Immunotoxins (ITs) are antibody-based reagents which generally consist of monoclonal antibodies(mAbs) and toxins or their subunits. For the last two decades studies of ITs have made great progress in treating cancers. More recently, possibilities of treating AIDS and some autoimmune diseases by ITs have stared to attract attentions of researchers who are looking for effective drugs for these intractable diseases. Previously constructed ITs for infectious diseases were mainly for HIV ; however, ITs for other viral infection are also valuable to be investigated. The only ITs so far studied for the treatment of autoimmune diseases are those specific for IL-2, IL-2 receptor, and L3T4. In this report, we discuss possible use of ITs for treatment of autoimmune diseases and viral infections referring to the latest related publications.

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Antisense DNA are able to bind to complementary sequences in DNA, pre-mRNA, mRNA and thus, interrupt gene expression with high specificity. This innovative concept has aroused great attention of pharmaceutical scientists in developing of antisense DNA as potential therapeutic reagents. However, this approach has several shortcomings including instability, low membrane permeability. Although modified DNA have been synthesized to overcome these shortcomings, there is no analogue structure yet devised fulfils all the requirements of an ideal antisense effector so far. For the successful application of antisense DNA, it is prerequisite to take considerations in terms of biological stability, cellular uptake, hybridization efficiency, non-toxicity and delivery tools. In this review, basic concept of antisense strategy and possible application of antisense DNA as anti-inflammatory reagents will be discussed. Furthermore, the current trends and future prospects of antisense DNA will be addressed.

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IHC which is an application of characteristics of tumor microcirculation for drug delivery, makes possible to increase chemotherapeutic effects. To examine a role of selective enhancement of drug delivery in biochemical modulation (BCM), cytodegenerative and growth inhibitory effects of methotrexate (MTX) and 5-fluorouracil (5-FU) on LY-80 hepatoma cells were investigated. A combination of MTX : 2 mg/kg+5-FU : 20 mg/kg of 5-consecutive-days-administration (day 3∼7 after inoculation)showed the highest cytodegenerative effects on intraperitoneal LY-80 cells, comparing with the other MTX/5-FU and 5-FU/leucovolin (LV)combination. Time interval effect was not obviously defined in this system. Growth inhibitory effect of MTX 2 mg/kg+5-FU 20 mg/kg on subcutaneous tumor which 5×10⁵ of LY-80 were transplanted, was signifficantly enhanced by IHC, comparing with that of non-IHC in both day 7, 9, 11 and 9, 12, 15 administration groups. LV rescue which 5 mg/kg was administered 1 hour after MTX/5-FU, had prevented inhibitory effect on tumor as well as had reduced weight loss of rats. According to this preliminary results, it showed that enhancement of drug delivery had an important role for chemotherapy using BCM.

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The usefulness of anti-idiotypic(Id) antibodies was investigated in the malignant melanoma antigenic system. Anti-Id monoclonal antibodies (MoAbs) were established to MoAb M2590 (1gM) which recognized the glycolipid GM3 on the syngeneic Melanoma B16 cells. Anti-Id MoAb D704 had a specificity only to MoAb M2590, recognized the private idiotype, and furthermore was serologically supposed to have an internal image of Ag. In vivo experiments were performed to see the anti-Id MoAb effect to melanoma cells transplanted black mouse. Internal image-bearing anti-Id MoAb D704 showed the vaccine effect against transplanted syngeneic melanoma cells. Therefore, internal image bearing anti-Id antibodies may be useful for induction of a host's immune response against tumors.

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Transfer of fluorescein isothiocyanate labeled dextrans(FD) to parapulmonary lymph nodes following intratracheal administration was investigated in rats, to clarify relationship between transfer of drug to parapulmonary lymphatic system and molecular weight. The concentrations of FD in parapulmonary lymph nodes increased with increasing molecular weight. For selective transfer of anticancer drugs to a parapulmonary lymphatic system, a macromolecular cisplatin(CDDP) derivative was synthesized by chemical modification with polyethyleneglycol, and the transfer of drug to the parapulmonary lymphatic system following intratracheal administration of the CDDP derivative was investigated. The concentrations of CDDP derivative in parapulmonary lymph nodes were much higher than that of CDDP. These findings suggested that chemical modification of CDDP with macromolecules is an effective approach for its selective transfer to parapulmonary lymphatic system.

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The inhibitory potency of facteur thymique serique(FTS) on the mouse metastatic lung cancer induced by Lewis 3LL lung carcinoma cells was investigated. The consecutive treatments with FTS resulted in a significant prolongation of the survival time for mice injected i. v with Lewis 3LL lung carcinoma cells. FTS also suppressed the tumor growth and prolonged the survival time for Ehrlich solid tumor-bearing mice. FTS was fastly cleared from the blood circulation with an initial halfe life of about 10 min after i. p administration. Ganglioside GM1-containing liposomes remarkably increased the blood level and prolonged the halfe life of FTS. A few time of treatment of FTS entrapped liposomes showed the same potency as the consecutive treatments of free FTS in the metastatic lung cancer model. These results suggest that the GM₁-liposomes with prolonged circulation time would be useful for the sustained release of drug with a short halfe life.

