Biomedical subjects
Publications and source records attributed to Y Tanio.
Multiple intralesional injections of quinonylmuramyl dipeptide-66, a new synthetic immunoadjuvant, with a vehicle oil such as squalene or squalane resulted in the regression of line-10 hepatocarcinoma in strain-2 guinea pigs. This chemically synthesized adjuvant should be a useful immunotherapeutic agent for cancer.
The cell-wall skeletons of Listeria monocytogenes strain EGD and Propionibacterium acnes strain C7, which have the ability to induce macrophage activation, were analyzed, and the structures of the peptidoglycans were investigated. The analytical data indicate that both peptidoglycans have glucosamine residues with free amino groups, which are responsible for the resistance to lysozyme. Possible structures of these peptidoglycans were deduced from the composition and the results of determination of N- and C-terminal amino acids, together with the characterization of fragments obtained by enzymatic treatment and partial acid hydrolysis of both peptidoglycans. The results suggested that the peptidoglycan of L. monocytogenes contains a cross-linkage region of peptide chains with meso-diaminopimelic acid and D-alanine, which belongs to the A1 gamma type (Schleifer, K.H. & Kandler, O. (1972) Bacteriol. Rev. 36, 407-477), whereas the peptidoglycan of P. acnes contains a cross-linkage region of peptide chains with L,L-diaminopimelic acid and D-alanine, in which two glycine residues combine with amino and carboxyl groups of two L,L-diaminopimelic acid residues. The latter type should be classified as a new type. These cell-wall skeletons and peptidoglycans were shown to have immunoadjuvant activity on the induction of delayed-type hypersensitivity and suppressive activity on the growth of 3-methylcholanthrene-induced fibrosarcoma in BALB/c mice, and the peptidoglycans were shown to be an immunological-active principle of these cell-wall skeletons.
The immunological properties of peptidoglycan (L-PG) purified from the cell wall skeleton (L-CWS) of Listeria monocytogenes strain EGD were investigated and compared with the properties of L-CWS. L-PG consisted of alanine, glutamic acid, alpha, epsilon-diaminopimelic acid, muramic acid, and glucosamine. L-PG showed potent adjuvant activities for circulating antibody formation and development of delayed-type hypersensitivity to bacterial alpha-amylase in vivo and for the primary immune response to sheep erythrocytes in vitro, as well as L-CWS. Both L-PG and L-CWS enhanced the generation of cell-mediated cytotoxicity in allogeneic mice and activated thioglycolate-elicited peritoneal macrophages and macrophage cell line RAW 264 to kill tumor target cells in vitro. We also found that L-PG acted on normal spleen cells as a mitogen. Both L-PG and L-CWS had tumor (Meth A)-suppressive and -regressive activities in syngeneic mice. Our results suggest that the L-PG moiety retains the adjuvant and antitumor activities of L-CWS.
The adjuvant and tumor-suppressive activities of the quinonyl [2,3-dimethoxy-5-methyl-6-(9'-carboxynonyl)-1,4-benzoquinone (QS-10)] derivatives of N-acetyl muramyl dipeptides were examined. N-Acetyl muramyl-L-valyl-D-isoglutamine (MurNac-L-Val-D-isoGln), QS-10-MurNAc-L-Val-D-isoGln, and their methyl esters were shown to have potent adjuvant activity on the induction of delayed-type hypersensitivity to monoazobenzenarsonate-N-acetyl-L-tyrosine in guinea pigs and on the primary immune response against sheep erythrocytes in vitro; however, only QS-10-MurNAc-L-Val-D-isoGln methyl ester, i.e., QS-10-MurNAc-L-Val-D-Glu(OCH3)NH2 (quinonyl-MDP-66), was shown to be an active adjuvant for the induction of allogeneic killer T cells in mice and the suppression of tumor growth in syngeneic mice when it was administered as a suspension in phosphate-buffered saline. The effectiveness of the chain length of the quinonyl moiety in quinonyl-MDP-66 and the replacement of the L-valine residue with L-serine or L-threonine were also examined in comparison with the adjuvant and tumor-suppressive activities of quinonyl-MDP-66.
The 6-amino-6-deoxy-N-acetylmuramyldipeptides and their 6-acylamino derivatives were shown to be active as adjuvants on the induction of delayed-type hypersensitivity to azobenzenearsonate-N-acetyl-l-tyrosine in guinea pigs. However, 6-acylamino-6-deoxy-N-(acyl)muramyldipeptides were inactive as adjuvants.
The adjuvant activity of 29 kinds of carbohydrate analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine on the induction of delayed-type hypersensitivity to azobenzenearsonate-N-acetyl-L-tyrosine was examined in guinea pigs. It was found that the D-manno- and D-galacto-type muramyldipeptides were as active as the D-gluco-type muramyldipeptide (MDP). The structural requirement of the carbohydrate moiety of analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine is discussed.
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The effect of the cell-wall skeleton (CWS) of Propionibacterium acnes C7 on the metastasis of Lewis lung carcinoma in C57BL/6J mice was examined. Intratumoral or intravenous injection of P. acnes-CWS was effective for both prolongation of the survival period and protection against pulmonary metastases, but intraperitoneal injection was ineffective in tumor-bearing mice. Intratumoral injection of P. acnes-CWS also inhibited lymph node metastases and produced some complete tumor regressions. These cured mice were rechallenged with the same tumor but no evidence of transplantation resistance was found. On the other hand, neither inhibition of lymph node metastases nor complete tumor regressions were observed in the groups treated with intravenous and intraperitoneal injection of P. acnes-CWS. Intrapleural injection of P. acnes-CWS after surgical excision of the primary tumor was also effective for the prolongation of survival period but not for protection against pulmonary metastases.
The adjuvant activity of 23 kinds of synthetic N-acetyl muramyl dipeptide analogs on the induction of delayed-type hypersensitivity to azobenzenearsonate-N-acetyl-l-tyrosine was examined in guinea pigs.
The antitumor activity of the cell-wall skeleton (CWS) of Propionibacterium acnes C7 was examined by using transplantable tumors in syngeneic mice and in guinea pigs, and autochthonous tumors in mice. P. acnes-CWS was shown to suppress the growth of fibrosarcomas, EL4 leukemia, and MH134 hepatoma in syngeneic mice, and to regress the established tumors of a fibrosarcoma (MC104) in C57BL/6J mice, and a hepatoma (line-10) in strain-2 guinea pigs. The oil-attached P. acnes-CWS mixed with fructose mycolate was effective for suppression of the autograft of fibrosarcoma in mice. The repeated intralesional injections of suspension of P. acnes-CWS in phosphate-buffered saline was effective for prolongation of survival period of mice bearing 3-methylcholanthrene-induced fibrosarcoma. The test results on the cell fractions of P. acnes indicated that the CWS, but not the cytoplasmic or glucan fraction, of P. acnes had anti-tumor activity. The activation of peritoneal macrophages of mice was observed when P. acnes-CWS, but not the cytoplasmic fraction, was injected intraperitoneally 4 days before. The relationship between the cytolytic activity of peritoneal macrophages and antitumor activities of P. acnes-CWS was also discussed.
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