Antitumor effect of liposome-entrapped adriamycin administered via the portal vein

We examined the distribution in tissues and antitumor effect of freeze-dried liposome-entrapped adriamycin (Lipo-ADM) administered via the portal vein to rabbits bearing VX2 tumors. Liposomes composed of egg phosphatidylcholine (cholesterol 50 mol%) were used as drug carriers. The liver concentration of ADM increased after delivery and cardiac uptake decreased compared with free drug treatment. The in vivo antitumor effect of Lipo-ADM was determined in rabbits inoculated with VX2 tumor. Repeated injections of free ADM via the portal vein prolonged the life span of tumor-bearing rabbits. The life span was further prolonged by Lipo-ADM treatment compared with the control group and the free ADM group. Histological examination revealed that the damage to the liver caused by Lipo-ADM administered via the portal vein did not differ from that observed in animals treated with free ADM. These results indicate that portal vein administration of Lipo-ADM may be more effective in dealing with liver metastases than treatment with free ADM and may be therapeutically useful without toxic side effects.     

Endoscopic injection of liposomal adriamycin targeting lymph node metastasis of gastric cancer

Gastric submucosal injection of 5 mg liposomal adriamycin (L-ADM) close to the main gastric cancer tumor was done in 15 patients by endoscopy. This approach was based on the idea that preoperative adjuvant chemotherapy targeting lymph node metastasis in patients with gastric cancer may be effective for prevention of lymph node recurrence. ADM concentrations in the regional lymph nodes were assessed and compared with those in patients who were administered 5 mg of free adriamycin (F-ADM) i.v. preoperatively. ADM concentrations in Group 7 lymph nodes (according to the General Rules for Gastric Cancer Study) were: After 2 days; 7.21 +/- 5.98 micrograms/g (n = 2) in the L-ADM group and 0.59 +/- 0.23 micrograms/g (n = 3) in the F-ADM group. After 4 days; 4.93 +/- 3.93 micrograms/g (n = 2) in the L-ADM group and 0.36 +/- 0.0 micrograms/g (n = 2) in the F-ADM group. After 6 days; 2.08 +/- 0.49 micrograms/g (n = 2) in the L-ADM group and 0.05 +/- 0.05 micrograms/g (n = 3) in the F-ADM group. L-ADM group: those who had L-ADM injected into the side of the lesser curvature of the stomach. F-ADM group: those who had F-ADM administered i.v. These data demonstrate that gastric submucosal injection of L-ADM is well suited for specific delivery to the regional lymph nodes, suggesting that this type of administration may prevent lymph node recurrence of gastric cancer by targeting lymph node metastasis.     

Experimental studies on prevention of liver metastases by continuous intraportal chemotherapy

Our experiment was designed to elucidate the efficacy of continuous intraportal chemotherapy (CIPC) for the prevention of liver metastases. Catheter was introduced into ileocecal vein of white rabbit for administration of adriamycin (ADM). VX2 cells were inoculated into portal vein to form liver metastases. Three experiments were designed as follows: 1) Immediately after inoculation of tumor cells, ADM was administered continuously for 7 days. 2) Continuous administration of ADM started on the 3rd day after inoculation of tumor cells. 3) Immediately after inoculation of tumor cells, ADM was administered by CIPC or systemically for 7 days. The same number of tumor cells were inoculated into portal vein and no treatment was given in control group. The rabbits were sacrificed on the 14th day. Number and size of liver metastases were calculated. Results were as follows: In 1) and 2), the metastases in CIPC group were significantly decreased in number and size compared with those in control group. In 3), no metastasis was observed in CIPC group, but a third of the rabbits developed metastases in systemic group. These results suggest that CIPC is effective for prevention of liver metastases and its efficacy is greater than for systemic chemotherapy.     

