Purified polyclonal or monoclonal antibodies to tumorrelated antigens have been conjugated with anti-cancer drugs or toxins. Radiolabeled antibodies are also included in this paper. Various conjugation methods are used to make stable conjugates. The effect of the conjugates on target tumor cells or tissues have been investigated in vivo as well as in vitro mostly in experimental tumor sytems and specific inhibition of tumor growth has been observed in these systems. Clinical application of the targeting chemotherapy has been revealed that the approach will be the promising method for the treatment of early cancer or residual micrometastasis after the resection of the primary tumor tissues.

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For anticancer effects on metastatic lymph node, activated carbon adsorbed anticancer drugs were injected preoperatively into the present study, the adsorption isotherm of activated carbon adsorbed aclarubicin (ACR) was measured and its stability in solution was investigated. The adsorption isotherms of 5-FU and MMC were prepared and compared with that of aclarubicin. In the adsorption isotherm of CH-40 activated carbon, the amount of ACR adsorbed was better than that of 5-FU and MMC. The amount of ACR adsorbed for CH-1500 activated carbon was also better than that for CH-40 activated carbon. The stability of ACR adsorbed on activated carbon solution decreased as the concentration of the activated carbon increased. The stability when the activated carbon and ACR concentration ratio was constant in saline solution was 100% after 2 hours and 40% after 7 days.

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Accumulation and antitumor effect of anti-ferritin antibody on the liver cancer implanted in nude mice were studied. Human hepatocellular car-cinoma strain (HC-4) was implanted on the back of Balb/c nu/nu mice. The following day after implantation, 131-I labeld antiferritin antibodies were administered intraperitoneally. Thirds and 7th days after administration, whole body scintigraphy was done and on the 10th days rats were sacrificed to measure the relative radioactivities of each organs. Furthermore, tumor growth rates were calculated. As the results, all of mono and polyclonal antibodies were well accumulated to the tumor tissue both of on day 3rd. and day 7th. Tumor growth curves were depressed in the groups of antibodies injection compared with normal IgG group. In conclusion ferritin may have a possibility to be a target of imaging of human hepatoma and targeting immunotherapy.

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We have developed a prolonged release preparation of adriamycin with silicon as a carrier for use in localized chemotherapy of recurrent and metastatic cancer and in embolism chemotherapy of primary cancer. In the present study, we observed the temperature sensitivity of the drug release and tissue degeneration due to embedding in the muscle and tumor tissue in this system, and investigated the antitumor effects using cancer bearing rats, The results indicated that the drug release increased about two-fold when the temperature was changed from 37 to 43°C, and there was a marked improvement in component drug release efficiency when glycine was added in place of the silicon. When the prolonged-release preparation of adriamycin was embedded in the muscle tissue, degeneration of the surrounding tissue increased with the increase in the dose of the drug, There was also tissue degeneration associated with necrosis in the rapidly growing tumor tissue, and the drug showed continuous action. In the experiment using tumor-bearing rats, all of the tumors died within 10 days with an average survival period of 8.5±1.3 days after bearing the cancer in the control group, and an average survival period of at least 46.8 days, with 40% surviving for 60 days, in the group given the timerelease preparation. The prolonged release preparation showd marked life extending effects.

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Disposition characteristics of uricase(UC)and its conjugate with dextran derivatives were studied in mice. UC was conjugated with neutral dextran, cationic diethylaminoethyl-dextran(DEAED), or anionic carboxymethyl-dextran(CMD) with an average molecular weight of about 10, 000 by periodate oxidation. Conjugation with neutral dextran slightly accelerated the disappearance of UC which has a relatively long plasma half-life in mice. Conjugation with DEAED resulted in an extremely shorter plasma half-life and enhanced hepatic up-take and urinary excretion. On the other hand, conjugation with CMD gave a longer one than that of the native enzyme and uptake by the liver was restricted. These results suggest the biopharmaceutical properties of peptide drugs can be controlled by choosing the physicochemical properties of dextran derivatives. The usefulness of chemical modification with dextran derivatives was thus demonstrated.

