Genetic enzyme deficiencies are diseases caused by defective enzyme expression or function due to abnormalities in the gene. Not sufficient therapeutic methods are available for most of these diseases. Thus, diet therapy, drug therapy and enzyme sup-plementation therapy are sometimes effective. Although there have been many attempts both in in vivo and in vitro systems to treat patients with genetic enzyme deficiencies by enzyme sup-plementation therapy, good results have been obtained from only a few of them. Adenosine deaminase deficiency causes severe combined immunodeficiency. Muscular injection of polyethyleneglycol-conjugated bovine adenosine deaminase to the patients effectively maintain near normal ability of them to resist microorganisms. Weekly injection has been able to maintain the near normal level of serum adenosine deaminase, and decrease the level of deoxyadenosyl nucleotides which were considered to be the toxic compounds in this disease. Among others, polyethyleneglycol-conjugated uricase was useful to treat patients with lymphoma who had undergone chemotherapeutic therapy. The most promising approach in this field might be gene therapy in which exogenous gene is introduced to the patients.

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Therapeutic applications of hypothalamic hypophysiotropic hormones were discussed. Pulsatile administration of gonadotropin-releasing hormone (Gn RH) is effective to maintain menstrual cycles and ovulation in female patients with hypothalamic gonadal dysfunction and testicular function in male patients. On the other hand, continuous administration of Gn-RH or its analog is able to suppress gonadal function and thereby gonadal hormonedependent activities effectively. Application of this medical gonadectomy includes treatments for excessive menstrual bleeding, endometriosis, prostatic cancer and benign prostatic hypertrophy. Thyrotropin-releasing hormone has been applied in patients with spinocerebellar degeneration or some kinds of consciousness disturbance and somatostatin analog has benn tried to treat acromegaly. Corticotropin-releasing hormone and growth hormone-releasing hormone have also therapeutic potentials. We believe that many-sided research trials, which include development of new potent analogs, new effective drug delivery systems and further elucidation of physiology and pathophysiology about the functions of the hypothalamic hormones, are inevitable to materialize therapeutic potentials of these hormones.

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Human IgG, which was used as a model of biological active peptides, was conjugated with lecithin. The lecithinized IgG showed a high accumulation in several organs in C₃H mice following intravenous injection. Moreover, it showed a high affinity to human lymphocytes, MM46 and Sarcoma 180 cancer cells. Particularly, the affinity of lecithinized lgG to MM46 and Sarcoma 180 cancer cells was about 6∼7 times as high as IgG only or the mixture of IgG and lecithin. In preliminary study, the lecitinized IgG accumulated higher in the injured arterial vascular lesions of SHR than that of normal rat. IgG showed the same accumlation into injured and normal arterial vascular lesions. The property of lecithinized IgG is similar to that of lipid microsphere with a 0.2 μm diameter in terms of tissue distribution SOD was conjugated with lecithin by the same method for IgG. The activity of the lecithinized SOD was not decreased in xanthine-xanthine-oxidase-cytochrome C method. The lecithinization of biological active peptides would be an effective DDS in the clinical application.

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Based on molecular mechanisms for various diseases, treatment of a patient with drugs that specifically normalize pathologic metabolisms occurring at the site of tissue injury has been focused attention. Since enzymes and bioactive peptides, such as peptide hormones, function extremely specifically even in vivo, they have been assumed to be excellent therapeutics. Recent progress in genetic engineering permits to produce sufficient amounts of human types of enzymes and bioactive peptides that can be used for medical treatment without any immunological complications. The technique of site-specific mutagenesis also permits to obtain protein-peptide drugs that are highly resistant to proteolysis. in vivo. Such a remarkable improvement in the technology of molecular biology seemed to open the new tactics for treating patients at molecular level. However, recent studies also revealed that these protein-peptide drugs are often ineffictive predominantly because of their unfavorable behavior in vivo, such as short half lives in the circulation and insufficient mobilization to their site (s) of action. The present work describes biological mechanisms by which the fates of enzymes and peptides in the circulation are determined, the theoretical background required for drug design by which in vivo behaviors of protein-peptide drugs can be controled to efficiently exhibit thier therapeutic actions. The new strategy for targeting enzymes and bioactive peptides by gene and protein engineering is also described.

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Recently, a remarkable progress has been done in thrombolytic therapy. The progress mainly depends on the newly develped route of administration (for example, intracoronary), and the development of more fibrin-specific fibrinolytic agents. The newly developed thrombolytic drugs, called as the “third generation” agents are t-PA(tissue-type plasminogen activator), which is fibrin-specific, scu-PA(single-chain urokinase-type plasminogen activator), which is activated on fibrin surface, and APSAC(acylated plasminogen-streptokinase activator complex), which has rather long in vivo half-life. The physiological half-lives of these agents in the circulation are short except a kind of acylated plasminogen-streptokinase activator complex (RBL 33575). Plasmin(“first generation” agent)is not used because of its extremely short half-life(0.1 sec)and its lack of fibrin-specificity. However, the “second” and the “third” generation drugs are useful notwithstanding their relatively short half-lives, because fibrinolytic agents must be administered as quick as possible before the development of organ failure due to disturbances of circulation. Quite recently, the drugs with more increasing fibrin selectivity have begun to be designed. These are mutants of the scu-PA, kimeras of these drugs with plasminogen, and hybrids of fibrinolytic agents and anti-fibrin antibody. Moreover, fibrotide, which inhibits activity of PAI, which neutralizes t-PA and urokinase.

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As prophylactic therapy of gastrointestinal carcinomas, we have made a study of immunotherapy with the liver regarded as local. An attempt was made to administer OK-432 emulsified with medium chain tryglyceride in order to increase transfer of the drug to the portal vein and target the liver by means of oral administration. Oral medication allows repeated administration and long-term treatment. The result of experiment using RI(¹⁴C-OK-432) showed that ¹⁴C-OK-432 levels in portal blood was higher by oral adminstration of OK-432-MCT emulsion than OK-432 solution. With regard to internal organ distribution, higher levels in the liver were presumed. The study on experimental hepatic metastasis, the group administered OK-432-MCT emulsion showed the most excellent inhibit effect of experimental hepatic metastasis as compared with the control group and OK-432 solution group.

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During last two decades cancer immunotherapy has become popular, and various biological response modifiers (BRMs) have been applied. We have studied an oral application of BRMs, especially PSK and OK-432 for immunotherapy of gastrointestinal cancer. Orally administered PSK and OK-432 augment antitumor immunity, such as NK cell activity, responsiveness to lectins, etc. of spleen and mesenteric lymph node lymphocytes of the mice transplanted with cecal tumor. They also augment antitumor immunity of peripheral blood and regional node lymphocytes in patients with gastric or colorectal cancer. The patients were orally administered with OK-432 after resection of gastric cancer, and their survival rate was significantly higher than that of the patients administered intradermally with OK-432 and of the patients administered orally with placebo. There results suggest that oral application of BRM may be beneficial for immunotherapy of gastrointestinal cancer.

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