β_胡萝卜素对丝裂霉素C致小鼠骨髓细胞遗传损伤的保护作用

背景与目的： 探讨β_胡萝卜素(β_carotene,βC)对丝裂霉素C(mitomycin_C,MMC)诱导的小鼠骨髓细胞遗传损伤的保护作用。 材料与方法： 分别用3 mg/kg和30 mg/kg的βC连续饲喂小鼠8 d后,以2 mg/kg MMC进行腹腔注射染毒,另设阳性对照组(用生理盐水)和阳性对照组(一次性腹腔注射MMC 2 mg/kg)。各组于末次给药后12、24 h处死小鼠,分别采用单细胞凝胶电泳技术和染色体畸变分析检测骨髓细胞DNA损伤及染色体畸变情况。 结果： 两个不同剂量的βC与MMC联合作用组小鼠骨髓细胞拖尾率、平均尾长及染色体畸变率均低于阳性对照组(单独MMC),但均高于阴性对照组,差异均有统计学意义(P<0.01)。 结论： βC对MMC诱导的小鼠骨髓细胞遗传损伤有明显的保护作用,但在实验所给剂量范围内(3～30 mg/kg)并不能完全抑制MMC所造成的遗传损伤。     

β—胡萝卜素对荷瘤小鼠腹腔巨噬细胞吞噬功能和自然杀伤细胞活性的影响

作者以正常的或荷瘤的(荷实体型ERLICH乳腺癌)ICR系小鼠的腹腔巨噬细胞(简称Mφ)和脾脏组织为材料,观察了β-胡萝卜素对小鼠Mφ功能和自然杀伤(NK)细胞活性的影响。结果表明:β-胡萝卜素(15mg/kg,po d_(1-15)),对正常小鼠Mφ功能和NK细胞活性影响不明显(P>0.05)。但给予β-胡萝卜素(15mg/kg po d_(1-22)),能提高荷瘤小鼠Mφ的吞噬功能(P<0.05)和NK细胞活性(P<0.01),并能对抗环磷酰胺的免疫抑制作用,与单用环磷酰胺的小鼠比较,有显著的差异(P<0.05)。     

导向逆转剂Ab-IL2体外偶联以及协同抑瘤作用的研究

探讨利用乳腺癌单克隆抗体作为导向载体,将逆转剂IL2特异性地导向肿瘤细胞,使其发挥逆转作用的临床应用价值,为将此方法用于肿瘤的临床治疗提供医学依据。方法:分别制备人基因重组白细胞介素2（IL-2）以及人乳腺癌单克隆抗体（记为Ab）,将其经过体外的偶联与纯化,并对偶联产物进行严格的质量检测,最终得到导向多药耐药（MDR）逆转剂Ab-IL2,并通过体外MDR逆转作用检测其活性保留。将对阿霉素（ADM）耐药的人乳腺癌细胞系MCF-7/ADM,种植于BALB/c裸鼠皮下,每只小鼠注射量为106个细胞,将得到的荷瘤小鼠分为三组,并于接种后的第14,19天分别进行如下处理:1）对照组:腹腔注射生理盐水;2）ADM组:腹腔注射阿霉素（1 mg/kg体重）;3）协同用药组:同时注射阿霉素（1 mg/kg体重）和前述实验获得的多药耐药逆转剂Ab-IL2（1 mg/kg体重）。分别于14、16、18、20天测量肿瘤大小,并于第20天处死小鼠,取出瘤块并称重,据此计算肿瘤抑瘤率。结果:Ab-IL2的质量合格,活性保留为90.7%。多药耐药逆转剂Ab-IL2与阿霉素联合应用显示出体内协同抑瘤作用,至第20天处死小鼠时,协同用药组的抑瘤率为60.48%,是ADM组（抑瘤率19.44%）的3.11倍。结论:将单克隆抗体介导技术应用于肿瘤MDR导向逆转,可以促进逆转剂有效地发挥其应有的作用,本研究为实现临床上MDR逆转剂的成功应用提供了有力保证。      