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We studied the promoting effect of glycyrrhetinate and its derivatives on nasal absorption of insulin in rats. These derivatives can be divided into two groups based on mother structural skeleton. One group is 3-O-ester derivatives of glycyrrhetinate and the other group is 3-O-and 30-O-ester derivatives of a hydrogenated glycyrrhetinate analog. The former group consists of G2 2K, GA Na, GA-MHS 2Na and GA-HPh 2Ha and the latter group consists of DG-DHPh 2Na, HomAD-DHPh 2Na and HetAD-DHPh 2Na. These derivatives significantly promoted nasal absorption of insulin and decreased plasma glucose levels in rats. We found that the optimum concentration of these derivatives such as GA-MHS 2Na, GA-HPh 2Na and DG-DHPh 2Na was about 1%. The promoting effect of glycyrrhetinic ester groups on nasal absorption of insulin in rats is GZ 2K < GA Na < GA-MHS 2Na < GA-HPh 2Na. These results indicated that strength of the promoting effect differed by 3-O-ester groups. On the other hand, hydrogenated glycyrrhetinic ester analogs were more effective than the glycyrrhetinic ester group. Particularly, DG-DHPh 2Na and HomAD-DHPh 2Na were significantly promoted nasal absorption of insulin in rats, and bioavailability in the presence of these promoters was comparable to that following intravenous injection. It is indicated that glycyrrhetinate and its derivatives can be applicable to promotion of nasal absorption of insulin.

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In order to establish a new assay to detect shedding tumor associated antigens, anti-idiotypic monoclonal antibodies were prepared against monoclonal antibody 149.53 which reacted with human high moleculor weight-melanoma associated antigen. Serological characterization of anti-idiotypic monoclonal antibodies suggested that these monoclonal antibodies recognized private and distinct idiotopes of monoclonal antibody 149.53. Idiotype mapping of monoclonal antibody 149.53 showed that there might be at least three idiotopes on it ; one idiotope at a combining site, one at a noncombining site and another at an intermediate site. A new assay to detect shedding antigens is based on the inhibition of idiotype-anti-idiotype interaction. Anti-idiotypic monoclonal antibody against near combining site showed high % inhibition of idiotype-anti-idiotype interaction, while anti-idiotypic monoclonal antibody against non-combining site did not. The results of this assay were correlated significantly with those of double deter-minant immuno assay. The assay requires only one epitope of a given antigen, while double determinant immuno assay requires two distinct epitopes that are spatially far from each other on the same antigenic molecule, And therefore it may be useful for detection of shedding antigen.

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The drug release behavior and bioavailability of newly developed controlled release suspensions of ibuprofen were investigated. The suspension was prepared by suspending spherical matrices(particle diameter 350-800 μm) of the drug with acrylic polymer in aqueous media containing sodium carboxymethylcellulose and D-sorbitol whose pH was adjusted below 3.0. The drug release behavior of suspension precisely followed to that of original spherical matrix, suggesting little leakage of the drug from the suspended matrices during storage, The bioavailability of rapid drug release suspensions administrated orally was determined by the initial drug release rate of the suspended matrices in vitro dissolution test. Whereas the bioavailability of sustained drug release suspension orally administrated depended on the particle sires of suspended matrices, even with same drug release behavior in vitro. Finally, twice a day regimen was successfully achieved by administering orally 225.0 mg of the sustained release matrices suspended to beagle dogs.

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Selective increasing of drug delivery to tumor tissue is essentially required for enhancement of effects in cancer chemotherapy as same as selection of sensitive drugs. Based on the functional difference between tumor and normal tissue in microcirculation, marked and selective increase of blood flow in tumor was observed by angiotensin induced hypertension. Since 1978, clinical application has been carried out as IHC. In an experimental result, increase of life span of tumor bearing rats was obtained in the MMC under AII hypertension treatment group comparing with usual MMC i. v. group at each same dose, It suggests that total dose of drug administered obtaining the similar effect may be reduced in comparison with usual i. v. administration. According to the clinical results of IHC, dose intensity (DI) was calculated in induction and maintenance chemotherapy courses. DI of ADM was 7.2±2.8 mg/sq m/w for induction and 2.2±1.2 mg/sq m/w for maintenance course, and 5-FU was 540.2±341.6, 132.9±174.3 mg/sq m/w, and then MMC was 1.2±0.5, 0.2±0.1 mg/m²/w, respectively. Although these DIs, futhermore, must he compared with others in usual i. v. chemtherapy, selective enhancement of drug delivery to tumor tissue would be possible either to increase effects or reduce accumulation of toxicity in the hosts.

