[Modified Shengma Biejia Decoction Combined with CAG Program for Elderly Acute Myeloid Leuke- mia Patients with Yin Deficiency Toxin Stasis Syndrome].

OBJECTIVE: To observe the efficacy and safety of modified Shengma Biejia Decoction (MSBD) combined with CAG program in treating elderly acute myeloid leukemia (AML) patients with yin deficiency toxin stasis syndrome (YDTSS). METHODS: Totally 46 elderly AML patients were assigned to the treatment group (24 cases; treated with MSBD + CAG) and the control group (22 cases; treated with CAG + placebos of Chinese medicine) according to random digit table. The therapeutic course of CM placebo or MSBD was 21 days. The clinical efficacy and adverse reactions were observed. Meanwhile, physical state (ECOG Score), transfusion dependency, and TCM syndrome score were compared before and after treatment. RESULTS: (1) The complete remission rate was 54% (13/24) and the objective response rate (ORR) was 71% (17/24) in the treatment group, obviously higher than those of the control group [36% (8/22); 54% (13/24)], with statistical difference (P = 0.036, 0.042). When comparing the efficacy based on risk level, the moderate and poor ORR was 71% (10/14) and 67% (6/9) in the treatment group, and 57% (8/14) and 33% (2/6) in the control group, with statistical difference between the two groups (P = 0.048; P = 0.010). (2) Compared with before treatment in the same group, the ECOG score significantly decreased, the average infusion time of red cells and platelets were markedly prolonged in the treatment group after treatment (P < 0.05). ECOG score, the average infusion time of red cells and platelets were significantly better in the treatment group than in the control group after treatment (P < 0.05). (3) Compared with before treatment in the same group, scores of fever, hemorrhage, and bone pain were markedly reduced in the control group (P < 0.05); scores of fever, fatigue, hemorrhage, dry mouth, and bone pain were markedly reduced in the treatment group (P < 0.05). Better effect in relief of fever, fatigue, hemorrhage, dry mouth, and so on was obtained in the treatment group than in the control group (P < 0.05). (4) In aspect of hematotoxicity, the incidence of neutropenia, anemia, thrombocytopenia was obviously lower in the treatment group than in the control group [29.2% (7/24) vs 54.5% (12/22); 16.7% (4/ 24) vs 45.5% (10/22); 33.3% (8/24) vs 63.6% (14/22); P < 0.05]. The incidence of fatigue and anorexia was obviously lower in the treatment group than in the control group [37.5% (9/24) vs 63.6% (14/22), 37.5% (9/24) vs 81.8% (18/22); P < 0.05]. CONCLUSION: MSBD combined with CAG program in treating elderly AML patients with YDTSS, with efficacy enhancing toxicity reducing effect, had distinct advantages in improving physical condition and clinical symptoms, and reducing transfusion dependency.