β-胡萝卜素对丝裂霉素C诱导的小鼠DNA损伤的保护作用

目的:研究β-胡萝卜素(βC)和维生素E(V-E)对丝裂霉素C(MMC)诱导的小鼠DNA损伤的保护作用.方法:选择雄性昆明种小鼠48只,随机分4组,其中正常对照(A)分别喂予基础饲料和阳性对照组(B),另外2组分别喂含V-E(200 mg/kg·bw)的基础饲料(C组)和含天然β-胡萝卜素晶体(200 mg/kg*bw)的基础饲料(D组).喂养4周后,除A组外,间隔24 h按1 mg/kg*bw腹腔注射MMC(A组注射同等剂量的生理盐水).12 h后,处死小鼠,无菌条件下取出脾脏、胸骨,观察小鼠脾细胞双链DNA剩余率和骨髓嗜多染红细胞微核发生率.结果:A、B、C、D组脾细胞双链DNA剩余率(%)分别为66.44±5.97,43.06±5.95,58.69±8.28,63.26±7.95,B组明显低于A、C、D组(P＜0.01);A、B、C、D组小鼠骨髓嗜多染红细胞微核发生率(‰)分别为1.87±0.83,31.00±6.32,17.37±2.88,15.25±4.68,B组明显高于A、C、D 3组(P＜0.01).结论:βC和V-E可抑制MMC诱导小鼠脾细胞DNA断裂和骨髓细胞微核发生的作用.     

几种抗致癌物对环磷酰胺致小鼠骨髓微核的影响

本文报告几种抗致癌物[维生素A酸(RA)、二丁基烃基甲苯(BHT)、β-萘黄酮(βNF)及亚硒酸钠(Na_2SeO_3)]对环磷酰胺(CP)致C57小鼠骨髓微核的影响及可能的机理。RA150mg/kg灌胃4天、BHT600mg/kg灌胃4天、βNF80mg/kg灌胃2天和Na_2SeO_320ppm饮水7天可抑制CP(30mg/kg腹腔注射一次)致小鼠骨髓多染红细胞微核率分别至CP对照组的70.7％、13.8％、67.5％及     

三氧化二砷治疗Scid小鼠鼻咽癌移植瘤的初步实验研究

目的 :研究三氧化二砷 (As2 O3)对人鼻咽癌小鼠移植瘤的抑制作用。方法 :以人鼻咽癌细胞株CSNE 1为研究对象 ,观察腹腔注射As2 O3对鼻咽癌在Scid小鼠体内生长的抑制作用及其毒副反应。结果 :As2 O3腹腔注射 1mg/kg和 5mg/kg均能在小鼠体内诱导鼻咽癌细胞凋亡。在 5mg/kg剂量组 ,凋亡诱导最明显且能诱导鼻咽癌细胞分化 ,并有显著的抑制肿瘤生长作用 ,抑瘤率为 70 %。上述剂量对小鼠外周血白细胞无抑制作用 ,但病理组织学检查显示对肝脏和心脏有轻度毒性。 10mg/kg迅速致实验鼠中毒死亡。结论 :砷剂在Scid小鼠体内治疗人鼻咽癌移植瘤有效 ,但存在最适剂量问题 ,诱导调亡和分化可能是其抑瘤机制     

