酮肟对实验动物有明显的抗着床作用。小鼠、大鼠和家兔在妊娠第2天起,分别给予醋炔诺酮肟0.5、1和2毫克/公斤,每天一次,连续3天,均有显著的抗着床作用。大鼠在妊娠第2或3天一次给醋炔诺肟酮5或10毫克/公斤,亦有明显的抗着床作用。家兔4只,每日灌服醋炔诺酮肟10毫克/公斤(约为临床剂量500倍),连续3周,给药后肝功能升高,停药2周后恢复正常,血象和肾功能均无明显变化。犬3只,每日灌服醋炔诺酮肟1～2毫克/公斤(约为临床剂量50～100倍),连服14个月,无明显毒性。     

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.     

Anti-tumor and adverse effect of etoposide and cisplatin on human choriocarcinoma transplanted to nude mice--a correlation between effect and tissue distribution of the drugs

The study dealt with anti-tumor and adverse effects of etoposide and cisplatin on human choriocarcinoma cell line (GCH-1) transplantable in nude mice in relation to the rate of their uptake into tumor tissue. Nude mice were divided into 3 groups (etoposide, cisplatin and MTX-group), 7 to 9 per group and received drug treatment which started when their tumor grew to 100 approximately 300 mm3 in volume. All drugs were intraperitoneally administrated to nude mice (each drug: 1/4 mouse LD50 dose X3, weekly). The inhibiting action on the tumor was observed to be etoposide greater than cisplatin greater than MTX. The body weight loss of nude mice was observed to at its maximum in the cisplatin-treated group. The serum beta-HCG level did not rise in the drug-treated groups but rose in the non-treated control group. No histopathological changes characteristic of each drug were found. A concentration of etoposide and cisplatin in various tissues was serially measured after one shot intraperitoneal injection of etoposide 25 mg/kg or cisplatin 5 mg/kg. Etoposide reached its peak concentration after 30 minutes in tumor, liver and kidney and, after 4 hours, was left with 37.1%, 10.4% and 2.3% concentrations after 30 minutes in tumor, liver and kidney, respectively. Cisplatin showed similar kinetics, but was found to remain at a comparatively high concentration in both liver and kidney. Thus, it was demonstrated that etoposide and cisplatin were active against the human choriocarcinoma cell line. Furthermore, the less adverse effect of etoposide was felt to be partially due to its lower residue in liver and kidney.     

甲氨蝶呤损伤大鼠输卵管的实验研究

目的:观察甲氨蝶呤(MTX)对假孕SD大鼠输卵管急性损伤及远期恢复效应.方法:假孕SD大鼠72只随机分4组(每组18只),3组行MTX腹腔注射:1 mg/kg组、2mg/kg组、5 mg/kg组,另1组(对照组)用0.9%氯化钠液.处理后10天、2月分别选取半数大鼠输卵管组织行组织学和雌激素受体(ER)、孕激素受体(PR)观察.结果:①MTX处理后10天的各组输卵管标本中,均出现了与MTX作用剂量相关的炎性反应,但2月时逆转至正常;②10天时ER阳性率随MTX剂量增加而下降,且ER阳性率1 mg/kg组、2 mg/kg组在2月时明显高于10天时(P＜0.05),有回升现象,但5 mg/kg组在两个时间点的ER表达则无明显差异(P＞0.05);③PR阳性率10天时各组内不同剂量MTX处理后差异均无统计学意义(P＞0.05),但2月时各组内PR阳性表达率差异有统计学意义(P＜0.05).结论:MTX作用后的输卵管出现了剂量依赖性的近期及远期、可逆或不可逆性的结构及功能的损伤,为临床使用MTX行肿瘤化疗或保守治疗异位妊娠提供了理论依据.     