Modified Shengma Biejia Decoction Combined with CAG Program for Elderly Acute Myeloid Leuke- mia Patients with Yin Deficiency Toxin Stasis Syndrome / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the efficacy and safety of modified Shengma Biejia Decoction (MSBD) combined with CAG program in treating elderly acute myeloid leukemia (AML) patients with yin deficiency toxin stasis syndrome (YDTSS).</p><p><b>METHODS</b>Totally 46 elderly AML patients were assigned to the treatment group (24 cases; treated with MSBD + CAG) and the control group (22 cases; treated with CAG + placebos of Chinese medicine) according to random digit table. The therapeutic course of CM placebo or MSBD was 21 days. The clinical efficacy and adverse reactions were observed. Meanwhile, physical state (ECOG Score), transfusion dependency, and TCM syndrome score were compared before and after treatment.</p><p><b>RESULTS</b>(1) The complete remission rate was 54% (13/24) and the objective response rate (ORR) was 71% (17/24) in the treatment group, obviously higher than those of the control group [36% (8/22); 54% (13/24)], with statistical difference (P = 0.036, 0.042). When comparing the efficacy based on risk level, the moderate and poor ORR was 71% (10/14) and 67% (6/9) in the treatment group, and 57% (8/14) and 33% (2/6) in the control group, with statistical difference between the two groups (P = 0.048; P = 0.010). (2) Compared with before treatment in the same group, the ECOG score significantly decreased, the average infusion time of red cells and platelets were markedly prolonged in the treatment group after treatment (P < 0.05). ECOG score, the average infusion time of red cells and platelets were significantly better in the treatment group than in the control group after treatment (P < 0.05). (3) Compared with before treatment in the same group, scores of fever, hemorrhage, and bone pain were markedly reduced in the control group (P < 0.05); scores of fever, fatigue, hemorrhage, dry mouth, and bone pain were markedly reduced in the treatment group (P < 0.05). Better effect in relief of fever, fatigue, hemorrhage, dry mouth, and so on was obtained in the treatment group than in the control group (P < 0.05). (4) In aspect of hematotoxicity, the incidence of neutropenia, anemia, thrombocytopenia was obviously lower in the treatment group than in the control group [29.2% (7/24) vs 54.5% (12/22); 16.7% (4/ 24) vs 45.5% (10/22); 33.3% (8/24) vs 63.6% (14/22); P < 0.05]. The incidence of fatigue and anorexia was obviously lower in the treatment group than in the control group [37.5% (9/24) vs 63.6% (14/22), 37.5% (9/24) vs 81.8% (18/22); P < 0.05].</p><p><b>CONCLUSION</b>MSBD combined with CAG program in treating elderly AML patients with YDTSS, with efficacy enhancing toxicity reducing effect, had distinct advantages in improving physical condition and clinical symptoms, and reducing transfusion dependency.</p>

Selected drugs with reported secondary cell-differentiating capacity prime latent HIV-1 infection for reactivation.

Reactivation of latent HIV-1 infection is considered our best therapeutic means to eliminate the latent HIV-1 reservoir. Past therapeutic attempts to systemically trigger HIV-1 reactivation using single drugs were unsuccessful. We thus sought to identify drug combinations consisting of one component that would lower the HIV-1 reactivation threshold and a synergistic activator. With aclacinomycin and dactinomycin, we initially identified two FDA-approved drugs that primed latent HIV-1 infection in T cell lines and in primary T cells for reactivation and facilitated complete reactivation at the population level. This effect was correlated not with the reported primary drug effects but with the cell-differentiating capacity of the drugs. We thus tested other cell-differentiating drugs/compounds such as cytarabine and aphidicolin and found that they also primed latent HIV-1 infection for reactivation. This finding extends the therapeutic promise of N'-N'-hexamethylene-bisacetamide (HMBA), another cell-differentiating agent that has been reported to trigger HIV-1 reactivation, into the group of FDA-approved drugs. To this end, it is also noteworthy that suberoylanilide hydroxamic acid (SAHA), a polar compound that was initially developed as a second-generation cell-differentiating agent using HMBA as a structural template and which is now marketed as the histone deacetylase (HDAC) inhibitor vorinostat, also has been reported to trigger HIV-1 reactivation. Our findings suggest that drugs with primary or secondary cell-differentiating capacity should be revisited as HIV-1-reactivating agents as some could potentially be repositioned as candidate drugs to be included in an induction therapy to trigger HIV-1 reactivation.

Combined effect of low-power laser irradiation and anthraquinone anticancer drug aclarubicin on survival of immortalized cells: Comparison with mitoxantrone.

The photodynamic response of the anthraquinone anticancer drug aclarubicin (ACL) was investigated in vitro and compared with that of mitoxantrone (MTX). Cultured immortalized rodent B14 and NIH 3T3 cells were used in the experiments as a model for cells with neoplastic phenotype. Long-term cytotoxicity and inhibition of cell proliferation assayed by the clonal growth and MTT-tetrazolium methods were estimated to compare the efficacy of aclarubicin and mitoxantrone in photosensitizing cells and their death after non-thermal exposure to monochromatic laser light. Green He-Ne (543.5 nm) or red semiconductor (670 nm) low-power laser (LPL) irradiations were applied. Different dose-responses of both cell lines to aclarubicin and mitoxantrone were found so that the cytotoxicity of MTX was considerably greater than the cytotoxicity of ACL. Phototherapy response (P < 0.0001) was observed only for B14 cells after sensitisation with aclarubicin. Under the same conditions no significant effect of red light irradiation (semiconductor 670 nm laser) on survival of both cell lines treated with mitoxantrone was found.