海胆肠提取物的抗肿瘤作用

目的 :观察海胆肠提取物的抗肿瘤活性。方法 :体外采用四唑盐 (MTT)比色法测定药物对人胃腺癌 SGC- 790 1细胞的生长抑制率。体内采用 S1 80 移植性实体瘤和腹腔积液瘤小鼠模型 ,分别腹腔注射不同剂量的海胆肠提取物 ,连续给药 10天。计算抑瘤率和生命延长率。结果 :MTT实验显示 ,海胆肠提取物对体外培养的 SGC- 790 1细胞增殖有明显的抑制作用 ,且抑制程度与浓度呈正相关。 2 0 0 mg· kg- 1 · d- 1 提取物腹腔注射给药 ,对小鼠肉瘤 S1 80 实体瘤的生长抑制率为为 33.5 8%(与对照组相比差异有显著性 ,P<0 .0 1) ;对腹腔积液瘤小鼠的生命延长率为 76 .94% (与对照组相比差异有显著性 ,P<0 .0 1)。结论 :海胆肠提取物在体内和体外都有明显的抗肿瘤作用     

三氧化二砷治疗Scid小鼠鼻咽癌移植瘤的初步实验研究

目的：研究三氧化二砷（As2O3)对人鼻咽癌小鼠移植瘤的抑制作用。方法：以人鼻咽癌细胞株CSNE-1为研究对象，观察腹腔注射As2O3对鼻咽癌在Scid小鼠体内生长的抑制作用及其毒副反应。结果：As2O3腹腔注射1mg/kg和5mg/kg均能在小鼠体内诱导鼻咽癌细胞凋亡。在5mg/kg剂量组，凋亡诱导最明显且能诱导鼻咽癌细胞分化，并有显著的抑制肿瘤生长作用，抑瘤率为70%，上述剂量对小鼠外周血白细胞无抑制作用，但病理组织学检查显示对肝脏和心脏有轻度毒性，10mg/kg迅速致实验鼠中毒死亡。结论：砷剂在Scid小鼠体内治疗人鼻咽癌移植瘤有效，但存在最适剂量问题，诱导凋亡和分化可能是其抑瘤机制。     

真菌植物提取物AMH抑制苯并[a]芘诱发小鼠肿瘤作用

背景与目的:研究具有抗突变作用的真菌植物提取物AMH是否具有抑制化学致癌物苯并[a]芘(B[a]P)的致癌作用。材料与方法:采用B[a]P诱发小鼠肿瘤试验。ICR小鼠随机分为AMH(AntimutagenicHerb)预防组、B[a]P对照组和阴性对照组,共三组,预防组经水饮用AMH,1周后腹腔注射B[a]P100mg/kg,对照同时等量腹腔注射B(a)P,阴性对照组腹腔注射等体积玉米油,其后观察小鼠肿瘤发生情况。结果:腹腔注射B[a]P能诱发小鼠产生肝癌、胃癌、膀胱癌、腹壁肌肉瘤、肺腺瘤等各种实体瘤。真菌植物提取物AMH(AntimutagenicHerb)能显著性抑制苯并[a]芘对小鼠的诱发肿瘤作用。实验期间,AMH预防组14只雄性小鼠未发现肿瘤;而苯并[a]芘对照组14只雄性小鼠中11只出现实体瘤、3只出现血性腹水;AMH对苯并[a]芘诱发雄性小鼠肿瘤发生的抑制率达100%。AMH预防组雌性小鼠肺腺瘤发生率为71.43%,平均每只小鼠的荷瘤数为2.14个;苯并[a]芘对照组肺腺瘤发生率为92.86%,平均每只小鼠的荷瘤数为7.43个;两组间差异具有统计学意义(P<0.05)。结论:真菌植物提取物AMH能有效抑制强致癌物苯并[a]芘诱发小鼠肿瘤作用。     

松塔球提取物的抑突变性研究

目的：了解松塔球提取物的抑突变作用。方法：不同剂量（50、250和500mg/kg）的松塔球碱性提取物溶液与环磷酰胺（50mg/kg）联用,连续4d腹腔注射昆明小鼠,取骨髓制片,计数含微核的骨骼嗜多染红细胞。结果：50mg/kg松塔球提取物溶液和环磷酰胺联用时与环磷酰胺组比较微核率差异无统计学意义（P〉0.05）;松塔球提取物250和500mg/kg剂量与环磷酰胺联用组微核率明显低于环磷酰胺组（P〈0.05）,其微核抑制率分别为22.35%、65.35%。雌性和雄性小鼠组间微核率差异无统计学意义（P〉0.05）。结论：松塔球提取物可有效抑制环磷酰胺诱导的小鼠骨髓细胞微核的产生,并且存在明显的剂量-反应关系,具有抑突变性,提示松塔球提取物对肿瘤的防治可能具有积极的作用。     

