The action of ubenimex on aminopeptidase (APase) activity was studied in intact spleen cells and peritoneal macrophages from mice. Ubenimex strongly inhibited hydrolyzing activities against arginine-^-naphtylamide (Arg-NA), Lys-NA and Pro-NA in both cells.
Factor analysis was applied to the data matrix of in vitro growth inhibitory activities of 52 platinum complexes against 9 tumor cell lines, L1210, P388, Lewis lung, AH66, AH66F, HeLa S3, KB, HT-1197 and HT-1376 cell lines. Three factors were obtained by the principal factor analysis method. After the varimax rotation of these three factors, tumor cell lines were classified into four groups according to their factor loadings. The platinum complexes were characterized by the factor scores. Cisplatin was situated in an extreme position as compared with the other platinum complexes. In vivo antitumor activities of the platinum complexes were tested against L1210 and LL murine tumor models. The in vivo activity against L1210 showed a negative correlation with that against LL. Factor 2 scores of the complexes obtained by factor analysis of in vitro antitumor activities showed a good correlation with these in vivo antitumor activities. Then, the structure-factor 2 score relationships among platinum complexes were analyzed by the Free-Wilson method. From this analysis, structure-activity relationships for carrier ligands and leaving groups are proposed. Factor analysis is suggested to be a useful method to establish an efficient screening system for platinum complexes.
Liblomycin (NK313), a novel analog of bleomycin and peplomycin (PEP), produced acid soluble DNA,base propenals and nucleo bases from isolated DNA.This was similar to the action of PEP. However, the DNAcleavage activity of NK313 was l/2~1/10 of that of PEPin the absence of reducing agents. In the presence of reducing agents such as 2-mercaptoethanol and ascorbic acid, the activity of NK313was stimulated more strongly than PEP. NK313was also different from PEP in the formation and decomposition of active intermediates. This result suggested that differences in DNAcleavage activity between NK313and PEP may be due to the different properties of their active intermediates. NK313released preferentially pyrimidine bases from DNA,and the molar ratio of the released pyrimidine bases to the total of the released bases was little affected by the concentration of NK313rela-tive to DNA. In contrast, the ratio of the released purine bases by PEP increased with the concentration of PEP relative to DNA.NK313induced double strand cleavage on pBR322 DNAas efficiently as did PEP. The major cleavage sites of NK313on pBR322DNAwere similar to those of PEP. However,certain minor cleavage sites of NK313 were specific for NK313. Increase of PEP concentration led to increased degradation of DNAfragments; this was not the case with NK313.These results indicate that the cleavage sites of NK313were similar to, but more limited than those for PEP.Bleomycin (BLM) is a chemotherapeutic agent for human cancers and useful in combination chemotherapy because of its lack of myelosuppressive properties. However, its use is limited by pulmonary toxicity. Peplomycin (PEP), an analogue of BLM,has been used clinically since 198115. PEP has a lower pulmonary toxicity in animals, but this toxicity remains dose-limiting. Liblomycin (NK313) is an analog of BLMselected after an intensive screening program to find analogs with a stronger antitumor activity and reduced pulmonary toxicity2). NK313 has a bulky lipophilic substituent on terminal amine2) ; it exhibits activity against PEP-unresponsive tumors and has only slight or no pulmonary toxicity in mice and dogs, respectivity2'3). In the present study, in order to understand the modeof action of NK313,we compared NK313 and PEP in their DNAcleavage activity, the specificity of their DNAcleavage sites and the properties of active intermediates formed with ferrous ion and oxygen. Materials and Methods ChemicalsNK313 and PEP were products of Nippon Kayaku Co., Ltd., Tokyo. Fe(NH4)2(SO4)2à"6H2O, 2-mercaptoethanol and L-ascorbic acid were purchased from
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