Superior outcome of infant acute myeloid leukemia with intensive chemotherapy: results of the Japan Infant Leukemia Study Group.

This study analyzed data on 35 infants with acute myeloid leukemia (AML) who were treated with intensive chemotherapy between 1995 and 1998 in Japan. The incidence of boys, younger age (< 6 months old), and hyperleukocytosis at onset was high in patients with the M4/M5 subtype (n = 23) in the French-American-British classification, compared with the non-M4/M5 subtype (n = 12). Thirteen (56%) and 16 (70%) patients with the M4/M5 subtype also showed 11q23 translocations and MLL gene rearrangements, respectively, whereas only one patient with the non-M4/M5 subtype had this rearrangement. All 35 patients were treated with the ANLL91 protocol consisting of etoposide, high-dose cytarabine, and anthracyclines. Overall survival and the event-free survival (EFS) rates at 3 years of all patients were 76% (95% confidence interval [CI], 61.3%-90.7%) and 72% (95% CI, 56.4%-87.9%), respectively. EFS showed no significant difference between 2 subgroups divided by age, gender, presence of the MLL gene rearrangements, and white blood cell count at onset; EFS in patients with the M4/M5 subtype tended to be better than those with the non-M4/M5 subtype. Although all 6 patients who underwent allogeneic stem cell transplantation (SCT) have been in complete remission, no benefit of SCT was confirmed. These findings suggest that the intensive chemotherapy with the ANLL91 protocol might have been responsible for the observed good outcome of infant AML, even without SCT. The presence of the MLL gene rearrangements or the age at onset had no impact on the outcome of infant AML.

Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients.

Proximal spinal muscular atrophy (SMA) is a common motor neuron disorder caused by mutation of the telomeric survival of motor neuron gene SMN1. The centromeric survival of motor neuron SMN2 gene is retained in all SMA patients but does not produce sufficient SMN protein to prevent the development of clinical symptoms. The SMN1 and SMN2 genes differ functionally by a single nucleotide change. This change affects the efficiency with which exon 7 is incorporated into the mRNA transcript. Thus, SMN2 produces less full-length mRNA and protein than SMN1. We have screened a library of compounds in order to identify ones that can alter the splicing pattern of the SMN2 gene. Here, we report that the compound aclarubicin increases the retention of exon 7 into the SMN2 transcript. We show that aclarubicin effectively induces incorporation of exon 7 into SMN2 transcripts from the endogenous gene in type I SMA fibroblasts as well as into transcripts from a SMN2 minigene in the motor neuron cell line NSC34. In type I fibroblasts, treatment resulted in an increase in SMN protein and gems to normal levels. Our results suggest that alteration of splicing pattern represents a new approach to modification of gene expression in disease treatment and demonstrate the feasibility of high throughput screens to detect compounds that affect the splicing pattern of a gene.

Effective hepatic artery chemoembolization for advanced hepatocellular carcinoma with extensive tumour thrombus through the hepatic vein.