The protective activity of ICRF-187 against doxorubicin-induced cardiotoxicity in the rat

Summary The protective activity of the bisdioxopiperazine ICRF-187 against the cardiotoxicity of doxorubicin was evaluated in the rat using both functional and histological assays. Animals that had received a single i. v. dose of doxorubicin (4 mg/kg) alone were compared with those that had been pretreated with a single i. v. injection of saline or ICRF-187 (40 or 60 mg/kg). All rats showed a transient reduction in body weight during the first 3 weeks after drug administration. The greatest reduction (16%) was observed in animals that had received a combination of ICRF-187 (40 or 60 mg/kg) and doxorubicin. Deaths related to cardiotoxicity were observed only in rats that had received doxorubicin alone and in those treated with saline; most of the deaths occurred at between 8 and 13 weeks after drug administration. Sequential assessments of heart function showed a persistent depression of cardiac output in animals that had received doxorubicin, with or without pretreatment with ICRF-187. The reduction in cardiac output observed in rats that had been pretreated with ICRF-187 (40 or 60 mg/kg) amounted to 15% and 30% after 12 and 20 weeks, respectively, indicating that cardioprotection was only partial. Nevertheless, this represented a marked improvement as compared with the 35% reduction in cardiac output measured at 12 weeks in animals that had received doxorubicin but without pretreatment with ICRF-187. Histological examination of animals that had died during the course of the study and had received doxorubicin after pretreatment with saline revealed severe myocardial lesions typical of doxorubicin-induced damage. In contrast, animals that had been pretreated with ICRF-187 and survived for up to 20 weeks after treatment showed a marked amelioration of these lesions. The present findings may be interpreted as a true cardioprotection or a delay in the onset of the cardiotoxicity of doxorubicin resulting from pretreatment with the bisdioxopiperazine ICRF-187. Although prior and ongoing clinical trials clearly indicate that ICRF-187 protects patients well against doxorubicin-induced heart damage, further investigations are required beforehigh doses of ICRF-187 can be used as a means of increasing the protective activity of this drug against doxorubicin-induced cardiotoxicity.This work was supported by the Cancer Research Campaign     

Comparison of the effectiveness of (+/-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) and N-acetylcysteine in preventing chronic doxorubicin cardiotoxicity in beagles

This investigation examined the potential of N-acetylcysteine (NAC) and ICRF-187, alone and in combination, to protect against chronic doxorubicin cardiotoxicity. Adult beagles of either sex (7.3 to 12.5 kg) were given doxorubicin (1.75 mg/kg i.v.) either alone or 30 min after either ICRF-187 (25 mg/kg i.p.), NAC (200 mg/kg i.p.), or ICRF-187 (25 mg/kg i.p.) and NAC (200 mg/kg i.p.) at 3-week intervals. Control dogs received ICRF-187 (25 mg/kg i.p.), NAC (200 mg/kg i.p.), ICRF-187 (25 mg/kg i.p.) and NAC (200 mg/kg i.p.), or 0.9% NaCl solution without doxorubicin. The experiment was terminated 3 weeks after the seventh injection (total doxorubicin dose, 12.25 mg/kg). Three animals pretreated with NAC and one pretreated with ICRF-187 before receiving doxorubicin died or were in poor condition and were killed before the end of the study. The frequency and extent of myocardial lesions (vacuolization and myofibrillar loss) were assessed on a scale of 0 to 4+. Such lesions were present in all six dogs given doxorubicin alone and were marked to severe (3+ to 4+) in five of these dogs and moderate (2+) in one. Lesions of comparable severity (2+ to 4+) were also apparent in the hearts of dogs given the combination of NAC and doxorubicin. In contrast, no abnormalities (lesion score 0) were found in the hearts of three of six dogs given doxorubicin and ICRF-187 and in four of six dogs given doxorubicin following the combination of ICRF-187 and NAC; the remaining animals in these two groups had minimal lesions. At the dosage regimen used in the present experiments, doxorubicin, NAC, or ICRF-187 alone or in combination did not cause alterations in lungs, liver, kidney, or small intestine. Decreases in WBC count, RBC count, and hemoglobin occurred in dogs given doxorubicin with or without the various pretreatments. Thus, pretreatment with ICRF-187 was effective and pretreatment with NAC was ineffective in reducing chronic doxorubicin cardiotoxicity.     

