[A case of primary intrapulmonary thymoma: its entity and the problem of lymph node dissection].

Primary intrapulmonary thymomas are defined as primary thymomas arising in an intrapulmonary location without an associated mediastinal component, and they are very rare. A total of 20 cases have been reported only sporadically in the English literature since 1951. We reported the case of 41-year-old woman who had a 3.5 x 3.0 x 3.0 cm lower right lobe mass with nodal metastasis that extended over the left atrium. We also summarized the clinicopathological features of a total of 21 cases and discussed the problems involved with diagnosis, pathogenesis and treatment. Knowledge of the biological behavior of primary intrapulmonary thymomas is limited because of their rarity. In particular, the issue of the need for lymph node dissection has not been adequately discussed. In this case, pathohistological examination revealed that the routes of lymphatic spread and the sites of noda metastases from primary intrapulmonary thymoma resemble those of primary lung cancer. Therefore, systematic mediastinal lymph node dissection according to the lymph node map for primary lung cancer should be recommended for malignant cases.

Synthesis of 4'-C-methylnucleosides.

Several 4'-C-methylnucleosides were prepared. 1H-NMR studies on these nucleotides showed that they have the 3'-exo furanose ring conformation different from the 3'-endo conformation of natural nucleosides.

Synthetic study on 4C'-methyl nucleosides: Part I, Synthesis of 4C-methyl-D-ribofuranose derivative.

The 4C-methyl-D-ribofuranose derivative, a key intermediate for the synthesis of 4C'-methyl nucleosides, was prepared from D-glucose via regioselective benzylation of hydroxymethyl groups and the reduction of iodide made from the remaining hydroxymethyl group.

Inhibitory activity and protein binding of L-lysine derivatives as angiotensin converting enzyme inhibitors.

Four compounds 1a-4a containing one L-lysine residue in the molecule including a diastereomer mixture of lisinopril (N-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline) and N epsilon-carbobenzoxy-L-lysine derivatives 1b-4b of each of the four compounds were synthesized to compare the angiotensin converting enzyme (ACE) inhibitory activities in vitro and in vivo. They all showed high ACE inhibitory activity in vitro (IC50 = 0.14-42 nmol/l). A marked difference, however, was observed in inhibition of the pressor response to angiotensin I between 1a-4a (high activity) and 1b-4b (low activity). The binding of these compounds to human serum proteins in vitro was investigated by means of equilibrium dialysis and ultracentrifugation. Compounds 1b-4b showed higher levels of binding to serum albumin than that of the corresponding compounds 1a-4a, and the percentage of binding ranged from 20.1 to 89.1%. Furthermore, the inhibitory activity of compounds 1b-4b in vitro was decreased by the addition of albumin in a concentration-dependent manner. These results suggested that the difference in the protein binding rate of compounds is one of the important factors influencing the inhibitory activity in vivo.

Synthesis and angiotensin converting enzyme inhibitory activity of N-carboxymethyldipeptides with omega-(4-piperidyl)alkyl group.

The synthesis of a series of novel, potent angiotensin converting enzyme (ACE) inhibitors containing 1(S)-carboxy-omega-(4-piperidyl)alkyl group at the N-terminal of the dipeptide is described. These 1-carboxy-omega-(4-piperidyl)alkyl derivatives possess greater or equivalent in vitro potency and in vivo efficacy than captopril and enalapril. The length (n) of the carbon chain in the omega-(4-piperidyl)alkyl moiety was varied from two to six to investigate the optimal structure for long-acting ACE inhibitors. 1-[N-[1(S)-Carboxy-6-(4- piperidyl)hexyl]-L-alanyl]-(2a,3a beta, 7a beta)-octahydro- 1H-indole-2-carboxylic acid (9b), the most potent member of the series, had an in vivo area under the curve (AUC) of 685, which was calculated by the inhibition of angiotensin I-induced pressor response vs. time curves (0 to 8 h) after p.o. administration.

Synthesis and angiotensin converting enzyme inhibitory activity of N-carboxymethyldipeptides with an omega-aminoalkyl group.