BACKGROUND AND AIMS: Advanced hepatocellular carcinoma (HCC) with extensive tumour growth through the hepatic vein still has an extremely poor prognosis, even after cancer chemotherapy and/or transarterial embolization. Although aggressive surgical treatments using extracorporeal circulation and liver transplantation have been performed by some authors, the reported results were still unsatisfactory. In this study, we report the favourable result of hepatic artery chemoembolization and subsequent surgical resection in three patients with advanced HCC with extensive tumour thrombus through the hepatic vein. METHODS AND RESULTS: Three irresectable patients with HCC with extensive tumour thrombus through the hepatic vein underwent hepatic artery chemoembolization with aclarubicin, mitomycin C, lipiodol and/or Gelfoam. After the reduction of tumour extent with hepatic artery chemoembolization, two of the three patients underwent surgical resection. These two patients are still alive at 59 and 21 postoperative months, respectively. In the other case, the extent of the tumour and functional reserve of the liver prevented us from performing surgical resection, but the patient is doing well 62 months after the initial treatment. CONCLUSIONS: Hepatic artery chemoembolization with aclarubicin, mitomycin C, lipiodol and/or Gelfoam might be an effective treatment for irresectable advanced HCC with extensive tumour thrombus into the inferior vena cava or the right atrium through the hepatic vein. Radical surgical resection might be applicable for selected patients without high surgical risk after reducing tumour extent by hepatic artery chemoembolization.

Adjuvant regional chemotherapy after hepatic resection for colorectal metastases.

BACKGROUND: This study explored the possibility of achieving a better survival rate and reduced recurrence in the remaining liver in patients with colorectal hepatic metastases undergoing hepatic resection. Adjuvant postoperative regional chemotherapy was administered via the hepatic artery or the portal vein. METHODS: A retrospective study was performed on 174 patients after hepatic resection for colorectal metastases. These comprised 78 patients who had hepatic artery infusion (HAI) chemotherapy (HAI group), 30 who had portal vein infusion (PVI) chemotherapy (PVI group) and 66 who had no regional chemotherapy (resection alone group). The three groups were compared with one another in terms of complications, survival rate and patterns of recurrence. RESULTS: Severe complications did not occur at any point during adjuvant HAI or PVI chemotherapy. The 5-year disease-free survival rate of patients in the HAI, PVI and resection alone groups were 35, 13 and 9 per cent respectively, including six hospital deaths. Patients in the HAI group showed significantly improved recurrence rates in the remaining liver compared with the resection alone group (P = 0.03), and more prolonged disease-free and overall survival than those in the PVI (P = 0.01 and P = 0.02 respectively) and resection alone (P = 0.0001 and P = 0.0006 respectively) groups. CONCLUSION: This study suggests that adjuvant HAI chemotherapy after hepatic resection may have therapeutic potential for improved management of patients with colorectal metastases.

Evidence of the role of protein kinase C during aclacinomycin induction of erythroid differentiation in K562 cells.

At subtoxic concentrations, aclacinomycin is effective in controlling erythroid differentiation of K562, a human erythroleukemic cell line. To better understand early events implicated in this process, we have used bisindolylmaleimide (GF109203X), an inhibitor with a high selectivity for protein kinase C (PKC). Our data show that GF109203X inhibits aclacinomycin effects on K562, evidenced by a strong reduction of hemoglobinized cells and a marked decrease of mRNA rates of erythroid genes. To establish firmly PKC involvement, we also verified that aclacinomycin stimulates its rapid translocation, from the cytosolic to the membrane compartment. By Western blot analysis, we also show that after short induction times, PKCalpha was the most implicated.

A successful treatment for hepatocellular carcinoma with atrial tumor thrombus.

A 66-year-old man with an advanced hepatocellular carcinoma and tumor thrombus extending into the right atrium was treated by transcatheter arterial infusion of lipiodol and aclarubicin. This brought about a remarkable reduction of the tumor and the disappearance of the right atrial tumor thrombus. The tumor was then radically resected by hepatic posterior segmentectomy with combined resection of the right hepatic vein, where the tumor thrombus remained. He is doing well without any signs of recurrence 22 months after the operation.

[Successful adjuvant therapy of M-CSF with chemotherapy of two cases of chemotherapy resistant acute promyelocytic leukemia].