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In patients with Stage III or more advanced gastric cancer, a suspention of OK-432 and lipiodol was administered by local injection into the retroperitoneal space at the time of lapalotomy. Then, computed tomography (CT) at the hilum pulmonis was conducted to observe the extent of the suspention by taking a picture of lipiodol. CT performed 1 week after the operation showed the cumulation of lipiodol at the hilm pulmonis and mediastinal lymph nodes only in a patients with gastrectomy and a patient with total gastrectomy and pancreaticosplenectomy. These 2 patients had greater intraperitoneal lymph node metastasis (N4) than other patients(N2 or smaller). In patients more likely to develop lymph node metastasis, the hilum pulmonis and mediastinal lymph node might be in a state of easily taking up a foreign matter lipiodol, and therefore the CT performed even after 1 week could catch lipiodol. From these results, the present local injection is expected to be useful therapeutically and prophylactically in patients with lymphogenenous metastasis or those likely to have metastasis.

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Inhibitory effect of superoxide dismutase derivatives modified with various sugar moieties on hepatic injury was examined in rats. Four types of superoxide dismutase (SOD) derivatives, SOD-carboxymethyl dextran conjugate (SOD-CMD), SOD-diethylaminoethyl dextran conjugate (SOD-DEAED), galactosylated SOD (Gal-SOD), and mannosylated SOD (Man-SOD), were used and hepatic injury induced by ischemia/reperfusion was evaluated by analysis of biliary excretion of bromosulfophthalein (BSP) injected intravenously. SOD and SOD-DEAED did not show significant inhibitory effect. SOD-CMD exhibited a slight recovery of biliary excretion of BSP, but the effect was not significant. On the other hand, Gal-SOD and Man-SOD, which were targeted to the liver parenchymal and non-parenchymal cells respectivery by a receptor-mediated endocytosis, almost completely inhibited the hepatic injury. In particular, Man-SOD showed a great inhibitory effect. These results demonstrated that two types of glycosylated SOD derivatives, Gal-SOD and Man-SOD, were useful for the prevention of hepatic ischemia/reperfusion injury. Thus, targeted derivery of SOD to the liver at a cellular level was achieved by chemical modification with sugars. The findings of the present study also will give useful basic information on the mechanism and prevention of tissue injury induced by ischemia/reperfusion.

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Oxidized carboxymethyl-D-manno-D-glucan (MG-CM-AD)-DXR conjugates were prepared via Schiff's base formation and compared tissue distribution of the conjugates with that of DXR. The water-soluble conjugates, which had DXR contents of 11∼13% (w/w) and degrees of substitution(DS)of CM groups of 0.5∼1.0, released DXR with an increase in the DS values in 50 mM phosphate buffer(pH 7.4)at 37°C. The conjugates showed higher plasma and tumor concentration but lower heart concentration than DXR at 24 hr after the intravenous injection into Walker 256 bearingrat. The area under the concentration-time curve from 0 to 48 hr of MG-CM [0.5]-AD-DXR(DS of CM groups : 0.5) was 2 times higher on tumor, but 2 times lower on heart than that of DXR. These findings suggest that MG-CM [0.5]-AD-DXR should exhibit a higher antitumor effect and less toxicity than DXR.

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We prepared new water-in-oil-in-water emulsions (W/O/W), containing water-soluble anti-cancer drugs, epirubicin and carboplation, in the lipiodol droplets(oil) by the membrane emulsification technique with controlled pore glass membrane. Epirubicin(10 mg) or carbopiatin(150 mg)was dissolved in 5 ml of 0.58% glucose solution or 15 ml of 0.75% saline, respectively. Each solution was mixed with lipiodol containing 5 wt% of tetraglycerol esters of interesterified ricinoleic acid. The mixture was sonicated to form a submicron particle sized water-in-oil-emulsion (W/O) containing one of the anticancer agent. W/O was permeated through the membrane at a pressure of 54 kPa into glucose solution forming new W/O/Ws. Mean particle size of the oil droplet was about 25 μm and 8 μm when prepared with 4.2 μm pore sized membrane and 1.4 μm, respectively. Stability of oil droplets was maintained over 40 days after preparations. This was confirmed by microscopic observations and by measurements of droplet size with laser reflection particle analyser. Dissolution rate of epirubicin from the droplet into outer water is measured by dialysis in the constant flow of 5% glucose solution, which was, after 9 days, calculated to be 15%. The W/O/W will be used in the field of chemoembolization for hepatocellular carcinoma, or in general, targeting chemotherapy.

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