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M Hashida

Publications and source records attributed to M Hashida.

At least 235 records · Page 13Linked to original sources
PubMed1984

Macromolecule-drug conjugates in targeted cancer chemotherapy.

Although clinical trials using macromolecular conjugates of cytotoxic drugs in a treatment of malignant disease are fragmentary at best, a number of carrier systems that have been examined in vitro, in tissue culture, and in vivo animal experiments demonstrate great promise and warrant further extensive examination. The optimal drug delivery and, consequently, maximum therapeutic effect will be accomplished when all available information from diverse disciplines can be integrated. This review has attempted to point out some of the limitations of taking an optimistic view of the question of targeting drug delivery using macromolecule-drug conjugates. For example, a strategy for the development of macromolecular conjugates can be established based on characteristics of the targeted tumors and the drugs in prospect of great success. Biological and physiological features of the tumor such as a cell type, site, and the pharmacological and physicochemical properties of chemical agents such as site of action and chemical stability must be considered at the first step. Selection of the optimum carrier system will be accompanied when all these problems are carefully considered. Similarly, the optimum method of conjugation is likely to vary as a function of the carrier, the chemotherapeutic agent, and the delivery site or site of action of the agent. The stability of the bond must adopt itself to the mode and site of action of the agent, the necessity for release, and the availability of hydrolytic enzymes which break the linkage and release the agent. On the other hand, the success of such conjugates synthesized according to this strategy will depend on physicochemical properties of the conjugates such as molecular size, electric charge, and solubility; chemical and biological stability of active components of conjugates and linkages; interaction with the tumor cells; cytotoxicity in tissue culture system; pharmacokinetics in the body such as absorption profile, localization, and elimination manner; in vivo antitumor activity; and biodegradability and antigenicity of the conjugates. The practitioners of macromolecular conjugate research find themselves in the interesting, but difficult, position of being at the interface between basic information on the drugs and biological systems and an expanding clinical demand for more sophisticated therapeutic agents. Consequently, knowledge is demanded not only of the chemical, physical, and pharmaceutical properties of macromolecules, but also of pathophysiology of the condition being treated.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Enhanced lymphatic delivery of mitomycin C conjugated with dextran.

Absorption and lymphatic transfer of a polymeric prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D), following i.m. injection were studied in rats in order to assess the feasibility of a macromolecular prodrug as a lymphotropic delivery system. Three types of MMC-D, conjugates with dextran with molecular weights of 10,000, 70,000 and 500,000, were synthesized, and the disposition of MMC was determined by bioassay. Following i.m. injection of MMC-D, MMC was retained at the injection site for a long period in a conjugated form while MMC administered as a free form disappeared rapidly. The disappearance was markedly influenced by the size of carrier dextran, because the remaining amount of MMC increased with an increase of molecular size. The lymphatic uptake of the drug was evaluated by determining the concentration in the regional lymph nodes and thoracic lymph fluid. In contrast to a slight lymphatic uptake following i.v. and i.m. injection of free MMC, MMC-D exhibited remarkable accumulation in the regional lymph nodes after i.m. injection which persisted up to 48 hr. MMC-D (Mr 10,000) appeared in the thoracic lymph as both the conjugated and the free form. Larger MMC-D gave a persistent supply of free MMC in thoracic lymph, suggesting that it was accumulated in the lymph node and supplying MMC continuously. These MMC-Ds suppressed the lymph node metastases introduced by a s.c. inoculation of L1210 leukemia cells. The usefulness of MMC-D as a lymphotropic delivery system for preventing lymphatic metastasis of cancer was suggested.

Animals↗
PubMed1984

[Local administration of anti-cancer drugs].

Anti-cancer drugs in the forms of an emulsion, a microsphere, and of conjugates with high molecular dextran have been developed in our laboratories, namely a fat emulsion of anticancer drug, MMC-microsphere, or MMC-dextran conjugates. The main advantages of these forms of pharmaceutical preparation are that they give prolongation of pharmacological actions by slow release and that they are applicable for topical use because of their reduced toxicities to local tissue yet maintaining local therapeutic potency. In this study we found that the rate of sustained release of drugs and antitumor effects were enhanced when used in such modified forms of drugs for topical injections. Results of clinical trials of those drugs have been promising. However, the number of trials has been limited so far. Further studies would be required for evaluating on of their clinical utilities.

Adult↗
PubMed1983

Prodrugs of 6-thiopurines: enhanced delivery through the skin.

Soft-alkylated derivatives of 6-mercaptopurine, its riboside, and 2-amino-6-mercaptopurine riboside have been prepared and evaluated to improve the delivery of the thiopurines through the skin. The soft-alkylated derivatives were prepared by the alkylation of the thiopurines with acylheteroalkyl halides under neutral or basic conditions. The penetration of the derivatives through hairless mouse skin was measured using diffusion cells. All of the derivatives underwent extensive degradation during their diffusion through skin so that the parent thiopurine, even in the case of the ribosides, was the major product observed in the receptor phase. The pivaloyloxymethyl derivatives showed the greatest potential for enhancing the penetration of the thiopurines through the skin. Among the 6-mercaptopurine derivatives, VII and XI were the most effective; they delivered 5 and 13 times, respectively, more 6-mercaptopurine than 6-mercaptopurine itself.

Animals↗
PubMed1981

Antitumor activity of mitomycin C-dextran conjugate against various murine tumors.