Basic study on hepatic artery chemoembolization and tumor selective drug targeting by temperature-sensitive liposome with local hyperthermia

Temperature-sensitive liposome entrapping adriamycin (L-ADM) was administered into the hepatic artery of hepatic tumor-bearing rats. The embolization of the hepatic artery with liposome and bio-distribution of ADM were examined. ADM concentration in blood showed a peak at 30 min after local heating on tumor (the heating had been performed for 6 min at 41-42 degrees C 2 hr. after injection). The value at the peak was about 3 times higher than that just before heating. ADM administered in liposomal form showed a high accumulative property to tumor with heating; ADM concentration in tumor 8 hr. after administration of ADM in liposomal form was about 5 times higher than that in liver and about 30 times higher than that in the heart, and about 20 times higher than that in tumor after administration in free form.     

Pharmacokinetic and imaging studies in patients receiving a formulation of liposome-associated adriamycin.

Pharmacokinetic and imaging studies in 19 patients receiving liposome-entrapped adriamycin (L-ADM) were carried out within the framework of a Phase I clinical trial (Gabizon et al., 1989a). The formulation of L-ADM tested consisted of 0.2 microM-extruded multilamellar vesicles composed of egg phosphatidylcholine, egg-derived phosphatidyl-glycerol (PG), cholesterol, and ADM intercalated in the fluid lipid bilayer. Plasma clearance of total drug extracted from the plasma after L-ADM infusion followed a biexponential curve with a pattern similar to that reported for free ADM. The plasma concentration of drug circulating in liposome-associated from was also measured in a subgroup of seven patients. Liposome-associated drug was found to be rapidly cleared from plasma. Its ratio to non-liposome-associated drug appeared to correlate with liver reserve, with highest ratios in patients with normal liver function. Liposome clearance, as measured by the plasma concentration of PG in three patients was slower than the clearance of liposome-associated ADM, suggesting that liposomes lose part of their drug payload during circulation. To learn about the liposome organ distribution, imaging studies were carried out with 111Indium-deferoxamine labelled liposomes of the same composition. Liposomes were cleared predominantly by liver and spleen and to a lesser extent by bone marrow in seven out of nine patients. In two patients with active hepatitis and severe liver dysfunction, there was minimal liver uptake and increased spleen and bone marrow uptake. Except for one hepatoma patient, intrahepatic and extrahepatic tumours were not imaged by liposomes, suggesting that liposome uptake is restricted to cells of the reticulo-endothelial system (RES).(ABSTRACT TRUNCATED AT 250 WORDS)     

肝动脉栓塞加门静脉置泵治疗晚期原发性肝癌(附160例病例分析)

延长晚期原发性肝癌患者的生存时间，提高生活质量，为二期手术切除创造条件。方法：采用肝动脉栓塞化疗加门静脉置泵，术中栓塞药物为：ADM、泛影葡胺、碘化油及MMC；术后门静脉药泵常用ADM、干扰素注射。结果：术后二个月复查B超，肿瘤缩小明显者（缩小至原肿瘤1／3）者74例，占46％，其中18例施行二期肝癌切除术，160例1年后存活率78．6％，2、3、5年存活率分别为65．6％、43．5％及16．3％。结论：采取肝动脉栓塞加门静脉置泵治疗晚期原发性肝癌160例，效果良好，延长了晚期原发性肝癌的生存时间，为二期手术切除创造了条件。     

Tumor and liver drug uptake following hepatic artery and portal vein infusion

Anatomic dye injection studies of the blood supply of colorectal hepatic metastases suggest that tumors are supplied predominantly by the hepatic artery. Using 13N amino acids with dynamic gamma camera imaging in patients with colorectal hepatic metastases, it has been shown that hepatic artery infusion results in a significantly greater nutrient delivery to tumor compared with portal vein infusion. However, direct measurements of drug levels in tumor following hepatic artery and portal vein infusion in humans have not previously been reported. Patients with metastatic colorectal cancer confined to the liver received fluorodeoxyuridine (FUdR) through the hepatic artery or through the portal vein. All patients had previously failed systemic chemotherapy. Five patients with hepatic artery catheters were matched (by age, serum lactic dehydrogenase levels, percent hepatic replacement, and tumor size) with five patients with portal vein catheters. At operation, 3H-FUdR (1 microCi/kg) and 99mTc-macroaggregated albumin (MAA) (6 mCi) were injected into the hepatic artery or portal vein. Liver and tumor biopsies were obtained two and five minutes later. 3H and 99mTc were measured per gram tissue by scintillation and gamma counting. The mean liver levels following hepatic artery infusion (23.9 +/- 11.4 nmol/g) and portal vein infusion (18.4 +/- 14.5 nmol/g) did not differ. However, the mean tumor FUdR level following hepatic artery infusion was 12.4 +/- 12.2 nmol/g, compared with a mean tumor FUdR level following portal vein infusion of 0.8 +/- 0.7 nmol/g (P less than .01). This low level of tumor drug uptake after portal vein infusion of FUdR predicts minimal tumor response to treatment via this route. Thus, regional chemotherapy for established colorectal hepatic metastases should be administered through the hepatic artery.     