直流电结合阿霉素抑制小鼠S180实体瘤生长的实验研究

本文探讨了直流电(DC)结合阿霉素(ADM)时小鼠S_(180)实体瘤的抑制作用。ADM+DC组抑瘤率为56.79％;单用DC(3v,1h/d·3) 治疗抑瘤率为28.24％;单用ADM(5mg,kg~(-1)/d·3)抑瘤率为33.62％。ADM+DC组与DC组和ADM组相比较,P<0.05。静注等量阿霉素后最大血药浓度是电治疗时肿瘤局部注射阿霉素的2.12倍,曲线下峰面积是1、40倍,心脏最大浓度为3.56倍。本研究提示直流电和阿霉素有协同作用。在直流电治疗肿瘤时,肿瘤局部注射阿霉素不仅提高了肿瘤局部药浓度,而且较传统的静注降低了阿霉素副作用,尤其是心脏毒性。     

Reduction of chronic doxorubicin cardiotoxicity in beagle dogs by bis-morpholinomethyl derivative of razoxane (ICRF-159)

Summary Addition of morpholinomethyl substitutents to razoxane (ICRF-159) produced a compound (bis-4-morpholinomethyl-3,5-dioxopiperazinyl-1,2-propane (MM-159) considerably more water-soluble than razoxane. The increased solubility allowed MM-159 to be examined for protective activity against chronic doxorubicin (DXR) cardiotoxicity. Adult beagle dogs of either sex were given, i. v. at 3-week intervals, either DXR (1.75 mg/kg) alone or DXR 15 min after MM-159 (25 mg/kg). Control animals received MM-159 (25 mg/kg) or saline without DXR. The experiment was terminated 3 weeks after the ninth injection (total DXR dose, 15.75 mg/kg). Of the eight animals given DXR alone, five died after receiving seven to eight injections (12.25–14 mg/kg DXR) and the remaining three were killed after eight injections because they were in poor condition. Marked ascites was noted in four of these eight dogs. When frequency and extent of myocardial lesions (vacuolation and myofibrillar loss) were assessed on a scale from 0 to 4+, severe lesions (3+) were present in all eight dogs given DXR alone, but no abnormalities (lesion score 0) were found in the hearts of three of eight dogs given MM-159 and DXR and the five remaining animals in this group had minimal (1+; four dogs) or mild (2+; one dog) alterations. DXR reduced the erythrocyte count, hemoglobin, and hematocrit when administered alone, but not in combination with MM-159. Such protection against DXR hematologic effects was not noted previously [14] when dogs were pretreated with ICRF-187, the d-isomer of razoxane, despite the fact that pretreatment with ICRF-187 was as effective as MM-159 in reducing chronic DXR cardiotoxicity. It remains to be determined whether there are other differences in biological activity between MM-159 and ICRF-187.     