We demonstrate two conventional chemotherapy-resistant cases of acute promyelocytic leukemia (APL) who were successfully treated with macrophage-colony stimulating factor (M-CSF). Case no 1 was a 40-year-old woman who was made diagnosis of APL on June, 1992, and treated repeatedly with a conventional chemotherapy, BHAC-DMP regimen, resulting in complete remission on October, 1992. After a couple of years, she had relapse with marked growth of APL cells in bone marrow. She was treated with BHAC-AMP and modified B-triple V but could not obtain remission. Case no 2 was a 36-year-old-man with APL who was treated with BHAC-DMP and BHAC-AMP and modified B-triple V therapy. These three conventional chemotherapy regimen were not effective for him. Eight million units of human native M-CSF was administered intravenously for 14 days after the last BHAC-AMP therapy in case no 1, and for 5 days after the last modified B-triple V therapy in case no 2. After the therapy, APL cells in peripheral blood or bone marrow of both patients disappeared completely and normal hemopoietic cells increased, obtaining in complete remission in both cases. These successful cases treated with M-CSF combining chemotherapy may suggest a new therapeutic strategy for APL in addition to all-trans retinoic acid.

[Intraportal infusion of 5-FU and lipiodol-aclarubicin after hepatic resection for colorectal liver metastasis].

Fifty-five patients with hepatic metastasis from colorectal cancer underwent curative hepatic resection. Postoperative intraportal infusion of 5-fluorouracil (500mg per day) for 14 days from 21 postoperative days (POD) and lipiodol-aclarubicin (40mg) at 35 POD was carried out in twenty-eight patients for reducing the recurrence in the remnant liver and improving the prognosis. Twenty-seven patients had hepatectomy alone as controls. Intraportal infusion chemotherapy did not induce any hepatotoxicity and hematologic severe abnormalities. The cumulative survival rates for the infusion group and the control group, respectively, were 89.3% and 63.0% at 1 year; 55.2% and 43.3% at 2 year; 27.0% and 27.5% at 3 year. The survival rate for the infusion group was significantly higher than that for the control group at 1 year (p < 0.05). No difference of the recurrent rate in the remnant liver was found between the two groups. It is suggested that intraportal infusion chemotherapy after curative hepatic resection for colorectal liver metastasis might improve survival rate at the early postoperative period. Intraportal infusion chemotherapy could be an effective adjuvant therapy especially in the patients with bilateral and multiple hepatic metastasis.

Targeted chemotherapy for unresectable primary and metastatic liver cancer.

In targeted chemotherapy, Lipiodol Ultrafluid was used as a carrier of anticancer drugs; these combinations were termed oily anticancer agents. Arterial injection therapy with these oily anticancer agents was performed in 330 patients with unresectable hepatocellular carcinoma (HCC) and 110 patients with unresectable metastatic liver cancer. The alpha-fetoprotein (AFP) level decreased in 178 of 186 AFP-positive patients with HCC. Tumor size was reduced in 256 of 269 evaluable patients with HCC. The treatment seemed to prolong survival and in 193 HCC patients who were good candidates for therapy (those without Child C liver cirrhosis, without tumor occupying all four segments of the liver, or without extrahepatic spread) the 1-, 2-, and 5-year survival rates were 85, 52, and 34% respectively. In the 110 patients with metastatic liver cancer, the carcinoembryonic antigen level and tumor size were reduced. The 1-, 2-, and 5-year survival rates of these 110 patients were 61, 32, and 22% respectively.

Synergistic effects of hyperthermia and intratumorous injection of anti-cancer drugs.

In an attempt to improve the combined effects of hyperthermia and anti-cancer drugs, an intratumorous (i.t.) injection of the drugs was performed and its effect compared with that obtained by intraperitoneal (i.p.) injection. Using Lewis lung carcinoma growing in the legs of BDF1 mice, weakly toxic drug derivatives, Aclarubicin (ACR), a new platinum complex (DWA2114R), or Peplomycin (PEP) were injected either into the center of the tumors, or intraperitoneally, before or after usual hyperthemia in a 43.5-43.7 degrees C water bath for 45 min. The effects on tumor growth delay and the number of lung metastases were assessed, and the enhancement ratios (ERs) due to the combination were calculated. Tumor growth inhibition by i.t. injection was enhanced additively with ACR (ER; 1.2) and synergistically with DWA2114R (ER; 3.49) and PEP (ER; 2.4) plus hyperthermia. Hyperthermia after i.t. injections of DWA2114R (ER; 3.4) was more effective than either i.t. or i.p. injections after hyperthermia (ER; 2.4). Lung metastases were also inhibited significantly by the combination of hyperthermia and drugs, except when emulsified PEP was injected three times. It was concluded that the i.t. injection of DWA2114R was of value when used in combination with hyperthermia.

