macromomycin-protein and Lung-Neoplasms

With the use of three human lung cultured cell lines: normal diploid fibroblasts (WI38), their SV40-transformants (VA13) and carcinoma cells (A549), whose doubling times were similar, the cytotoxicity of the protein antitumor antibiotics, auromomycin (AUR) and macromomycin (MCR), was studied by colony formation method. The susceptibilities of the three cell lines to these antibiotics were in the order: WI38 less than VA13 less than A549. This differentiality in the cytotoxic effect was similar between AUR and MCR. The differential cytotoxic effect did not depend on cell densities of each cell line at the time of the antibiotic-treatment. Alcohol-extracted chromophores of the antibiotics also showed a similar differential cytotoxic effect, while the apo-proteins of the antibiotics showed no cytotoxicity. It is concluded that the differential cytotoxic effect of AUR and MCR to normal, transformed and carcinoma cells is attributed to the chromophore moiety and the protein moiety is not involved in this effect.

Topics: Anti-Bacterial Agents; Antibiotics, Antineoplastic; Cell Cycle; Cell Line; Cell Survival; Cell Transformation, Neoplastic; Humans; Lung; Lung Neoplasms; Peptides; Simian virus 40; Structure-Activity Relationship

The free chromophores isolated from the antitumor protein antibiotics, auromomycin (AUR) and macromomycin (MCR), were rapidly inactivated by incubation in serum-containing medium at 37 degrees C in the dark with respect to cytocidal activity to human lung carcinoma A549 cells. Under the same conditions, the intact antibiotics, their pronase-hydrolysates and reconstituents from the chromophores and apo-proteins were stable. Intact and reconstituted AUR and MCR were more resistant to pronase digestion than the apo-proteins. The analyses of the pronase-hydrolysates of AUR and MCR by SDS-polyacrylamide gel electrophoresis and ultrafiltration showed that the antibiotics (13 kilodaltons (kDa] were degraded to produce peptide fragments (1-3 kDa) in which most cytotoxicity of the pronase-hydrolysates resided. The pronase-hydrolysates exhibited a differential cytocidal activity to normal diploid fibroblasts (WI38), their SV40-transformants (VA13) and carcinoma cells (A549) of human lung origin as was observed for the intact antibiotics. These results indicate that specific interaction between the chromophores and the pronase-resistant peptide segments (1-3 kDa) of the protein moiety stabilizes the cytocidal activity of the chromophores and also protects the peptide segments from pronase digestion.

Topics: Anti-Bacterial Agents; Antibiotics, Antineoplastic; Cell Line; Cell Survival; Cell Transformation, Neoplastic; Humans; Kinetics; Lung; Lung Neoplasms; Peptides; Pronase; Simian virus 40; Structure-Activity Relationship

An antitumor activity of macromomycin, a polypeptide antitumor antibiotic, was tested in vitro and in vivo. The results obtained were as follows: 1) The cytostatic effect on L1210 cells in culture was identical to that of neocarzinostatin. 2) The effect of MCR on the survival of L1210 or P388 leukemia was as same level as NCS. 3) Effects of MCR were independent from the treatment schedules. 4) MCR was inactive on the survival of Lewis lung carcinoma.

Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Drug Administration Schedule; Leukemia L1210; Leukemia P388; Lung Neoplasms; Mice; Neoplasms, Experimental; Peptides