经肝动脉门静脉途径化疗栓塞治疗原发性肝癌

 18例原发性肝癌病人采用肝动脉门静脉置入化疗泵，术后经药系反复化疗栓塞治疗。药物包括霉素（ADM）、丝裂霉素（MMC）和卡铂（CBP），超乳化碘化油。每次相隔4～6周。结果一年内死亡4例，成活已超过一年的14例。作者认为经肝动脉门静脉化疗栓塞是治疗不可切除肝癌的有效方法。     

Reduced toxicity of adriamycin by incorporation into ion exchange microspheres: a therapeutic study using a rat liver tumour model

A comparison of the systemic toxicity and therapeutic efficacy of adriamycin carrying microspheres with conventional chemotherapeutic use of adriamycin was performed using a rat liver tumour model. The drug-microspheres were administered via the gastro-duodenal artery for delivery to the liver, whilst similar quantities of free adriamycin were given by systemic intravenous or regional intra-arterial routes. Significant leukopenia, thrombocytopenia and mortality were observed in the systemically treated free drug group (P less than 0.05) with a similar trend for for myelosuppression occurring in the intra-arterial free drug group. The adriamycin-microsphere group showed no toxic side-effects despite retarding tumour growth by similar amounts to the other drug modalities. This work demonstrates a large potential for the use of adriamycin carrying ion-exchange microspheres in the treatment of human malignancy.     

Prognostic analysis for treatment modalities in hepatocellular carcinomas with portal vein tumor thrombi

Objective: To assess prognostic aspects of treatment modalities for cases of hepatocellular carcinoma (HCC) with portal vein tumor thrombi (PVTT). Method: 121 treated cases were retrospectively divided into five groups: 1 (liver transplantation); 2 (transcatheter arterial chemoembolization); 3 (hepatectomy plus thrombectomy); 4 (hepatectomy plus thrombectomy combined with adjuvant chemobiotherapy via portal vein); and 5 (conservative treatment). The Kaplan-Meier method with difference in survival estimated by Log-rank test was used to compare between groups. Result: Groups 1-5 had a significantly differing median survival times of 7, 7, 10, 16, 3 months (P<0.05), respectively. One- and three-year survival rates were 30.0% and 10.0%, 20.0% and 0.0%, 47.0% and 22.0%, 70% and 20%, and 12% and 4%. Conclusion: Surgical resection combined with adjuvant chemotherapy via the portal vein is an effective and safe treatment modality for hepatocellular carcinoma with portal vein tumor thrombi.     

The significance of reinduction chemotherapy with adriamycin for relapsed non-Hodgkin's lymphoma of Waldeyer's ring

Of those patients with localized (CS I-II) non-Hodgkin's lymphoma of Waldeyer's ring who were treated with radiotherapy or radiotherapy plus chemotherapy and who suffered relapses at the National Cancer Center Hospital over the past 22 years, 24 cases were analyzed on the basis of their response rate and duration of remission with reinduction chemotherapy, and survival time after recurrence. The group [ADM (+)], treated with regimens including adriamycin, was compared with the group [ADM (-)] treated with regimens excluding adriamycin. Complete response was seen in 9 out of 11 cases (81.8%) and in 8 out of 13 cases (61.5%) for the ADM (+) group and the ADM (-) group, respectively (p greater than 0.1). The period of complete response of the ADM (+) and ADM (-) groups was compared using the logrank method. The prognosis of the former was significantly (p less than 0.01) better than that of the latter and the median duration of remission was 30 months and 7 months, respectively. When the survival after recurrence of the ADM (+) and ADM (-) groups was compared, the median survival time was 38 months for the ADM (+) group and 12 months for the ADM (-) group, but no significant difference was observed between the two groups (0.05 less than p less than 0.1).     