Effect of pH and moderate hyperthermia on doxorubicin, epirubicin and aclacinomycin A cytotoxicity for Chinese hamster ovary cells.

The influence of extracellular pH on the cytotoxicity of the anthracyclines doxorubicin, epirubicin, and aclacinomycin A was examined at 37 degrees C and 41 degrees C in tissue culture. Chinese hamster ovary (CHO) cells were exposed for a total of 24 h to anthracyclines at doses ranging between 0.12 and 0.69 nmol/ml at pH 7.4, 6.7, and 6.4 and at 37 degrees C. Temperature elevation to 41 degrees C was carried out for 3 h after the initiation of the drug treatment. Doxorubicin and epirubicin were about equally cytotoxic in the pH range examined at both temperatures. Aclacinomycin A demonstrated a higher cytotoxicity at pH 7.4 and 37 degrees C only at low doses. At low pH, however, aclacinomycin A was increasingly more effective with increasing dose as compared with doxorubicin and epirubicin. At 41 degrees C and at higher doses aclacinomycin A was even less cytotoxic than doxorubicin or epirubicin. Doxorubicin and epirubicin were less effective at lower pH. However, aclacinomycin A at doses of greater than 0.25 nmol/ml was more cytotoxic at low pH. Moderate hyperthermia did not increase the cytotoxicity of the three drugs at low pH, except for aclacinomycin A at doses of less than 0.25 nmol/ml. At pH 7.4, aclacinomycin A was even less effective at the elevated temperature. At doses of greater than 0.25 nmol/ml, moderate hyperthermia decreased the cytotoxicity of aclacinomycin A at low pH.

Portal vein infusion of cancer chemotherapeutic agent emulsified with Lipiodol in regenerating liver after partial hepatectomy in rats.

Portal vein infusion of aclarubicin (ACR) emulsified with Lipiodol (LP) in regenerating liver after 70% partial hepatectomy in rats was evaluated for its safety and usefulness. DNA synthesis in regenerating liver was transiently suppressed by LP, ACR or LP+ACR, but no obvious inhibition was seen in aminopyrine N-demethylase activity and liver weights. LP significantly enhanced hepatic tissue levels of ACR and its active metabolites by long-term retention in the sinusoidal space. This study demonstrates that in rats LP has a powerful effect on the long-term retention of anticancer agents in the sinusoidal space after infusion into the portal vein, without aggravating hepatic damage by anticancer agents.

Collection of peripheral blood stem cells mobilized by high-dose Ara-C plus VP-16 or aclarubicin followed by recombinant human granulocyte-colony stimulating factor.

We developed an effective method for harvesting large numbers of peripheral blood stem cells (PBSC) for use in autotransplantation. Twenty patients with hematological malignancies were treated with high doses of Ara-C (12 g/m2) and VP-16/aclarubicin followed by administration of rhG-CSF (50 micrograms/m2). The optimal time for starting PBSC collection was determined by monitoring the CD34-positive stem cells in blood using immunomagnetic beads. PBSC were collected with a CS-3000 blood cell separator. A total blood volume between 7000 and 9000 ml was processed in each apheresis. Under these conditions, a total of 64 apheresis procedures was performed in the 20 patients. The mean numbers of mononuclear cells and of CFU-GM harvested per apheresis were 4.1 x 10(8)/kg and 110 x 10(4)/kg, respectively. A number of CFU-GM sufficient for engraftment (> 30 x 10(4)/kg) could be harvested by a single apheresis in 15 of the 20 patients. So far, 11 patients have been transplanted with PBSC and obtained rapid hematopoietic recovery. The median time to recover neutrophils more than 0.5 x 10(9)/l was 10 days, and that for platelets 50 x 10(9)/l was 11 days. This method for harvesting large numbers of PBSC allows safer autotransplantation in patients with chemoradiosensitive tumors, and is applicable to older patients.

