1-氯甲基杂氮硅三环对大鼠致畸毒性试验

背景与目的： 观察1-氯甲基杂氮硅三环对大鼠的致畸毒性。 材料与方法： 将SD孕鼠随机分为1-氯甲基杂氮硅三环高、中、低3个不同剂量(10.29、32.54、102.89 mg/kg)的给药组,以及溶剂对照组(3％淀粉糊)和敌枯双阳性对照组(1 mg/kg),共5组。大鼠妊娠第6～15 d每天灌胃染毒1次,妊娠第20 d处死,检查各项指标。 结果： 1-氯甲基杂氮硅三环中、高剂量组胎仔骨骼畸形率较溶剂对照组增加(P<0.05或P<0.01),主要表现为胸骨骨化不全、缺失和形状异常等,其最小致畸量为32.54 mg/kg;各剂量组孕鼠的体重和胚胎毒性与阴性对照组比较差异无统计学意义(P>0.05);各剂量组胎仔的生长指标、外观和内脏均未见异常。 结论： 在本实验条件下, 1-氯甲基杂氮硅三环一定剂量下对SD大鼠有致畸毒性。     

Toxicology studies of bromodichloromethane (CAS No. 75-27-4) in genetically modified (FVB Tg.AC Hemizygous) mice (dermal, drinking water, and gavage studies) and carcinogenicity studies of bromodichloromethane in genetically modified [B6.129-Trp53(tm1Brd) (N5) haploinsufficient] mice (drinking water and gavage studies)