Evaluation of cisplatin combined with ondansetron in Ehrlich ascites carcinoma in vitro and in vivo

AIMS AND BACKGROUND: Nausea and vomiting occur in the majority of patients receiving cisplatin (CDDP) chemotherapy. Ondansetron, a new 5-HT3 receptor antagonist, has been used effectively to control CDDP-induced nausea and vomiting. This study examined the potential of ondansetron to interfere with CDDP antitumor activity and toxicity in Ehrlich ascites carcinoma (EAC). METHODS: The influence of ondansetron on CDDP cytotoxicity was evaluated using EAC cells in culture. In addition, the influence of ondansetron pretreatment on CDDP-induced antitumor activity and host tissue toxicity was studied in EAC-bearing mice. RESULTS: Ondansetron (0.25 microM) enhanced CDDP (0-32 microM) cytotoxicity against EAC cells in vitro. In EAC-bearing mice ondansetron (0.2 mg/kg,ip) administered 1 h before CDDP (7 mg/kg, ip) did not modify the antitumor activity of CDDP. CDDP (7 mg/kg, ip) single treatment induced significant increases in blood urea nitrogen (2-fold) and serum creatinine (2.5-fold) and significant decreases in hematocrit (25%) and white blood cell count (39%) compared to saline treatment. Mice receiving ondansetron 1 h before CDDP showed no significant enhancement of CDDP-induced nephrotoxicity or myelosuppression compared to those pretreated with saline receiving the same dose of CDDP. CONCLUSIONS: This study suggests that the use of ondansetron to control CDDP-induced nausea and vomiting does not affect CDDP antitumor efficacy.     

Modulatory effects of melatonin and vitamin E on doxorubicin-induced cardiotoxicity in Ehrlich ascites carcinoma-bearing mice

Doxorubicin (Dox), an anthracycline antibiotic, has a wide spectrum of antitumor activity with dose-limiting cardiotoxicity. The drug's toxicity is known to be closely related to the generation of active oxygen free radicals. In our study the normal cardiac tissue contents of total protein, glutathione (GSH) and malondialdehyde (MDA) were significantly decreased, by 25%, 33% and 92%, respectively, in the group of mice bearing Ehrlich ascites carcinoma (EAC) and treated with Dox (4 mg/kg/week x 2, ip). Administration of melatonin (5 mg/kg/day x 15, po) starting 24 hours prior to Dox treatment significantly increased the cardiac contents of total protein and GSH as well as the superoxide dismutase (SOD) activity, by 31%, 36% and 39%, respectively, compared to treatment with Dox only, while the content of MDA was decreased by 26%. Similarly, administration of vitamin E (250 mg/kg/day x 15, po) starting 24 hours prior to Dox treatment significantly increased the cardiac contents of total protein, GSH and SOD, by 23%, 26% and 42%, respectively, while the cardiac content of MDA was decreased by 35% compared with the Dox-only-treated group. As to the oncolytic activity of Dox, pretreatment of EAC-bearing mice with melatonin (5 mg/kg/day x 30, po) or vitamin E (250 mg/kg/day x 30, po) 24 hours prior to Dox administration (4 mg/kg/week x 4, ip) improved the antitumor activity of Dox as indicated by the increase in the average life span of the animals and the number of long-term survivors as well as the decrease in body weight loss induced by Dox treatment. It is clear from these results that administration of melatonin not only protects against the cardiotoxicity induced by Dox treatment but also enhances its antitumor activity to a more significant extent than does vitamin E.     