A new approach to chemoembolization for unresectable hepatocellular carcinoma using aclarubicin microspheres in combination with cisplatin suspended in iodized oil.

Sixty-six consecutive patients with unresectable hepatocellular carcinoma (HCC) were treated with transcatheter arterial chemoembolization (TACE) using aclarubicin microspheres (ACRms) in combination with cisplatin suspended in iodized oil (Lipiodol, Laboratoire Guerbert, Paris, France) (CSL). The stages of the disease were as follows: Stage I (n = 1), Stage II (n = 10), Stage III (n = 26), and Stage IV (n = 29). The effectiveness of TACE was assessed by comparing ACRms with CSL with ACRms without CSL. Of 66 patients treated with ACRms and CSL, 62 (93.9%) could be examined for response. According to response criteria, there were 31 (50.0%) partial responses and 17 (27.4%) minor responses. In 13 cases (21.0%) there was no change and in 1 case (1.6%) there was progressive disease. The cumulative survival rate was 80.7% at 1 year, 64.2% at 2 years, and 50.6% at 3 years. The rates were significantly higher than those of the group treated with ACRms. Eleven patients in the ACRms and CSL group experienced clinical complications: cholecystitis (4.5%), pancreatitis (3.0%), liver abscess (3.0%), hepatic failure (3.0%), gastrointestinal bleeding (1.5%), and renal failure (1.5%). No lethal side effects related to the therapy were observed. TACE using ACRms in combination with CSL prolongs the survival of patients with unresectable HCC.

[Enhancement of selective drug accumulation and retention in normal and regenerating liver by the use of lipiodol in portal venous infusion in rats].

We studied selective accumulation and retention of lipiodol (LP) and anticancer agents in normal and regenerating liver tissue following portal infusion in rats. Total concentration of Aclarubicin (ACR) and its metabolites in liver tissue was higher in ACR + LP portal infusion group than in ACR portal infusion group both in normal and regenerating liver, concentration of active metabolites of ACR was higher in ACR portal infusion group than in ACR peripheral infusion group. Much higher concentration was found in ACR + LP portal infusion group. Histologic examination revealed more toxic effect on regenerating liver in ACR portal infusion group than in ACR + LP portal infusion group. Oil red staining demonstrated the retention of lipiodol more than 7 days following intraportal infusion in regenerating liver tissue. This study confirms that the ACR + LP portal infusion induces selective accumulation and long-term retention in normal and regenerating liver tissue, and may enhance the antitumor effect of drugs.

Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium.

Arterially administered Lipiodol Ultrafluid contrast medium selectively remained in various malignant solid tumors because of the difference in time required for the removal of Lipiodol contrast medium from normal capillaries and tumor neovasculature. Although blood flow was maintained in the tumor, even immediately after injection Lipiodol contrast medium remained in the neovasculature of the tumor. To target anti-cancer agents to tumors by using Lipiodol contrast medium as a carrier, the characteristics of the agents were examined. Anti-cancer agents had to be soluble in Lipiodol, be stable in it, and separate gradually from it so that the anti-cancer agents would selectively remain in the tumor. These conditions were found to be necessary on the basis of the measurement of radioactivity in VX2 tumors implanted in the liver of 16 rabbits that received arterial injections of 14C-labeled doxorubicin. Antitumor activities and side effects of arterial injections of two types of anti-cancer agents were compared in 76 rabbits with VX2 tumors. Oily anti-cancer agents that had characteristics essential for targeting were compared with simple mixtures of anti-cancer agents with Lipiodol contrast medium that did not have these essential characteristics. Groups of rabbits that received oily anti-cancer agents responded significantly better than groups that received simple mixtures, and side effects were observed more frequently in the groups that received the simple mixtures. These results suggest that targeting of the anti-cancer agent to the tumor is important for treatment of solid malignant tumors.