Bromodichloromethane is a by-product of the chlorination of drinking water. It is formed by the halogen substitution and oxidation reactions of chlorine and naturally occurring organic matter (e.g., humic or fluvic acids) in water containing bromide. Bromodichloromethane was nominated to the NTP by the United States Environmental Protection Agency for toxicology and carcinogenicity studies. Male and female Tg.AC hemizygous mice received bromodichloromethane (at least 98%pure) by dermal application for 26 or 39 weeks, in drinking water for 26 or 42 weeks, or by gavage for 26 or 41 weeks. p53 Haploinsufficient mice received bromodichloromethane in drinking water for 26 or 42 weeks or by gavage for 26 or 41 weeks. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. 26- and 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were dermally administered 0, 64, 128, or 256 mg bromodichloromethane/kg body weight in acetone, 5 days per week for 26 weeks, and groups of 10 male and 10 female Tg.AC hemizygous mice were dermally administered the same doses 5 days per week for 39 weeks. The survival and mean body and organ weights of all dosed groups of males and females were similar to those of the vehicle controls. There were no statistically or biologically significant increases in the incidences of neoplasms or nonneoplastic lesions. 26- AND 42-WEEK DRINKING WATER STUDIES IN TG.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were exposed to drinking water containing 0, 175, 350, or 700 mg/L bromodichloromethane for 26 weeks (equivalent to average daily doses of approximately 20, 36, or 61 mg bromodichloromethane/kg body weight to males and 31, 61, or 130 mg/kg to females). The survival of exposed males and females was similar to that of the control groups. Mean body weights of males exposed to 350 or 700 mg/L were less than those of the controls during most of the study. Mean body weights of 175, 350, and 700 mg/L females were greater than those of the controls after weeks 10, 22, and 23, respectively. In exposed males, water consumption declined with increasing exposure concentration. Water consumption by exposed females was less at the beginning of the study, but was similar to that by controls at the end of the study. The decreased water consumption was related to poor palatability. Absolute heart and right kidney weights of exposed males were significantly less than those of the control group. The incidences of hepatocyte fatty change and hypertrophy in 350 and 700 mg/L females and cytoplasmic vacuolization in 700 mg/L females were significantly greater than those in the control group. Incidences of renal tubule dilatation in males exposed to 175 mg/L or greater, renal tubule hypertrophy in 350 and 700 mg/L males, and nephropathy and renal tubule degeneration in 700 mg/L males were also increased. Groups of 10 male and 10 female Tg.AC hemizygous mice were exposed to drinking water containing 0, 175, 350, or 700 mg/L bromodichloromethane for 42 weeks (equivalent to average daily doses of approximately 18, 33, or 64 mg/kg to males and 28, 49, or 111 mg/kg to females). The survival of exposed males and females was similar to that of the control groups. Mean body weights of 350 and 700 mg/L males were less than those of the controls at the end of the study. Due to poor palatability, water consumption decreased with increasing exposure concentration. Absolute right kidney weights of 350 and 700 mg/L males were significantly less than those of the control group. The incidences of hepatocyte fatty change in all exposed groups of females, renal tubule dilatation in all exposed groups of males, and nephropathy in 700 mg/L males were significantly increased. 26- AND 41-WEEK GAVAGE STUDIES IN TG.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 25, 50, or 100 mg bromodichloromethane/kg body weight in corn oil by gavage, 5 days per week for 26 weeks. The survival of dosed males and females was similar to that of the vehicle control groups. Mean body weights of dosed females were generally greater than those of the vehicle controls at the end of the study. The incidence of multiple squamous cell papilloma of the forestomach in 100 mg/kg females was significantly greater than that in the vehicle controls. The incidences of hepatocyte fatty change in all dosed groups of females, hepatocyte cytoplasmic vacuolization in 25 and 50 mg/kg females, renal tubule hypertrophy in 100 mg/kg females, and renal tubule degeneration in 100 mg/kg males were significantly increased. Groups of 10 male and 10 female Tg.AC hemizygous mice were administered 0, 25, 50, or 100 mg/kg in corn oil by gavage, 5 days per week for 41 weeks. The survival of dosed males and females was similar to that of the control groups. Mean body weights of 25 mg/kg males and 100 mg/kg females were greater than those of the vehicle controls at the end of the study. The incidences of multiple squamous cell papilloma of the forestomach in 25 and 100 mg/kg females and of all squamous cell papillomas of the forestomach in 100 mg/kg females were significantly greater than those of the vehicle controls. The incidences of hepatocyte cytoplasmic vacuolization in 50 mg/kg females and hepatocyte fatty change in 50 and 100 mg/L females were significantly increased; the incidences of renal tubule degeneration in 100 mg/kg males was also significantly greater than that in the vehicle control group. 26- AND 42-WEEK DRINKING WATER STUDIES IN P53 HAPLOINSUFFICIENT MICE: Groups of 15 male and 15 female p53 haploinsufficient mice were exposed to drinking water containing 0, 175, 350, or 700 mg/L bromodichloromethane for 26 weeks (equivalent to average daily doses of approximately 16, 31, or 65 mg/kg to males and 26, 50, or 100 mg/kg to females). The survival of exposed males and females was similar to that of the control groups. Mean body weights of 350 and 700 mg/L males were less than those of the controls throughout most of the study. Mean body weights of 175, 350, and 700 mg/L females were less than control body weights after weeks 15, 23, and 18, respectively. In exposed males, water consumption declined with increasing exposure concentration. Water consumption by exposed females was similar to that by controls by the end of the study. The absolute heart weight of 700 mg/L males and absolute right kidney and liver weights of 350 and 700 mg/L males were significantly less than those of the control group. The incidences of renal tubule dilatation in all exposed groups of males, renal tubule degeneration in 350 and 700 mg/L males, and the incidence of fatty change in hepatocytes of 700 mg/L females were significantly greater than those in the control groups. Groups of 10 male and 10 female p53 haploinsufficient mice were exposed to drinking water containing 0, 175, 350, or 700 mg/L for 42 weeks (equivalent to approximately 14, 30, or 55 mg/kg to males and 22, 43, or 98 mg/kg to females). The survival of exposed males and females was similar to that in the control groups. Mean body weights of males exposed to 350 or 700 mg/L were less than those of the controls. Mean body weights in 700 mg/L females were less during the last three weeks of the study. Water consumption by exposed males was less than that by controls. The absolute right kidney weights in 350 and 700 mg/L males were significantly less than those of the control group. The incidences of renal tubule degeneration in 350 and 700 mg/L males were significantly greater than that in the control group. 26- AND 41-WEEK GAVAGE STUDIES IN P53 HAPLOINSUFFICIENT MICE: Groups of 15 male and 15 female p53 haploinsufficient mice were administered 0, 25, 50, or 100 mg bromodichloromethane/kg body weight in corn oil by gavage for 26 weeks. The survival of dosed males and females was similar to that of the vehicle control groups. The mean body weights of males administered 50 or 100 mg/kg and females administered 50 mg/kg were less than those of the vehicle controls during most of the study. The absolute heart, right kidney, and right testis weights in 100 mg/kg males were significantly less than those of the vehicle controls. The absolute liver weight of 100 mg/kg females was significantly greater. The incidences of fatty change in hepatocytes of 100 mg/kg females and renal tubule degeneration in 100 mg/kg males were significantly greater than those in the vehicle control groups. Groups of 10 male and 10 female p53 haploinsufficient mice were administered 0, 25, 50, or 100 mg/kg in corn oil by gavage for 41 weeks. The survival of dosed males and females was similar to that of the vehicle control groups. Mean body weights of 50 and 100 mg/kg males were less than those of the vehicle controls throughout the study and those of 25, 50, and 100 mg/kg females were less after weeks 9, 14, and 24, respectively. The absolute liver weight of 100 mg/kg females was increased with respect to the vehicle controls, and the absolute heart and right kidney weights of 100 mg/kg males were decreased. The incidences of hepatocyte fatty change in 100 mg/kg males and females and renal tubule degeneration and nephropathy in 100 mg/kg males were significantly greater than those in the vehicle controls. GENETIC TOXICOLOGY: Peripheral blood micronucleus tests on male and female Tg.AC hemizygous and p53 haploinsufficient mice exposed to bromodichloromethane in drinking water, by dermal application, and by gavage for 26 weeks yielded mixed results but no clearly positive responses. Results in Tg.AC hemizygous mice were judged to be equivocal for both males and females in the drinking water study, equivocal in males and negative in females treated by dermal application, and negative in males and females treated by gavage. (ABSTRACT TRUNCATED)     