Epirubicin is equivalent to adriamycin in vitro against many cancer cells but more effective against gastric cancer cells.

We compared the cytotoxic effects of two anthracycline derivatives, epirubicin (EPI) and adriamycin (ADM), against human tumor cells in vitro. Various tumor specimens, obtained at surgery, included 57 liver, 19 lung, 16 gastric, 10 colorectal and 7 breast cancer specimens. These tumor cells were exposed to the same concentration of EPI or ADM for 3 days. The chemosensitivity of each tumor cell type to each drug was then assayed using the in vitro succinate dehydrogenase inhibition (SDI) test. Sensitivity to the treatment was defined as a 50% or greater reduction in the succinate dehydrogenase (SD) activity of the tumor cells, relative to that of the control (untreated) cells. Each cell type, except for gastric cancer cells, was equally sensitive to EPI and ADM. Gastric cancer cells were more sensitive to EPI than to ADM (P less than 0.05). The rate of coincidence, the sum of the co-sensitive and co-resistant rates of all the tumors, was quite high (90.8%). Thus, these findings indicate that EPI and ADM are equally cytotoxic to each tumor cell type, but EPI is more cytotoxic than ADM to gastric cancer cells. Since EPI is reported to be less cardiotoxic than ADM, EPI may replace ADM in cancer chemotherapy.     

CD20抗原及治疗性抗CD20抗体

目的: 研制阿霉素脂质体(AL)、阿霉素长循环脂质体(ALCL)和阿霉素长循环热敏脂质体(ALTSL).研究不同类型脂质体对H22荷瘤小鼠肿瘤的抑制作用.方法: 建立荷瘤小鼠模型,观察各实验组的抑瘤效果,计算抑瘤率和生命延长率; HPLC法研究静脉给药后各实验组阿霉素的药代动力学规律及组织学分布特征;制作病理切片,观察各实验组肿瘤和心脏等组织的病理变化.结果: ALCL和ALTSL对H22荷瘤小鼠肿瘤有显著的抑制作用,抑瘤率分别为57.8%和67.0% (P<0.01);尾静脉注射给药24 h后,ALCL和ALTSL组荷瘤小鼠肿瘤组织和血液中的阿霉素含量明显上升,而在心、肺中的含量显著降低;ALTSL使肿瘤细胞大量坏死,而对心肌细胞无明显损伤.结论: ALCL和ALTSL均能提高化疗药阿霉素的抗肿瘤效果,降低阿霉素的心肺毒性,延长荷瘤小鼠的存活时间.     

大肠癌术后门静脉置泵灌注化疗预防肝转移临床疗效分析

目的:探讨大肠癌术后门静脉置泵灌注化疗预防肝转移的临床疗效。方法:46例大肠癌患者随机分成治疗组和对照组,治疗组术后自门静脉化疗泵注药(5-FU、MMC和EPI),对照组自周围静脉注药。结果:治疗组5年生存率55·00%(11/20),肝转移率12·50%(3/24);对照组5年生存率33·33%(6/18);肝转移率27·27%(6/22);两组相比差异有统计学意义,P<0·01。结论:大肠癌术后门静脉置泵灌注化疗预防肝转移效果好。5年生存率明显提高。     