Effect of intraperitoneal chemotherapy on experimental peritoneal dissemination of gastric cancer

In vitro chemosensitivity test using a collagen-gel method was done on 165 primary gastric cancers. All of 5-FU, CBDCA, CDDP and docetaxel showed a high sensitivity. The effects of per oral (po) administration of TS-1, a combination of po TS-1 and intraperitoneal (ip) administration of CDDP, ip 5-FU and ip docetaxel, were evaluated in athymic mice bearing peritoneal dissemination of a gastric cancer cell line (MKN-45-P that shows a high rate of metastasis to the peritoneal cavity of nude mice). Nude mice were inoculated by ip with 10(7) MKN-45-P cells. No survival benefit was obtained after po administration of TS-1 (12 mg/kg) alone or ip CDDP alone. However, a combination of po TS-1 (8 mg/kg x 10 days, from day 3) and ip CDDP (3.5 mg/kg, day 6 and 13) showed a significant survival improvement than that of po TS-1 or ip CDDP treatment alone. ip administration of 30 mg/kg (3 times/week x 3 weeks) or 15 mg/kg (6 times/week x 3 weeks) of 5-FU significantly improved the survival of mice bearing MKN-45-P. 5-FU concentration of ascites after ip administration of 30 mg/kg of 5-FU was 600-fold higher than po administration of 12 mg/kg of TS-1 at peak level. ip injections of docetaxel of 8 mg/kg, and 2 mg/kg improved the survival of 4 and 1 mice, respectively, and they were tumor-free on day 90. Survival of mice treated with ip injection of CBDCA (100 mg/kg, on day 3, or 50 mg/ kg on day 3 and 10) was significantly better than the control group. These results suggest the potential of po TS-1 + ip CDDP, ip 5-FU, ip docetaxel and ip CBDCA administration for the treatment of peritoneal dissemination of gastric cancer.     

Effects of ICRF-187 on the cardiac and renal toxicity of epirubicin in spontaneously hypertensive rats

Summary A study was made of the protective effect of ICRF-187 against the cardiotoxicity and nephrotoxicity produced by epirubicin in spontaneously hypertensive rats (SHR). A total of 20 SHR were divided into 4 groups of 5 animals; the first group received i.v. injections of 1.5 mg/kg epirubicin; the second was treated with i.p. injections of 50 mg/kg ICRF-187 30 min before receiving 1.5 mg/kg epirubicin; the two remaining groups received ICRF-187 and saline, respectively, and served as controls. The experiment was terminated after 12 weekly injections (total cumulative dose of epirubicin, 18 mg/kg). Morphologic studies showed that severe cardiomyopathy manifested by myofibrillar loss and dilatation of the sarcoplasmic reticulum and nephropathy characterized by tubular dilatation and atrophy, protein casts in the lumina of renal tubules, and glomerular vacuolization occurred in SHR given epirubicin alone. Animals receiving the combination of ICRF-187 and epirubicin showed a marked reduction in the severity of cardiomyopathy and a moderate reduction in nephropathy. These changes, and their modification by ICRF-187, were similar to those we have previously observed in SHR treated with total cumulative doses of 12 mg/kg doxorubicin. Such pathologic changes were absent in animals receiving ICRF-187 or saline alone. The findings of this study suggest that ICRF-187 can be used clinically to prevent the cardiotoxicity of epirubicin, particularly in situations in which this drug may have to be given either in large doses or to patients at high risk of developing anthracycline cardiotoxicity.     

Effect of angiotensin II on the antitumor activity and cardiotoxicity of doxorubicin

The effects of angiotensin II (AII) on the antitumor activity and cardiotoxicity of doxorubicin (DXR) were tested in rats bearing Walker 256/A carcinoma. The animals received 2, 4 or 6 mg/kg of DXR as a bolus i.v. injection, with or without a concurrent i.v. infusion of 2 micrograms/kg/min of AII, starting 1 h prior to DXR administration for a total of 6 h. Neither the antitumor activity, nor the myocardial toxicity of DXR, as assessed by ECG evaluation (Q alpha T duration), were affected by AII at the tested dose. 100% of the animals receiving 6 mg/kg of DXR with or without AII were cured from the tumor, but subsequently some of them developed toxic signs and eventually died within the 12th week after treatment. Rats receiving DXR + AII showed a higher long-term survival than those receiving DXR alone; therefore, a possible interference with other DXR-induced side effects, such as nephrotoxicity, is hypothesized.