Low levels of chromosomal mutations in germ cells derived from doxorubicin-treated stem spermatogonia in the mouse

The mutagenic effects of doxorubicin (Adriamycin, ADR) on mouse spermatogonial stem cells were examined by analysis of spermatocyte chromosomes and of dominant lethality transmitted through the spermatozoa. The effects of ADR on mutations, cytotoxicity, and sperm head abnormalities were compared with those of radiation. The cytotoxic effect of 6 Gy of gamma-radiation on stem spermatogonia was equivalent to about 4-5 mg ADR/kg. Chromosomal translocations were observed in 0.6% of the spermatocytes of mice treated with ADR (2-6 mg/kg). In contrast, 6 Gy of radiation induced translocations in 11.1% of spermatocytes. No increase in dominant lethality was observed after treatment with ADR at doses up to 6 mg/kg, while the frequency after 6 Gy of radiation was 3.6%. Based on these results, ADR would be expected to be only a weak inducer of balanced chromosomal rearrangements. Because ADR at 4.5 mg/kg was much weaker than 6 Gy of gamma-radiation at inducing chromosomal translocations, but just as effective at inducing sperm head abnormalities, the level of sperm head abnormalities is not indicative of balanced chromosomal rearrangements induced in stem spermatogonia by cytotoxic agents.     

Genotoxic effect of smoke-dried meat extract in Swiss albino mice using sperm head shape abnormality test.

The genotoxic effect of an extract of smoke-dried meat was assayed by employing in vivo sperm head shape abnormality. A significant dose responsive mutagenic effect was observed using the sperm head shape abnormality test. The result indicates that higher doses i.e., 100 and 200 mg/kg body wt. of smoke meat extract, significantly induced sperm head shape abnormality as compared to lower doses i.e., 20 mg/kg body wt. and control.     

Lack of promotion of estrogen-dependent mammary gland tumors in vivo by an isopropanolic Cimicifuga racemosa extract

Cimicifuga racemosa (CR) is widely used in the treatment of menopausal symptoms. Mechanistic studies suggest that unlike hormone-replacement therapy, CR does not stimulate estrogen-receptor positive breast cancer cells. To evaluate CR safety, we performed an in vivo investigation of a clinically tested isopropanolic CR extract. Mammary tumors were induced in Sprague Dawley rats (n = 75) by the application of 7,12-dimethylbenz[a]anthracene. Five to nine weeks later, the animals were ovariectomized, allowed to recover, and administered daily doses of CR extract (0.714, 7.14, or 71.4 mg/kg body weight per day) or control substances (estrogen/positive control: 450 microg/kg/day mestranol; or CR vehicle/negative control). The animals were sacrificed 6 weeks later, and tumor number, size, plasma hormone levels, and the weight of estrogen-sensitive organs were analyzed. In contrast to mestranol treatment, CR treatment did not stimulate cancerous growth. There were no significant differences in tumor number or size between the CR groups and the vehicle control. Likewise, prolactin, follicle-stimulating hormone, and luteinizing hormone levels and organ weights and endometrial proliferation were unaffected. The lack of mammary tumor-stimulating effects of this extract is of great significance in establishing the safety of CR extracts for treatment of menopausal symptoms in women with a history of breast cancer in which hormone-replacement therapy is contraindicated.     