白细胞介素-15治疗3AO裸鼠移植瘤的实验研究

目的:探讨白细胞介素-15(IL-15)治疗3AO裸鼠皮下移植瘤的效果及其机制。方法:建立3AO裸鼠皮下移植瘤模型,随机分为5组,每组12只。I组为顺铂(cD-DP)3mg/kg;Ⅱ组、Ⅲ组分别为IL-1550μg/kg,100μg/kg;Ⅳ组为cDDP1.5mg/kg加IL-1550μg/kg;Ⅴ组为对照组,注射生理盐水(各组药物均腹腔注射,按每只裸鼠0.2ml配制),1次/d,连用1周。观察移植瘤成瘤率、裸鼠生存期、生存延长率及肿瘤生长曲线。停药1天,1周,2周后,观察移植瘤细胞凋亡率及细胞周期,NK细胞群计数;测定裸鼠脾脏重量;对移植瘤及裸鼠肝、脾、肾行常规病理学检查。结果:实验组与对照组相比荷瘤裸鼠生存延长率,脾脏重量,移植瘤细胞凋亡率,NK细胞群计数均有明显差异。病理学检查示各治疗组均见肿瘤坏死,肿瘤细胞周围及肿瘤内淋巴细胞明显浸润。IL-15治疗组脾脏有充血增生表现,肝脏肝细胞嗜酸性变性,肝细胞水肿,周围有浊肿;cDDP治疗组肾脏近曲小管和远曲小管细胞水肿,管腔变小;对照组裸鼠肝、脾、肾未见明显病理改变。结论:IL-15对人卵巢癌裸鼠皮下移植瘤有明显的抑制作用,其机制可能与IL-15增强NK细胞的细胞毒活性,诱导NK细胞及细胞因子产生有关。     

A ten-year remission maintained by 6,272 mg (3,920 mg/m2) cumulative dose of cisplatin-based chemotherapy for recurrent epithelial ovarian cancer

Since cisplatin is a heavy metal, renal and neurotoxicity is considered to be dose limiting in solid tumors. The current case is unusual in that remission has been maintained in a patient with recurrent epithelial ovarian cancer by cisplatin-based chemotherapy without evidence of renal or neurotoxicity, while receiving a total dose of 6,270 mg (3,920 mg/m2) of cisplatin over 11 1/2 years.     

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.     

The effect of clomiphene citrate on osteoporosis in ovariectomized rats

OBJECTIVE: The aim of this study was to investigate whether clomiphene citrate (CC) administration could be a new therapeutic agent in case of contraindication of estrogen therapy for hormone-dependent osteoporosis and to show the changes in bone structure by histomorphometric analysis in ovariectomized rats administered CC. STUDY DESIGN: This study was carried out in the Experimental Surgery Laboratory of the Brain Research Centre of the Medical Faculty of Ege University. Four-month-old Sprague-Dawley rats were used for the experiment. The study was carried out on six groups of animals each consisted of eight rats. Four groups of rats were ovariectomized and 2 groups of rats were used as control group. For 6 weeks every day, rats were injected physiological saline solution (1 ml/kg), clomiphene citrate (1 or 10 mg/1 ml/kg, Organon), 17beta-estradiol (50 microg/1 ml/kg, within susame oil, Sigma) or susame oil (1 ml/kg, Sigma). Drug administrations were carried out according to the weekly weight measurements. Group 1(PSS), n = 8, non-ovariectomized, were injected with physiological saline solution. Group 2(CC-1), n = 7, non-ovariectomized, were injected with CC (1 mg/1 ml/kg). Group 3(OVX + CC-1), n = 7, ovariectomized, were injected with CC (1 mg/1 ml/kg). Group 4(OVX + CC-10), n = 6, ovariectomized, were injected with CC (10 mg/1 ml/kg). Group 5(OVX + E), n = 8, ovariectomized, were injected with 17beta-estradiol (50 microg/1 ml/kg). Group 6(OVX), n = 8, ovariectomized, were injected with susame oil (1 ml/kg) Bone-specific serum alkaline phosphatase (ALP) levels were measured and statistical analyses were made by Kruskal Wallis test. Left femur bone histomorphometric studies were done. The uteri were dissected out to measure their weight and ANOVA was used to show the intergroup differences. RESULTS: The level of ALP in group 3 was significantly higher than the other five groups. Bone histomorphometric examination showed that total bone volume in group 3, 4, and 5 was higher than group 6, and group 4 had the highest level of bone volume compared to the rest of the groups. Uterus weights in group 1 were significantly higher than group 3 and 6 (P = 0.02, P = 0.01) and uterus weights in group 5 were significantly higher than group 3 and 4 (P = 0.00, P = 0.01) CONCLUSIONS: In ovariectomized rats, treatment with CC is seen as effective as estrogen treatment in preventing osteoporosis, without causing uterin hyperstimulation. Nevertheless, further investigations on more rats are needed to assess whether it is an alternative treatment method to estrogen.     