血液灌流对抗癌药物肝血管内注射作用的影响：与阿霉素注射剂量的关系

本研究采用DAC-树脂同步作吸附剂血灌流(DHP)2小时与对照柱灌流相比能明显降低Wistar大鼠门静脉输注ADM5 mg/kg对心肌组织中ADM的浓度,由9.8±1.8降至6.0±1.7μg/g(P<0.005)在10mg/kg时由46.3±4.2降到35.6±3.8μg/g(P<0.005);能明显降低心肌组织中MDA含量,由0.7129±0.1631降到0.4054±0.049 nmol/mg蛋白(P<0.005)由0.9922±0.2070降到0.6892±0.0968nmol/mg蛋白(P<0.01);而对肝脏组织中ADM浓度无明显影响(P均>0.25)。心肌超微结构观察表明,DHP能明显减轻ADM心肌损害程度。ADM剂量增大一倍,经DHP后肝脏药物浓度增加3.3倍,而心肌丙二醛(MDA)水平刚无明显增加(P>0.25),且形态学上心肌损害程度并不明显加重。研究结果表明,DHP在不能减低心肌中ADM的情况下,能明显减轻大剂量ADM所致心脏的毒性作用,而对肝脏药物浓度无明显影响。该疗法有望成为改善肝癌化疗的一项有效措施。     

Pilot study with adriamycin and ifosfamide in small cell lung cancer

Twenty-one patients with limited (12 cases) or extensive (9 cases) small cell lung cancer entered a pilot study with adriamycin (ADM) plus ifosfamide (IFX) as first line treatment for six planned cycles. ADM was administered at the dose of 60 mg/m2 iv push on day 1 and IFX at 3 g/m2/iv in 1-hour infusion on days 1 and 2. To prevent IFX-induced hemorrhagic cystitis, mercaptoethane sulfonate sodium (Mesna) was given after the administration of IFX at the dose of 500 mg/m2 by iv push four times (hour 0, 4, 8, 12) on days 1 and 2. In the absence of disease progression, chemotherapy was repeated every 3 weeks for 6 cycles. All patients were evaluable for analysis of response, toxicity and survival. The overall response rate clinically and radiologically assessed after four treatment cycles was 95.3% (CR 28.6%, PR 66.7%). However, by continuing the same drug treatment up to the sixth cycle, 7 of 14 partial responders showed tumor progression within the intrathoracic region. Therefore, at the end of the planned chemotherapy program the partial remission rate fell to 33.3%, for a total remission rate of 61.9% and a median total survival of 9 months (range 5 to 36+). The regimen was well tolerated with only one case presenting hemorrhagic cystitis. The results achieved with this drug combination appear comparable to those obtained with other conventional regimens. However, the high response rate achieved after four cycles and the low incidence of marrow toxicity suggest the use of this regimen for a short period with increased dose levels.     

Clinical experience of intra-arterial chemotherapy for liver metastases of breast cancer patients]

The aim of this study was to evaluate retrospectively the effect of intra-arterial chemotherapy for liver metastases of breast cancer patients. Eleven patients treated between August 1991 and July 1997 at Keio University Hospital, Tokyo, Japan, were the subjects for this study. The duration of disease-free periods after the operation ranged from 9 to 78 months (median 27 months). The site of the recurrence was the liver alone in 6 cases, and the liver and lung in 1 case, bone in 1 case, lymph nodes in 2 cases, and a local region, in 1 case. The main drugs were adriamycin (ADM) and 5-fluorouracil (5-FU), administered in a single injection or continuously via an indwelling catheter in the hepatic artery. This method had a 36% response rate, including PR in 4 cases, NC in 3 cases and PD in 4 cases. The survival duration was 1 to 19 months (median 14 months) following this treatment, and 3 to 49 months (median 17 months) after the recognition of the recurrence. The only side effects of Grade 3 or 4 were leucocytopenia or granulocytopenia and nausea. These results suggest that intra-arterial chemotherapy for liver metastases of breast cancer patients may be an effective method for the control of liver metastases with minor side effects. However, further study may be necessary to establish methods to manage the indwelling catheter and to control patients with multiple metastases of the other organs, to improve the prognosis for recurrent breast cancer patients.     