Pancreatic islet-cell and other tumors in rats given heliotrine, a monoester pyrrolizidine alkaloid, and nicotinamide.

Three rats of six males, surviving 22 to 27.5 months after one or two intragastric doses of the monoester pyrrolizidine alkaloid, heliotrine (230 mg/kg body weight), and pretreatment with nicotinamide (350 mg/kg body weight) by pretreatment with nicotinamide (350 mg/kg body weight) by i.p. injections, developed pancreatic islet-cell tumors, accompanied in one of the rats by transitory cell papillomas of the urinary bladder and interstitial testicular tumors and in another by a hepatoma. The lesions in the livers showed progression from megalocytosis, to microscopic hepatocellular hyperplasia, to increasingly larger nodules and hepatoma. One rat, given heliotrine, but no nicotinamide, also developed adenoma of the pancreatic islet cells. Adenomas of the pituitary were present among the experimental and also among the control rats killed between 19 and 27.5 months after the beginning of the experiment, and they are not likely to have been caused by the alkaloid. Heliotrine, in which the crucial double bond in the pyrrolizidine moiety is sterically hindered, appears to be less readily sequestered by the liver and also to affect other organs. Alkylation of nicotinamide at the N-1 position prevents its being reused for coenzyme biosynthesis. Hence, pretreatment of rats with large doses of nicotinamide prevents the depletion of nicotinamide adenine dinucleotide coenzymes and liver necrosis in rats given heliotrine (230 mg/kg body weight).     

Study on the long-term toxic efficacy of cytosine-arabinoside in Sprague-Dawley rats

This study describes the development of neoplasms and the suppression of bone marrow stem cells following chronic administration of cytosine-arabinoside (ara-C) in Sprague-Dawley rats. Ara-C was administered i.p. either at daily dosages of 5 mg/kg and 25 mg/kg or at pulse doses of three times 500 mg/kg within 1 week followed by a time interval of 11 weeks. The total doses of the higher daily dose and of the pulse dose were chosen to be equally high. No significant carcinogenic activity of ara-C could be assessed following either of these dose schedules. With regard to general toxicity, as expressed by body weight gain and long-term bone marrow toxicity, high pulse doses of ara-C were better or at least equally tolerated as were the equivalent daily low doses.     

Enhancing Effect of Cadmium on Rat Ventral Prostate Carcinogenesis Induced by 3,2'-Dimethyl-4-aminobiphenyl

The effects of cadmium given at different stages during 3,2'-dimethyl-4-aminobiphenyl (DMAB)-induced rat prostate carcinogenesis were investigated using male F344 rats. Animals were given 10 subcutaneous injections of 50 mg/kg body weight of DMAB or the corn oil vehicle at two-week intervals. In addition, cadmium was administered at doses of 0, 10, or 30 /μmol/kg body weight as single intramuscular injection on the 1st day of the experiment or one day after the last injection of DMAB at week 20. Two further groups were subjected to administration of cadmium at 10 μmol/kg at week 20 and then 5 μmol/kg at week 40, or 10 μmol/kg at week 20 and then 5 μmol/kg at weeks 30, 40 and 50. At the termination, 60 weeks after the beginning of the experiment, the incidences and multiplicity of ventral prostate carcinomas in the groups given cadmium plus DMAB demonstrated a consistent tendency for increase over control values (groups receiving DMAB or cadmium alone). The numbers of carcinomas per rat and per unit area of prostate section were significantly elevated in the two groups given low doses of cadmium after cessation of DMAB administration. Cadmium alone also induced a few prostate carcinomas. The influence on development of prostate tumors did not appear to be a result of the induced severe testicular atrophy because serum testosterone levels were not affected. The results indicate that cadmium and DMAB can act synergistically to cause rat prostate carcinogenesis.     