A series of novel L-alanyl- and L-lysyl-L-proline derivatives having an omega-amino-1-carboxyalkyl group was prepared, and assayed for their inhibitory activity against angiotensin converting enzyme (ACE). The dicarboxylic acids possesing S,S,S configuration showed potent in vitro ACE inhibitory activity with IC50 values of 0.68-1.4 nmol/l. The length of the carbon chain in the omega-aminoalkyl moiety was varied from 6 to 9 to investigate the optimal structure for long-acting ACE inhibitors. The most prolonged activity in vivo was observed with N-[8-amino-1(s)-carboxyoctyl]-L-alanyl-L-proline upon i.v. and p.o.

Synthesis and angiotension converting enzyme inhibitory activity of L-lysyl-N-substituted glycine derivatives.

The synthesis and biological activity of novel L-lysyl-N-substituted glycine derivatives which exhibit in vitro and in vivo angiotensin converting enzyme (ACE) inhibition, are described. Particularly, N-[N alpha-(1-carboxy-3-phenylpropyl)-L-lysyl]-N-(4-phenylcyclohexyl)glycine (11e), N-[N alpha-(1-carboxy-3-cyclopentylpropyl)-N epsilon-carbobenzoxy-L- lysyl]-N-cyclopentyl glycine (9h) and N-[N alpha-[1(S)-carboxy-3-cyclohexylpropyl]-L-lysyl]-N-cyclopentyl glycine (19a) showed a strong inhibitory activity at IC50 as low as 0.65, 0.64 and 0.11 nmol/l, respectively. The most potent activity in vivo was observed with the compound 19a after i.v. administration in the rat.

Cross-immunity among allogeneic tumors in rats immunized with gamma-irradiated ascites tumors.

Non-inbred rats of the Gifu strain were intraperitoneally challenged with Hirosaki sarcoma (tetraploid type, 10(5) cells) after repeated immunization with gamma-irradiated (13,000 rads 60Co) allogeneic non-viral tumors of ascites type (tetraploid or diploid type of Hirosaki sarcoma, Usubuchi sarcoma or AH130). In rats immunized not only with the same tumor as the immunizing tumor but also with a different tumor, the growth of the challenge tumor was markedly inhibited as compared with the control in non-immunized rats. It is considered that these tumors retained common antigen(s) by the resistance to irradiation because of their form of ascites tumor. The marked cross-immunity in rats immunized with AH130 may be explained by the fact that gamma-irradiated AH130 cells were alive longer in the peritoneal cavity than other tumors on account of its high resistance to irradiation.

Cross-immunity between syngeneic tumors in mice immunized with gamma-irradiated ascites tumors.

C3H/He mice immunized repeatedly with irradiated (13,000 rads 60Co) MM46 or MM48, both transplantable ascites mammary carcinomas of the same strain, were subcutaneously challenged with the identical or the different tumor. In mice immunized with irradiated MM46, the growth of challenges of not only MM46 but also MM48 was inhibited. On the other hand, in mice immunized with irradiated MM48, the growth of challenges of MM48 was inhibited, but the inhibition of the growth of MM46 was not observed. Cross-immunity, therefore, was shown by immunization with MM46 but not with MM48. These findings was considered to indicate that MM46 expressed cross-immunity against MM48 because of its high resistance to the irradiation, and that MM48 did not show cross-immunity to MM46 because of its low resistance to the irradiation.

Immunotherapy of autochthomous rat methylcholanthrene-induced sarcomas with a mixture of allogeneic tumor cells and BCG-CWS.

Experimental immunotherapy with a mixture of allogeneic tumor cells and BCG cell-wall skeleton (BCG-CWS) was carried out against established autochthonous fibrosarcomas induced by 3-methylcholanthrene (MCA) in the subcutaneous tissue of rats. The inhibitory effect on growth in the early stage, tumor-size up to 2 cm in diameter, was significantly observed. No significant difference, however, was shown as compared with the effect of treatment with allogeneic tumor cells alone. That is to say, a more effective inhibition of growth due to the addition of BCG-CWS was not demonstrated.