原位肝移植治疗原发性肝癌６８例报告

目的：探讨原位肝移植在原发性肝癌治疗中的价值。方法：对６８例接受肝移植原发性肝癌病例进行回顾性分析,随访６个月以上,对术后患者存活情况进行分析。结果：６８例肝移植手术均获成功,无围手术期死亡,５４例存活至今,最长无瘤存活已达６５个月。小肝癌复发率为２.２％（１／４６）,大肝癌复发率为５４.５％（１２／２２）,其中肝内门脉分支有癌栓者复发率为６６.６％（４／６）,门脉主干有癌栓者为１００％（３/３）;小肝癌患者的存活时间显著长于大肝癌（Ｐ＝０.０００）。此外,肝癌肝移植术后及早停用类固醇激素,并维持抗排斥药物在较低的药物浓度也可能有助于减少肿瘤术后复发。结论：原位肝移植是治疗肝癌特别是小肝癌的有效手段,对于门静脉主干无癌栓的中晚期肝癌也能起到积极治疗作用。     

The Comprehensive Analysis of Efficacy and Safety of CalliSpheres^® Drug-Eluting Beads Transarterial Chemoembolization in 367 Liver Cancer Patients: A Multiple-Center,Cohort Study

This study aimed to investigate the efficacy, safety, and prognostic factors of drug-eluting beads transarterial chemoembolization (DEB-TACE) in treating Chinese patients with liver cancer. A total of 367 liver cancer patients from 24 medical centers were consecutively enrolled in this multiple-center, prospective cohort study, including 275 hepatocellular carcinoma (HCC) cases, 37 intrahepatic cholangiocarcinoma (ICC) cases, and 55 secondary liver cancer cases. All the patients received CalliSpheres^® DEB-TACE treatment. Treatment response, overall survival (OS), change of liver function, and adverse events (AEs) were assessed. DEB-TACE treatment achieved 19.9% complete response (CR) and 79.6% objective response rate (ORR), with mean OS of 384 days [95% confidence interval (CI): 375–393 days]. CR and ORR were both higher in HCC patients compared with primary ICC patients and secondary liver cancer patients, while no difference was discovered in OS. Portal vein invasion was an independent risk factor for CR, while portal vein invasion, previous conventional TACE (cTACE) treatment, and abnormal blood creatinine (BCr) were independent risk factors for ORR. In addition, largest nodule size 5.0 cm, abnormal albumin (ALB), and abnormal total bilirubin (TBIL) independently correlated with unfavorable OS. Most liver function indexes were recovered to baseline levels at 1–3 months after DEB-TACE. Common AEs were pain, fever, vomiting, and nausea; most of them were at mild grade. CalliSpheres^® DEB-TACE is efficient and well tolerated in Chinese liver cancer patients. Portal vein invasion, previous cTACE treatment, largest nodule size, abnormal BCr, ALB, and TBIL correlate with worse prognosis independently.     

Therapeutic effect of transarterial infusion immunochemotherapy for metastatic liver cancer

In order to improve therapeutic efficacy for metastatic liver cancer, intermittent transarterial administration of BRM in combination with anticancer drugs was performed by use of reservoir apparatus. A total of 22 patients (12 cases of gastric cancer, 6 of colon cancer, 2 of pancreas cancer, 1 of gall bladder cancer and 1 of biliary tract carcinoid) were treated according to the following schedule: both 10 mg of ADM (or MMC) and 0.5 KE (or 1.0 KE) of OK-432 were administered on day 1 and 40 x 10(4) JRU of recombinant interleukin 2 (r-IL 2) on day 4, 7 and 11. The treatment was repeated as many times as possible. In terms of direct antitumor effect and decrease of tumor marker, the response rate was 43% (6 cases out of 14) and 75% (9 cases out of 12), respectively. As for performance status, improvement, no change and deterioration were seen in 4 cases, 8 cases and 3 cases, respectively. Even though 13 patients died, 8 of them survived more than 300 days. In the case of gastric cancer patients with liver metastasis, 50% survival time of 12 cases was 334 days, while that of 30 cases, who were administered anticancer drugs only systemically, was 144 days. In 3 cases the decrease in the size of tumors located in both liver and the other metastases also was seen. Every case developed high grade fever, but an antifebrile was effective. Otherwise severe side effects were not seen. These results indicated that intermittent arterial infusion immunochemotherapy was feasible for the treatment of metastatic liver cancer.