Doxorubicin and CCNU with or without vincristine in patients with advanced refractory breast cancer. A randomized trial

Cyclophosphamide (CP) was administered orally at a dose of 2.5 mg/kg body weight five times a week to 300 male Sprague-Dawley rats in a carcinogenicity experiment. Four groups of 50 rats were treated with two different doses of sodium 2-mercaptoethane sulfonate (mesna, Uromitexan) (single doses of 5 or 15 mg/kg body weight), or disodium 2,2'-dithio-bis-ethane sulfonate (dimesna) (single doses of 12 or 35 mg/kg body weight), and the effect on carcinogenicity by cyclophosphamide was investigated. Two groups received mesna or dimesna only, and one additional group of 100 rats served as an untreated control. Evaluation of the study after 20 months proved CP to be carcinogenic, the induced neoplasms being in a variety of organs including tumors of the urinary bladder in 30% of the rats. The additional administration of mesna and dimesna significantly reduced the bladder tumor risk, this reduction being dose-related. In the 100 rats treated with mesna or dimesna only, no evidence of a carcinogenic response or signs of other toxic effects were observed.     

NTP toxicity studies of toxicity studies of 2,4-decadienal (CAS No. 25152-84-5) administered by gavage to F344/N Rats and B6C3F1 mice

2,4-Decadienal is used as a synthetic flavoring and fragrance material and has been evaluated as a corrosion inhibitor for steel in oil field operations. 2,4-Decadienal was nominated by the National Cancer Institute for toxicity testing because the dienaldehydes occur naturally in a variety of foods and food components, are used as food additive/flavoring agents, and the potential for human exposure is high. In the toxicity studies, male and female F344/N rats and B6C3F1 mice received 2,4-decadienal (at least 93% pure) in corn oil by gavage for 2 weeks or 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. In the 2-week studies, groups of five male and five female rats and mice received 2,4-decadienal in corn oil by gavage at doses of 0, 45, 133, 400, 1,200, or 3,600 mg 2,4-decadienal/kg body weight 5 days per week for 16 days. All animals in the 3,600 mg/kg groups were found dead or sacrificed moribund by day 3 (rats) or day 9 (mice). One 133 mg/kg female rat was found dead on day 8, and one male and one female mouse in the 1,200 mg/kg groups were found dead on days 12 and 16, respectively. At 1,200 mg/kg, treatment-related ulceration of the forestomach was observed in male and female rats and mice. Focal necrosis of the forestomach occurred in a 1,200 mg/kg female mouse. Mean body weights of all 1,200 mg/kg groups were less than those of the vehicle controls, and 1,200 mg/kg female mice lost weight during the study. Diarrhea, lethargy, abnormal breathing (rats), and thinness (mice) occurred in the 1,200 and 3,600 mg/kg groups. Gross lesions seen at necropsy included ulcerations of the forestomach in 1,200 mg/kg rats and 1,200 and 3,600 mg/kg mice. Adhesions involving the stomach and other abdominal organs were also seen in 1,200 and 3,600 mg/kg mice. In the 3-month studies, groups of 10 male and 10 female rats and mice received 2,4-decadienal in corn oil by gavage at doses of 0, 50, 100, 200, 400, or 800 mg 2,4-decadienal/kg 5 days per week for 14 weeks. No chemical-related deaths occurred. Mean body weights of 400 mg/kg male rats and 800 mg/kg male and female rats and male mice were significantly less than those of the vehicle controls. Dosed male and female rats were lethargic after week 7; the severity of the lethargy was dose related. There were changes in the leukon of dosed rats compared to vehicle control rats characterized by decreased leukocyte, lymphocyte, and eosinophil counts and increased neutrophil counts. Spleen weights of 800 mg/kg female rats and thymus weights of 400 and 800 mg/kg female rats were significantly less than those of the vehicle controls. Thymus, spleen, testis, cauda epididymis, and epididymis weights of 800 mg/kg male rats were less than those of the vehicle controls. The incidences of epithelial hyperplasia of the forestomach were significantly greater in 400 and 800 mg/kg male and female rats, 200, 400, and 800 mg/kg male mice, and 800 mg/kg female mice than in the vehicle controls. Incidences of epithelial degeneration of the forestomach were significantly increased in 800 mg/kg rats and the incidence of chronic active inflammation of the forestomach was significantly increased in 800 mg/kg female rats. Incidences of exudate and olfactory epithelial atrophy of the nose were significantly increased in 800 mg/kg male rats, and incidences of olfactory epithelial necrosis occurred in 200 mg/kg or greater mice. Olfactory epithelial hydropic degeneration occurred in a single female mouse from the 100 mg/kg group. 2,4-Decadienal was not mutagenic in any of several strains of S. typhimurium tested with and without liver S9 activation enzymes. Acute bone marrow micronucleus tests in laboratory rodents administered 2,4-decadienal by intraperitoneal injection yielded mixed results. In male rats, a single injection of 2,4-decadienal gave a positive response, but no confirmatory trial was conducted. In male mice, a standard three-injection bone marrow micronucleus experiment yielded negative results but a 48-hour bone marrow analysis after a single dose of 600 mg/kg revealed a small but statistically significant increase in micronucleated polychromatic erythrocytes. Analysis of peripheral blood erythrocytes in these same mice also showed a dose-related increase in micronucleated polychromatic cells, but the increase was insufficient for a positive call and the results of the acute micronucleus assays in mice were judged to be equivocal overall. No increase in the frequency of micronucleated normochromatic erythrocytes was seen in peripheral blood of male or female mice administered 2,4-decadienal by gavage for 3 months. In summary, 2,4-decadienal administration caused decreased body weights and increased incidences of forestomach lesions in the 3-month studies in rats and mice. In addition, treatment-related lesions of the olfactory epithelium were observed in male rats and male and female mice. The no-observed-adverse-effect level was determined to be 100 mg/kg in rats and mice. 2,4-Decadienal was not mutagenic in vitro or in vivo. Synonyms: 2,4-De; deca-2,4-dienal; trans,trans-2,4-decadienal; trans,trans-2,4-decadien-1-al; heptenyl acrolein; RIFM#77-102.     

