Techniques and therapeutic effects for liver metastases of hepatic arterial infusion chemotherapy are introduced. The arterial redistribution by steel coils or liquid embolic material to gain the entire liver drug distribution and to prevent extra-hepatic drug distribution is very important for the long term repeated hepatic arterial infusion chemotherapy without complications, And the techniques for percutaneous hepatic arterial catheter placement is established and its invasion is very limited compared with that by laparotomy. In our phase II study, the response rate, median survival and prevention rate of death were 75%, 22mo, 62% in colorectal cancer (n=32), 72%, 17mo, 72% in gastric cancer (n=40) and 81%, 12mo, 70% in breast cancer (n=56), respectively. Thus, hepatic arterial infusion chemotherapy is highly active and has much potential for preventing death due to liver metastases without major reduction of pts' QOL. However, the role of this therapy on the therapeutic strategies for liver metastases is not established, because the impact on survival of this therapy compared with systemic chemotherapy is uncertain.

View full abstract

L-arginine-L-glycine-L-aspartic acid (RGD) sequence, originally found in fibronectin, one of main component of extracellular matrices, is known as a ligand to some adhesion molecules. Since the interaction of metastatic tumor cells with target endothelium and extracellular matrices under it, is important for establishment of blood-borne metastasis, analogs of the peptide have been developed for the suppression of tumor metastasis. In fact, some synthetic peptides having the RGD sequence have been found to decrease metastatic colonization. To enhance the metastasis-suppressing efficacy of these analogs, we attempted to stabilize and to prolong the circulation time of these analogs by liposomalization. Various structures of hydrophobizcd-RGD analogs (lipophilic antimetastatic peptides, LAPs) were synthesized, and incorporated into liposomes. Liposomes composed of distearoylphosphatidyl-choline, cholesterol, dipalmitoylphosphatidylglycerol and LAPs were injected intravenously with B16BL6 murine melanoma cells into mice. Liposomal RGD (0.6 μmol of the analog equivalent to ca. 200 μg RGD peptides) inhibited lung colonization up to 76%. This dose is an order of magnitude lower than that for comparable inhibition reported for free RGD. Multi-dose administration of LAP-liposomes (0.15 μmol of the analog equivalent to ca. 50 μg RGD peptides) also inhibited the spontaneous lung metastasis of cells from a primary tumorsite of B16BL6 cells subcutaneously implanted into the footpad of mice. In conclusion, liposomal RGD may be useful for the suppresion of tumor metastasis.

View full abstract

An application of zein, a water-insoluble corn protein, to sustained-release tablets was studied. It was found that the drug release from the tablets prepared from spray-dried particles of zein/theophylline/brilliant blue FCF (BB) was affected by drug amount in the tablets and pepsin in a release medium, but little by pH and pancreatin in the medium. The theophylline release was apparently zero-order in the release medium containing pepsin probably due to the erosion of the tablets by the enzyme. The zein tablets containing BB were pepsin-resistance and the drug release was retarded. The addition of BB in the release medium also showed the same effect. Salivary concentrations of theophylline following oral administration of the drug powder, the zein tablets and a commercially obtained sustained-release tablet were determined in 4 male healthy volunteers. The dose-normalized AUCs of these theophylline preparations did not differ significantly, suggesting that the extent of bioavailability of these preparations was much the same. The mean residence times (MRTs) of T41 tablet (pepsin-sensitive ; zein : theophylline=4 : 1) were not different from those of the commercial tablets significantly. However, the MRTs of T41B1 tablet (pepsin-resistant ; zein : theophylline : BB=4 : 1 : 0.1, 31.8±9.0h, mean±SD, n=4) was significantly longer than that of T41 (20.9±4.1h, mean±SD, n=4) (p<0.05, paired t-test). T41B1 tablets might be pepsin-resistance even in vivo.

View full abstract

The permeability of drugs across the Xenopus pulmonary membrane and the effects of various additives on transport of drugs and electrophysiological parameters were examined using an in vitro Ussing chamber technique. Insulin, phenol red and FITC-labeled dextrans (FDs) with various molecular weights were chosen as model drugs. Additives used in this study were N-lauryl-β-D-maltopyranoside (LM), sodium glycocholate (NaGC), sodium salicylate (NaSal), disodium EDTA (EDTA), soybean trypsin inhibitor (STI) and bacitracin. The permeability of drugs gradually decreased with increasing their molecular weights. There exists a good correlation between the logarithm of molecular weights of drugs and the logarithm of apparent permeability coefficients of drugs. The permeability of phenol red and insulin significantly increased by LM. However, other additives showed no significant effect. Transepithelial electrical resistance (TEER) was markedly decreased after the addition of LM. On the other hand, a slight decrease in the TEER value was observed in the presence of NaGC. These findings suggest that this method is useful for estimating the transport characteristics of drugs across the pulmonary membrane.