The antitumor activity of a high molecular weight pro-drug of mitomycin C(MMC), MMC-dextran conjugate (MMC-D), was examined against various murine tumors under different experimental conditions. A single intraperitoneal injection of MMC-D exhibited higher antitumor activity against intraperitoneally inoculated B16 melanoma, Ehrlich ascites carcinoma, and P388 leukemia than MMC, but lower activity against BDF1 mouse-transplanted L1210 leukemia. Intratumoral injection of MMC-D showed a superior effect on subcutaneously implanted B16 melanoma, while intravenous injection of MMC-D exhibited reduced activity against P388 and L1210 leukemia compared with MMC. Prior administration of MMC-D at 24 hr before tumor inoculation resulted in a significant increase of the life span of mice bearing L1210 leukemia, suggesting that it shows sustained pharmacological activity. These differences between the activities of MMC-D and MMC in various tumor systems are considered to reflect the improved biopharmaceutical properties of MMC-D resulting from the modification of MMC into a polymeric drug.

Animals↗
PubMed1981

Experimental study on lymphatic vascular changes in the development of cancer.

Sudan Black B and Sudan Blue can partly enter the lymphatics of the small intestine from the lumen with long chain fatty acids. By use of a fat emulsion saturated with them small intestinal and mesenteric lymphatics were clearly delineated. Subserosal and mesenteric lymphatics of the small intestine appeared as blue lines. With this method we studied anatomical changes of the lymphatic vessels during the development of cancer. As experimental tumor VX2 carcinoma was used. Lymphatic vessels were not be found in cancerous regions by this lymphangiographic procedure, even in the early stages of cancer. Lymphatics passing through the tumorous tissue were completely obstructed and accompanied with peripheral dilatation. Compared to the morphological changes of the blood vessels, which were studied microangiographically, the lymphatic vessels were more easily affected by the malignant growth.

Animals↗
PubMed1980

Mitomycin C-dextran conjugate: a novel high molecular weight pro-drug of mitomycin C.

A high molecular weight derivative of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D) has been synthesized and its biological and pharmacological properties investigated. MMC is released from MMC-D in vitro with a half-life of 24 h. After intraperitoneal injection of MMC-D, free MMC could be detected in plasma and urine of mouse for 5--8 h, while MMC administered as a free form was eliminated rapidly. After MMC-D, given to mice bearing Ehrlich ascites carcinoma or B16 melanoma there was a reduction in toxicitst that the high molecular weight MMC-dextran derivative is a kind of pro-drug which persists in the body giving a sustained release of free MMC thus significantly increasing the antitumour activity of the parent drug.

Animals↗
PubMed1980

Epidemiologic and preventive studies of rubella in female office workers.

In order to prevent maternal rubella infection, serum antibody titers for rubella were estimated in a total of 965 female office workers residing in the vicinities of Tokyo and Osaka using hemagglutination-inhibition test. Approximately 40% of the young women tested were then observed to be susceptible to the disease, and the percentage was not apparently changed by a large rubella epidemic which occurred while our research proceeded, suggesting the necessity to attain immunization in the suceptible before pregnancy. By our surveillance on the occurrence of rubella infection over one-year period among the women having received the serologic test, we found a particular case, where a titer of 1 : 8, being considered to be the immunized level, had been determined. The finding indicates that vaccination should be aimed at the persons having the titer of 1 : 8 as well as of less than 1 : 8. Attenuated live rubella-virus vaccine was administered to 42 volunteers susceptible to the disease, and their serum titers were estimated again about one year after the inoculation. Then, the vaccination proved effective in 41 of the vaccinees but one who was found still susceptible by unknown reason.

Adult↗
PubMed1980

Surgical chemotherapy against lymph node metastases: an experimental study.

Accompanying surgical resection of the primary tumor is removal of its drainage lymph nodes. However, all of the minute regional lymph nodes cannot be identified and some may be left behind. If a certain anticancer agent in the form of an emulsion is injected topically into the lymph nodes, it may suppress the lymphatic metastases. Domestic rabbits were used as experimental animals, because transplantable VX2 tumors are available. The vermiform appendix was selected as the transplantation site because of its rich supply of lymph follicles, simulating lymph nodes histologically, and because the path of lymph drainage is very simple. The drainage lymph node, which is located at the root of the appendix, was selected for study. The rate of transfer of bleomycin into lymph nodes and of its sustained release from the nodes was extremely enhanced by the use of a sphere-in-oil-type emulsion--more than two times higher than in the use of a W/O emulsion. Although prolongation of survival time did not take place in animals receiving the bleomycin solution topically or intravenously, five of the seven rabbits receiving the local administration of bleomycin as a sphere-in-oil or a water-in-oil emulsion, between which differences were not found in tumor effects, survived with complete reduction of the lymph node metastases.

Animals↗
PubMed1978

Antitumor activity of prolonged-release derivative of cytosine arabinoside, cytosine arabinoside-agarose conjugate.

A prolonged-release derivative of cytosine arabinoside (Ara-C), cytosine arabinoside-agarose bead conjugate (Ara-C-AB), was synthesized and its pharmaceutical and pharmacological characteristics were examined. Ara-C was released successively for considerably long period from Ara-C-AB in vitro. Following intraperitoneal injection of 3H-Ara-C-AB, radioactivity could be detected in plasma and urine of BDF1 mouse for four days, while 3H-Ara-C administered as a free form was excreted completely in the first 24 hr. Increase in lifespan of L1210 leukemia-bearing mice was demonstrated after intraperitoneal injection of Ara-C-AB with both the dosage schedules of three days before and one day after inoculation of L1210 cells at the dose of 30 mg equivalent Ara-C/kg.

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