小球藻片对大鼠的致畸试验

目的：评价小球藻片是否对SD大鼠具有致畸毒性,对其安全性进行毒理学评价。方法：孕鼠按体质量随机分为小球藻片低、中、高剂量组（分别为1 875、3 750、7 500 mg/kg,相当于人服用量的12.5、25、50倍）,阳性对照组（300 mg/kg阿司匹林）和阴性对照组（等体积纯净水）。于孕期7~16 d灌胃给予受试物,试验期间称量孕鼠体质量,第20天处死。剖腹检查子宫连胚胎质量、着床数、活胎数、死胎数、吸收胎数、胎质量和体长、胎仔雌雄比例、胎仔外观、骨骼和内脏发育情况。结果：阳性对照组大鼠具有明显的母体毒性、胚胎毒性和致畸毒性。低、中、高剂量组小球藻片无母体毒性、胚胎毒性和致畸毒性。高剂量组出现少数胎仔外观畸形和骨骼畸形,畸形率与阴性对照组比较差异无统计学意义（P > 0.05）。结论：在本实验条件下,小球藻片对SD大鼠无母体毒性、胚胎毒性和致畸毒性。     

Clastogenic effects induced in mice and rats by 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene, a phenobarbital-like enzyme inducer and liver tumour promoter

The clastogenic activity of l,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP), a phenobarbital-like enzyme inducer and livertumour promoter, was studied in mammalian cells exposed in vivoand in vitro. The effects of an oral treatment with 3 mg/kgbody weight of TCPOBOP were scored in the bone marrow cellsand in the liver cells of B6C3F₁ hybrid mice. A relevant increasein the frequency of chromosomal aberrations was observed inboth cell types. A co-administration of TCPOBOP and carbon tetrachloride(the latter given to stimulate liver cell divisions) producedsimilar effects to those induced by TCPOBOP alone. Several i.p.doses (1, 3, 10, 30 or 100 mg/kg body weight) were administeredto Swiss-albino mice and to Sprague - Dawley rats. In bone marrowcells, a remarkable concordance between the two species wasobserved: at any dose higher than 3 mg/kg body weight the increasein frequency of chromosomal aberrations was more than threetimes the control level, with a slight decrease at the highestdose. A dose of 300 mg/kg body weight was lethal. Doses of 3or 30 mg/kg body weight were also administered i.p. to partiallyhepatectomized rats and the effects on metaphase chromosomeswere detected in the liver cells. Besides an increase in structuralchromosomal aberration frequency, TCPOBOP induced high percentagesof hypodiploid and hyperdiploid-hypotetraploid liver cells.Since no changes in euploidy were observed in the bone marrowcells, this effect seems to be tissue specific. The clastogenicactivity of TCPOBOP was also confirmed in vitro by a rat lymphocyteassay without addition of any exogenous metabolic activation.     