View full abstract

To establish an acceptable postoperative chemotherapy for lung cancer, 2 mg/m²/day of CDDP was infused continuously with 300 or 400 mg/day of UFT. Hydration was not performed during CDDP administration. We treated 32 patients. The concentrations of the protein-bound platinum (total-Pt= T-Pt) (μg/ml) in serum from weeks 1, 2, 3, 4, 5, and 6 of the treatment were 0.249±0.143, 0.402±0.155, 0.494±0.142, 0.567±0.158, 0.574±0.132, and 0.567±0.125, respectively. After two weeks of treatment, the T-Pt augmented significantly (p<0.05) as compared with those of after one week. Non protein-bound-platinum was not detected during this period. Area under the concentration-time curve (AUC) of the T-Pt (μg·hr/ml) from weeks 1, 2, 3, 4, 5, and 6 were 22.36±11.09, 76.09±35.81, 152.62±59.10, 232.74±73.65, 334.22±75.16, and 438.27±95.96, respectively. After six weeks of treatment, the concentrations and AUCs of the T-Pt seemed to be sufficient for an anticancer treatment. The side effects associated with this treatment were grade I and II anorexia in six cases and leukopenia in three cases. The treatment was interrupted because of grade III anorexia in one case (3 weeks) and vomiting in one case (3 weeks), However, recovery from the side effects was immediate. We think this treatment contributes to an improvement in the patient's postoperative quality of life.

View full abstract

Novel assay method for antisense effect of oligodeoxynucleotides was designed. Antisense oligodeoxynucleotides (21mer) complementary to the region of the translation start site of c-jun and c-fos protooncogene inhibit apoptotic FM3A cell death induced by 5-fluoro-2'-deoxyuridine. Since antisense effect can be detected as survival of the cells, non-specific cytotoxicity of oligodeoxynucleotides can de neglected in this system. Though this inhibition effect is not directly related to a certain clinical target, the system is useful for the evaluation of novel designs in oligodeoxynucleotide molecules and/or antisense carriers. Phosphorothioate and 3'-terminal modified oligodeoxynucleotides were evaluated for their antisense effect in this system.

View full abstract

We prepared liposomes containing ultrafine magnetite particles as magnetically targeted drug delivery system, and evaluated their physicochemical and biological characters ; diameter, magnetic responsiveness, trapping efficiency and uptake to cells. A mixture of asolectin and cholesterol (4 : 1) was dispersed in physiological saline (final lipid concentration : 20 mg/ml), and coprecipitated magnetite particles were added to the medium and it was sonicated. Multi-lamellar liposomes (average diameter : 155nm) were prepared from this medium by the freeze-thawing method. We confirmed holding of the magnetite particles inside the liposomes by TEM. Trapping efficiency was evaluated by encapsulation of fluorescent calsein, and it was approximately 8%. Magnetic responsiveness was estimated by the capture of the flowed liposomes in a glass tube under magnetic field application. At least 50% of liposomes were retained by the applied magnetic field (gradient : 2.6 kG/cm). We also visualized uptake of the fluorescent labeled liposomes into porcine endothelial cultured cells with a confocal laser scanning microscope, and observed the localization of liposome uptake in small intracellular vesicles around nuclei. From these physicochemical and biological characterization of liposomes containing ultrafine magnetite particles, we demonstrated the feasibility of these liposomes as carriers for magnetically targeted drug delivery system.

View full abstract

[in Japanese]

View full abstract

Cepharanthine (CEP) is reported to be effective in prevention of immune suppression and leukopenia induced by administration of antitumor agents. In this study, we examined relationship between the phagocytotic activity of peritoneal macrophages and the immuno-modulating action of CEP-incorporating liposomes composed of egg phosphatidylcholine and cholesterol in a molar ratio of 7 : 2. Multilamellar liposomes (MLV) were prepared by vortexing dried lipid films, and small unilamellar liposomes (SUV) by ultrasonication of MLV. Antigen (pneumococcal polysaccharides) and CEP-containing liposomes were injected intraperitoneally to BALB/c mice, and peritoneal macrophages were collected at designated times. The phagocytotic activity of the peritoneal macrophages was assessed with regard to the uptake of latex beads by the cells. The time-course of phagocytotic activiy was shown to be correlated with the antigen-specific IgM antibody production. The phagocytotic activity was dependent on the dose of CEP, but was not influenced by peritoneal exudate cell number or the presence of antigen. The CEP-containing MLV increased the phagocytotic activity of peritoneal macrophages to a greater extent than SUV. In conclusion, it was demonstrated that the immuno-modulating activity of peritoneally injected CEP is closely related to the phagocytotic activity of peritioneal macrophages, that CEP-containing MLV exhibit greater stimulatory effect on the phagocytotic activity of macrophages than CEP-containing SUV, and that the immuno-modulating action of CEP is enhaced by incorporation into liposomes.

View full abstract