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Bovine liposomal-encapsulated superoxide dismutase (L-SOD) which was developed by A. M. Michelson has overcome the pharmacobiochemical problems (disadvantages) of the injection of SOD preparations ; the very short life span of free SOD (6 min) was to considerable extent prolonged (6-7 hr), and weak fixation and penetration (permeability) to the membranes of target cells where oxygen radicals or lipid peroxides are exerting their harms. As previously reported by us, the injection (2.5 mg twice a week) of L-SOD was markedly effective in Kawasaki's disease (mucocutaneous lymph node syndrome), intestinal ulcer of Behçet's disease, Crohn's disease and colitis ulcerosa, and lung fibrosis of progressive systemic sclerosis (PSS) and polymyositis (dermatomyositis). In addition, severe rheumatoid arthritis (RA), Sjögren syndrome and other oxygen radical-or lipid peroxide-related diseases are improved by L-SOD injection. Recently, it has been further found that L-SOD (1.5 mg twice a week) is effective in liver cirrhosis, fibrosis induced by radiation, and schizophrenics. Acute paraquat toxicosis taken for the purpose of suicide which had been completely beyond the treatment was well treated with continuous drip infusion of L-SOD. Skin ulcer lesions were also in shorter period healed and keloid formation was prevented with L-SOD injection. However, not only other free SOD preparations but also L-SOD have various problems and questions in their pharmacologic and biochemical actions in the body to be solved or to be answered. In animal experiment, it was verified that SOD does not work dose-dependently, but the dosis over optimal concentration adversely stimulate and increase inflammation. It has been the great question why only a very small amount of enzyme (1.5 mg twice a week) actually and effectively prevents inflammation ; this dosis is 1/20 to 1/150 of the SOD which usually exists in each tissue or organ in the body. Next, it is also the great question why allogeneic (human) SOD is ineffective in the diseases while heterogeneic (bovine) SOD is effective. Although in part answered by us^{1, 7)} and Michelson, why heterogeneic SOD has shown no severe allergy such as anaphylaxis? Further, regarding the clinical effectiveness of L-SOD in Behçet's disease, why L-SOD is ineffective in ocular type while it is dramatically effective in intestinal type? SOD preparations including L-SOD, although they seem to be actually recommendable for the various inflammatory diseases, there have been several problems to solved, and L-SOD is also still required to be improved, Additionally, it is not unlikely that allogeneic (human) SOD preparations are clinically effective in the diseases.

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In vivo targeting of urokinase by magnetic force was examined in mice, Urokinase was labeled with ¹²⁵I and was further conjugated with magnetite through a polyethylene glycol derivative. The magnetic urokinase was injected into the tip part of a tail vein of a mouse, while magnetic force (0∼12000 G) was applied to the root part of the tail as a target site. The distribution of radioactivity among various parts of a mouse was measured after the animal was sacrificed. By magnetic force of 12000 G, approximately as much as 60% of magnetic urokinase injected were localized in the target, the tail root. By applying magnetic force of 12000 G to the heart, approximately 20% of magnetic urokinase injected were attracted in the heart. There was almost no retention of magnetic urokinase in the tail root when the magnetic force of 12000 G was applied even 10 sec after the injection of the magnetic urokinase. It seems that if the magnetic urokinase misses the chance to be attracted by magnetic force and passes through the lung and the liver, it is readily trapped there. It is possible that magnetic urokinase might be used for targeting in the future.

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Disposition characteristics of uricase-polyethylene glycol cojugate (PEG-UC) in mice was compared with those of UC-carboxymethyl-dextran conjugate (UC-CMD). Native UC showed moderate elimination from plasma and significant accumulation in the liver, spleen, and kidney after intravenous injection. PEG modification resulted in a prolonged plasma circulation and a restricted tissue distributuion to a great extent, The effect of CMD modification was inferior to PEG modification. Thus PEG was revealed to be a excellent material for the chemical modification of peptide drugs to escape from the recognition of reticuloendithelial system. The present study also suggested that the modyfying material should be selected based on the elimination mechanism and purpose of delivery of aimed peptide.

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