Preclinical in vivo activity of a combination gemcitabine/liposomal doxorubicin against cisplatin-resistant human ovarian cancer (A2780/CDDP)

Both gemcitabine and liposomal doxorubicin are antineoplastic drugs with clinical activity in platinum-refractory ovarian cancer. The purpose of this study was to evaluate the antitumor activity of a combination gemcitabine/liposomal doxorubicin administered to athymic mice bearing cisplatin-resistant human ovarian cancer (A2780/CDDP) xenografts. Emphasis was on the use of very low doses of each drug and of different dosing schedules. Data obtained showed that combined treatment with 80 mg/kg gemcitabine and 15 mg/kg liposomal doxorubicin produced a significant enhancement of antitumor activity compared with monotherapy at the same doses of these agents. Noteworthy is the fact that the majority of xenograft-bearing animals receiving the combination therapy demonstrated a complete tumor regression at the end of the study. A similar trend was observed when doses of both drugs were reduced to 20 mg/kg gemcitabine and to 6 mg/kg liposomal doxorubicin. Again, three out of ten mice receiving the combination were tumor free at the end of the study. No significant differences were observed in antitumor activity when comparing the simultaneous vs the consecutive dosing schedule. Remarkably, no additive toxicity was observed in any experimental trials. These data encourage clinical trials to prove the advantages of this combination treatment with respect to the single-agent chemotherapy in platinum-refractory ovarian cancer patients.     

A novel tocolytic agent: effects of letrozole on gestational length and parturition time

The purpose of this study was to determine whether letrozole, a potent aromatase inhibitor, could prolong gestation and/or delay parturition in rats. Seventy-five rats were divided into five groups of 15 rats each. Group I and group II rats were administered letrozole orally at doses of 0.002 and 0.02 mg/kg/day from days 15 through 21 of pregnancy, respectively. Rats in group IA were administered a concomitant estradiol cyclopentylpropionate (ECP) injection on day 15 and 0.002 mg/kg letrozole in that same manner as for group I. Rats in group IIA were administered concomitant ECP on day 15 and 0.02 mg/kg letrozole in the same manner as for group II. The control group received sterile saline only. Study and control groups were compared with respect to gestational length, parturition time, fetal mortality rate, stillbirth rate, and fetal body weight. Oral administration of letrozole both at daily doses of 0.002 mg/kg/day (group I) and 0.02 mg/kg/day (group II) consistently prolonged gestation and parturition time. The values of stillbirth rate, fetal mortality rate, and fetal body weight of group I were similar to those in the control group; conversely, fetal mortality rate and stillbirth rate of group II were higher than those values in the control group, and fetal body weight of group II was lower than in the control group. It was observed that concomitant injection of ECP effectively reversed the deleterious effects of letrozole on gestational length, parturition time, fetal mortality rate, stillbirth rate, and fetal body weight. The results of this study indicate that the aromatase inhibitor letrozole can prolong gestation and delays parturition in rats. Its deleterious effects on parturition can be reversed by ECP injection.     

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。     

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.