Tannic acid raises survival rate of mice bearing syngeneic tumors

Tannic acid which was found earlier to have growth suppressive activity against cultured tumor cells, was given to Balb/c mice p.o. The mice had been inoculated with syngeneic tumor cells (Meth/A) i.p. When tannic acid was suspended in drinking water and given daily at doses of approximately 875 mg/kg/day and 1750 mg/kg/day, the respective survival rates were 59% and 48%, with that of the control mice being 29%. To study the cytotoxicity of tannic acid, we administered the tannic acid to mice at 875 and 1750 mg/kg/day for 35 days. The weight gain for each dose was lower than that of the control, although the difference was not significant. When tannic acid was given at 8750 mg/kg/day, the weight gain was significantly lower than the control. A histologic study did not show any pathological findings in the kidney, liver, or lungs in the mice given tannic acid at the above doses.     

A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours

Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m(-2)) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m(-2)) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m(-2) in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m(-2) in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug-drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m(-2) and 420 mg pertuzumab following a loading dose of 840 mg.     

Antiemetic efficacy of moderately high-dose metoclopramide in patients receiving varying doses of cisplatin. Controlled comparison with a combination of methylprednisolone and metoclopramide

In 29 patients (48 courses of chemotherapy), a randomized double-blind crossover study was undertaken to establish the antiemetic effectiveness of a combination of metoclopramide at a moderately high dose (5 mg/kg body weight) with 1 g methylprednisolone (treatment A) as compared with metoclopramide monotherapy (5 mg/kg body weight; treatment B). With cisplatin doses of 60 mg/m2, a good antiemetic effect (0-1 vomiting episodes in 24 h) was observed in 9 out of 10 patients under treatment A as well as under treatment B. With a cisplatin dose of 120 mg/m2, treatment A produced a good antiemetic effect in 9 out of 11 patients (82%), while treatment B produced such an effect in only 3 out of 11 patients (27%; p less than 0.5). The results obtained permit the following conclusions to be made: At doses of cisplatin of up to 60 mg/m2, the antiemetic effect produced by metoclopramide (5 mg/kg body weight) given alone is adequate. At doses of cisplatin of 120 mg/m2 and more, high-dose methylprednisolone has a good additive antiemetic effect vis-à-vis metoclopramide (5 mg/kg body weight). The antiemetic effect of this combination corresponds approximately to the antiemetic effect produced with high-dose metoclopramide (10 mg/kg body weight) administered alone.     

司丙红毒素对大鼠致畸性研究

背景与目的观察司丙红霉素对大鼠的致畸毒性。材料与方法应用SD大鼠进行致畸毒性研究,以75,200和400mg/kg3个剂量组给药,并设阴性对照组(0.5%羧甲基纤维素纳)及阳性对照组(水杨酸钠)给药时间为大鼠妊娠后第6~15d。结果200和400mg/kg组妊娠大鼠在给药后出现厌食、活动减少,对妊娠大鼠各期体重增长值进行t检验,显示200、400mg/kg组大鼠妊娠10~13d时体重增长值明显低于阴性对照组,停药后体重增长正常;各剂量组妊娠大鼠生育能力与阴性对照组比较无差异;各剂量组与阴性对照组胎仔的外观未见畸形,胎仔的身长、尾长经t检验,差异无统计学意义。胎仔骨骼、内脏发育未见异常。结论中、高剂量组对妊娠大鼠有母体毒性,表现为体重下降、厌食,但无胚胎毒和致畸作用。     

Effect of thymidine on the toxicity and antitumor activity of Cis-diamminedichloroplatinum (II)

Summary The effect of thymidine (TdR) on the preclinical toxicity of cis-diamminedichloroplatinum (II) (DDP) was investigated in the BDF₁ mouse and the Sprague-Dawley rat. The effect of TdR on the antitumor activity of DDP was investigated using the ascites P388 murine leukemia model. TdR at 500 mg/kg consistently decreased the recovery of body weight after DDP treatment IP, but did not affect the lethal toxicity of DDP to non-tumor-bearing mice or those with the P388 murine leukemia. This effect was greatest when TdR was injected 30 min prior to DDP and at higher doses of DDP. A500-mg/kg dose of TdR did not affect the antitumor activity of DDP 5 mg/kg administered on days 1, 5, and 9. Treatment of rats with TdR 500 mg/kg according to various schedules of timing relative to a 5-mg/kg dose of DDP did not consistently affect the DDP-related loss in body weight or nephrotoxicity at day 3. Pretreatment of mice with TdR 1,500 mg/kg 30 min prior to DDP 5 mg/kg (every 4 daysx3) resulted in a slower recovery of body weight, which became more pronounced with increasing doses of DDP. Pretreatment of ascites P388-bearing mice with TdR 1,500 mg/kg increased the number of early deaths when mice were treated with DDP 5 mg/kg (days 1, 5, and 9). These data suggest that the cytotoxicity of DDP is increased by TdR only at higher doses of either drug, but that the antitumor activity against P388 murine leukemia is not affected.     

钼对大鼠致畸和致突变作用的研究

背景与目的:研究钼对大鼠胚胎的致畸和致突变作用.材料与方法:105只妊娠Wistar大鼠,用75只进行致畸试验,30只进行微核试验,各试验随机分为5组,试验组分别给予10、20和40 mg/kg的钼酸铵,阴性对照组给予生理盐水,阳性对照组给予20mg/kg的环磷酰胺.致畸试验于孕20 d用传统胚胎致畸试验测定钼对大鼠的致畸作用,致突变试验于孕14 d用胚胎转移微核试验测定钼对大鼠的致突变作用.结果:与阴性对照组相比,40 mg/kg组和阳性对照组孕鼠增重、活胎率、胎鼠体重降低(P＜0.01);母鼠骨髓细胞的微核率、胎鼠肝血细胞和胎鼠外周血细胞的微核率、骨骼畸形率和内脏畸形率升高(P＜0.01),胎鼠的体长、尾长缩短(P＜0.05),外部畸形率增加(P＜0.05);20 mg/kg组活胎率降低(P＜0.05),胎鼠肝血细胞和外周血细胞的微核率、外部畸形率和骨骼畸形率升高(P＜0.05);10 mg/kg组胎鼠外部畸形率升高(P＜0.05).结论:钼酸铵在20～40 mg/kg剂量范围内对大鼠胚胎可产生致畸和致突变作用.     

Various sodium salts, potassium salts, a calcium salt and an ammonium salt induced ornithine decarboxylase and stimulated DNA synthesis in rat stomach mucosa

Studies were made on the possible tumor-promoting activities of various salts of food additives in the glandular stomach mucosa of F344 male rats after their administration by gastric intubation. Up to 100-fold increases in ornithine decarboxylase (ODC) activity in the pyloric mucosa of the stomach with maxima after 8 h were observed after administration of sodium acetate at doses of 3.68-13.6 mmol/kg body weight, sodium L-ascorbate at doses of 8.55-17.1 mmol/kg body weight, Na2CO3 at doses of 4.73-14.2 mmol/kg body weight, sodium L-glutamate at doses of 12.8-17.1 mmol/kg body weight, sodium sorbate at doses of 8.92-17.1 mmol/kg body weight and (NH4)2SO4 at doses of 7.56-20.1 mmol/kg body weight. Increases of up to 100-fold in ODC activity with maxima after 16 h were also observed after intubation of KCl at doses of 10.1-22.0 mmol/kg body weight, K2SO3 at doses of 2.84-8.45 mmol/kg body weight, K2S2O5 at doses of 2.25-6.75 mmol/kg body weight and CaCl2 at doses of 2.0-4.08 mmol/kg body weight. Sodium acetate at a dose of 11.0 mmol/kg body weight, KCl at a dose of 20.1 mmol/kg body weight, K2S2O5 at a dose of 5.40 mmol/kg body weight and CaCl2 at a dose of 3.4 mmol/kg body weight induced up to 10-fold increase in DNA synthesis in the pyloric mucosa of the stomach with maxima after 16-24 h. These results suggest that these salts of food additives may, like NaCl, have tumor-promoting activities in the pyloric mucosa of rat stomach.